Novel PLK1 degradation inducer compound

Abstract

The present invention relates to a novel PLK1 degradation-inducing compound, its preparation method, and its use. The compound of the present invention shows the effect of inducing PLK1 degradation. Therefore, the compound 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 in a pulsatile manner from the S phase through the G2 / M phase, becomes activated once, 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 slow the cell cycle of cancer cells, some cancer cells ultimately resume the cell cycle, resulting in insufficient clinical efficacy (see, for example, Gheghiani et al., CULM Reports, 2017). Indeed, while numerous pharmaceutical companies, including Boehringer Ingelheim and GlaxoSmithKline (GSK), have attempted to develop small molecule PLK1 inhibitors, most have failed or been discontinued during clinical trials, and no PLK1 inhibitors have been commercially available to date. 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 developing new drugs aimed at suppressing 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 connected by 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 binding moieties or linkers are effective for PROTACs. Numerous studies have demonstrated that for PROTACs to exhibit the desired level of efficacy, the binding moieties and linkers must be appropriately linked (see US2020-0325130A). In particular, when targeting CRBN (cereblon) E3 ligase, depending on the type of binding moiety or the structure of the compound to which it is bound, there is a risk of degrading CRBN neo-substrates (GSPT1, IKZF1 / 3, etc.) 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 Publication No. 106543185A partially discloses bifunctional compounds in which a volasertib derivative compound and an E3 ubiquitin ligase CRBN binding moiety are linked by a chemical linker. However, while the prior art publication only 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, e.g., Burslem and Crews, 2017).

[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, 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, e.g., Bolden et al., CULM Reports, 2014).

[0008] Furthermore, according to a paper published by the inventor of the aforementioned paper [Mu et al. BBRC, 2019], the PROTAC compound that simultaneously degrades PLK1 and BRD4 has a much stronger ability to degrade BRD4 at the cellular level than its ability to degrade PLK1, and it can be confirmed that it actually acts solely as a BRD4 inhibitor, irrespective of the way in which conventional PLK1 inhibitors exert their pharmacological effects, such as by arresting the cell cycle in the G1 phase.

[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. Another object of the present invention is to provide a method for producing a novel PLK1 degradation-inducing compound. A further object of the present invention is to provide uses of novel PLK1 degradation-inducing compounds. [Means for solving the problem]

[0011] To achieve the above-mentioned objectives, the inventors have completed the present invention by discovering 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 E3 ligase binders, target-binding moieties, and linkers.

[0012] 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. One embodiment of the present invention is a compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula I, The ULM is a moiety represented by the following formula 1: [ka] PTM is a moiety represented by Formula 2 below: [ka] Linker is a group that chemically links the ULM and PTM; Rx is -H or -C 1-4 is alkyl; V is -NH-C(=O)-, -(CH2)v-NH-, -(CH2)vNC 1-4 alkyl-, -O-, -C(=O)-, or -C(=NH)- {wherein the N atom of -(CH2)v-NH- in V can be bonded to Rx to form a 5- or 6-membered ring, and v is 0, 1, 2, 3, or 4}; Ring U is phenyl, pyridinyl, or pyrimidinyl, wherein one or more H in said phenyl, pyridinyl, or pyrimidinyl ring is R U may be replaced with}; R U -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, -NH, -OH, or -halo {wherein R U can be linked to the N atom of —(CH)—NH— in V to form a 5- or 6-membered ring, and one or more H in the 5- or 6-membered ring can be linked to —C 1-4 may be substituted with alkyl or ═O, U can be bonded to the N atom of —C(═NH)— in V to form a 5- or 6-membered ring [at which time, one or more H in the 5- or 6-membered ring can be bonded to the N atom of —C(═NH)—. 1-4 optionally substituted with alkyl]}; Y is CR7; R1 is -C 1-4 alkyl or 3- to 7-membered cycloalkyl; R2 is -H; R3 and R4 are each independently -H, -C 1-4 alkyl, or -halo; R5 is -C 1-4 is alkyl; R6 is -C 1-4 Alkyl or -C 1-4is alkoxy; R7 is -H or -halo.

[0013] In one embodiment of the present invention, ULM is a moiety represented by Formula 1-1 or Formula 1-2 below; [ka] [ka] Rx is -H or -C 1-4 is alkyl; V is -NH-C(=O)-, -(CH2)v-NH-, -(CH2)vNC 1-4 alkyl-, -O-, or -C(=NH)- {wherein the N atom of -(CH2)v-NH- in the V can be bonded to the Rx to form a 5- or 6-membered ring, and the v is 0, 1, or 2}; U1 to U5 are each independently U or N {where R of U1 U can be linked to the N atom of —(CH)—NH— in V to form a 5- or 6-membered ring, and one or more H in the 5- or 6-membered ring can be linked to —C 1-4 may be substituted with alkyl or ═O, R U can be linked to the N atom of —C(═NH)— in V to form a 5- or 6-membered ring [wherein one or more H in the 5- or 6-membered ring is not —C 1-4 optionally substituted with alkyl]}; R U -C 1-4 Alkyl, -C 1-4 It is haloalkyl, -NH2, or -halo.

[0014] In one embodiment of the present invention, [ka] [ka] R U1 and R U2 are each independently -C 1-4 Alkyl, -C 1-4 haloalkyl, or -halo.

[0015] In one embodiment of the present invention, [ka] R U1 and R U2 are each independently -C 1-4 It is haloalkyl or -halo.

[0016] In one embodiment of the present invention, [ka] R6 is -C 1-4 is alkoxy; R7 is -H or -halo.

[0017] In one embodiment of the present invention, Linker is -L U -L1-L2-L3-L P - and; L U is -(CH2)x-, -(CH2)x-NH-, -(CH2)xO-, -C(=O)-, phenyl, or null (wherein L U is connected to ULM [at this time, the L U is null, L1 is directly concatenated with ULM], where x is 0, 1, 2, 3, or 4}; L1 is heterocycloalkyl or null {wherein, when said L1 is null, then L U and L2 are directly linked, the heterocycloalkyl contains one or more N atoms in the ring, and one or more H in the heterocycloalkyl ring is -C1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 optionally substituted with alkoxy, -OH, -halo, or =O}; L2 is -(CH2)y1-, -(CD2)y1-, -(CH2)y2-C(=O)-(CH2)y3-, -(CH2)y2-NH-(CH2)y3-, or -(CH2)y2-N(C 1-4 alkyl)-(CH)-, wherein y to y are each independently 0, 1, 2, 3, 4, 5, or 6; L3 is cycloalkyl, heterocycloalkyl, or null (wherein, when L3 is null, L2 and L p is directly linked, said heterocycloalkyl containing one or more N atoms in the ring, and one or more H in said cycloalkyl or heterocycloalkyl ring is replaced by -C 1-4 Alkyl, -C 1-4 optionally substituted with haloalkyl, or -halo}; L P is —(CH2)p-NH—C(═O)— or —(CH2)pO—, P wherein -(C=O)- or -O- is linked to a PTM, and p is 0, 1, or 2.

[0018] In one embodiment of the present invention, L U is -(CH2)x- or -(CH2)x-NH-, where L U is concatenated with ULM, and x is 0 or 1}; L1 is a 4- to 12-membered heterocycloalkyl or null (wherein, when L1 is null, L U and L2 are directly linked, and the 4- to 12-membered heterocycloalkyl is a monocyclic, bridged bicyclic, or spirocyclic ring, and the 4- to 12-membered heterocycloalkyl contains one or more N atoms in the ring, and the N atoms are not linked to L U or directly linked to ULM, wherein one or more H in the 4-12 membered heterocycloalkyl ring is -C1-4 optionally substituted with alkyl, -OH, or -halo}; L2 is -(CH2)y1-, -(CH2)y2-C(=O)-(CH2)y3-, -(CH2)y2-NH-(CH2)y3-, or -(CH2)y2-N(C 1-4 alkyl)-(CH)-, wherein y to y are each independently 0, 1, 2, or 3; L3 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 Alkyl, -C 1-4 haloalkyl, or -halo; and L P is —(CH2)p-NH—C(═O)—, where L P -(C=O)- is linked to PTM, and p is 0 or 1}.

[0019] According to a specific embodiment of the present invention, the compound of formula I is a compound selected from the group consisting of compounds 1-44.

[0020] As used herein, a pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt that has a relatively non-toxic, innocuous effective concentration in a patient, and the side effects attributable to the salt do not diminish the beneficial efficacy of the compound of Formula I. For example, the pharmaceutically acceptable salt may be an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid, or an organic acid such as, but not limited to, 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.

[0021] Uses of compounds that induce selective degradation of PLK1 One embodiment of the present invention is a composition for inducing PLK1 degradation, comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof. Formula I is as defined above.

[0022] In the experimental examples of the present invention, it was confirmed that the compounds of the present invention effectively induce PLK1 protein degradation.

[0023] The PLK1 degradation-inducing PROTAC compounds of the present invention are capable of fundamentally degrading the target protein, PLK1, from the perspective of their mechanism of action, and therefore achieve superior PLK1 inhibitory effects compared to conventional PLK1 small molecule inhibitors that simply inhibit the activity of PLK1. Therefore, a composition comprising a compound of the present invention represented by formula I or a pharmaceutically acceptable salt thereof can be useful for selectively degrading PLK1.

[0024] One embodiment of the present invention is a pharmaceutical composition for preventing or treating a PLK1-related disease, comprising a compound of 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. Formula I is as defined above.

[0025] 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.

[0026] The cancers include all cancers that can be prevented or treated by inhibiting PLK1 activity, and may be solid cancers or blood cancers. For example, the cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, skin cancer, cutaneous or intraocular melanoma, rectal cancer, perianal adenocarcinoma, esophageal cancer, small intestinal 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, and large intestinal cancer. The cancer may be one or more selected from the group consisting of intestinal 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.

[0027] 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.

[0028] 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.

[0029] The pharmaceutical compositions of the present invention may contain, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, one or more other active ingredients exhibiting the same or similar pharmacological activity.

[0030] One embodiment of the present invention is a method for degrading PLK1 protein by administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a mammal, including a human.

[0031] Another embodiment of the present invention is a method for degrading PLK1 protein in vitro by administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a sample, which 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]

[0032] The compounds of the present invention have the effect of inducing PLK1 degradation, and therefore can be effectively used for the prevention or treatment of PLK1-related diseases. [Brief explanation of the drawings]

[0033] [Figure 1] 1 shows the results of luciferase analysis of compounds 1 to 41 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0034] 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. The present invention provides methods for synthesizing compounds 1 to 44 shown in the following table.

[0035] [Table 1] JPEG2024530495000012.jpg211146 JPEG2024530495000013.jpg205146 JPEG2024530495000014.jpg211146 JPEG2024530495000015.jpg211146 JPEG2024530495000016.jpg205146 JPEG2024530495000017.jpg224146 JPEG2024530495000018.jpg230146 JPEG2024530495000019.jpg39148

[0036] 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-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)butanoyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 1) [ka] Step 1. Synthesis of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)carbamate (3) To a solution of 4-((tert-butoxycarbonyl)amino)benzoic acid (1 g, 4.21 mmol) in DMF (10 mL) were added DIPEA (1.63 g, 12.64 mmol, 2.20 mL) and HATU (3.21 g, 8.43 mmol). After 30 min, 3-aminopiperidine-2,6-dione (693.74 mg, 4.21 mmol, HCl salt) was added at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS confirmed the desired mass peak (~70%). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). A white solid precipitated from the combined organic phase. The mixture was filtered. The filter cake was dried under vacuum to give tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)carbamate (0.8 g, 2.14 mmol, 50.87% yield, 93.1% purity) as a white solid. MS (M+H) + =348.2 1 H NMR (400 MHz, DMSO-d6) δ=10.84(s, 1H), 9.64(s, 1H), 8.59(d, J=8.0 Hz, 1H), 7.79(d, J=8.8 Hz, 2H), 7.54(d, J=8.8 Hz, 2H), 4.79-4.72(m, 1H), 2.84-2.75(m, 1H), 2.56-2.52(m, 1H), 2.14-2.09(m, 1H), 1.98-1.94(m, 1H), 1.49(s, 9H).

[0037] Step 2. Synthesis of 4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide (4) To a solution of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)carbamate (0.8 g, 2.30 mmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed complete consumption of the starting material. The mixture was concentrated under reduced pressure to give 4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide (660 mg, crude, HCl salt) as a white solid, which was used directly in the next step. MS (M+H) + =248.3

[0038] Step 3. Synthesis of benzyl (E)-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)but-2-enoyl)piperidin-4-yl)carbamate (6) To a solution of 4-amino-N-(2,6-dioxopiperidin-3-yl)benzamide (200 mg, 704.94 μmol, HCl) in DMF (3 mL) was added NaI (31.70 mg, 211.48 μmol), benzyl (E)-(1-(4-bromobut-2-enoyl)piperidin-4-yl)carbamate (322.52 mg, 845.93 μmol), and DIPEA (273.33 mg, 2.11 mmol, 368.37 μL). The mixture was stirred at 25 °C for 14 h. TLC (ethyl acetate:methanol = 10:1) confirmed the formation of several new spots. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, 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 0-40% petroleum ether:ethyl acetate / methanol (v / v=1 / 1) gradient @ 80 mL / min) to afford benzyl (E)-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)but-2-enoyl)piperidin-4-yl)carbamate (0.2 g, 365.23 μmol, 51.81% yield) as a yellow oil, which was used directly in the next step. MS (M+H) + =548.3

[0039] Step 4. Synthesis of 4-((4-(4-aminopiperidin-1-yl)-4-oxobutyl)amino)-N-(2,6-dioxopiperidin-3-yl)benzamide (7) To a mixture of Pd / C (20 mg, 18.26 μmol, 10% purity) in CF3CH2OH (5 mL) was added benzyl (E)-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)but-2-enoyl)piperidin-4-yl)carbamate (0.1 g, 182.61 μmol) at 25° C. The mixture was stirred at 25° C. under H2 (15 Psi) for 12 h. LCMS confirmed the reaction was complete. The mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give 4-((4-(4-aminopiperidin-1-yl)-4-oxobutyl)amino)-N-(2,6-dioxopiperidin-3-yl)benzamide (80 mg, 92.23 μmol, 50.51% yield, 47.9% purity) as a yellow oil, which was used directly in the next step. MS (M+H) + =416.2

[0040] 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-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)butanoyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 1) 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 (80 mg, 171.89 μmol) in DMF (2 mL) was added HATU (98.03 mg, 257.83 μmol) and DIPEA (66.65 mg, 515.66 μmol, 89.82 μL). After 30 min, 4-[[4-(4-amino-1-piperidyl)-4-oxo-butyl]amino]-N-(2,6-dioxo-3-piperidyl)benzamide (78.56 mg, 189.07 μmol) was added to the mixture. The mixture was stirred at 25 °C for 12 h. LCMS confirmed the desired mass peak (60%). The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; B%: 39% to 69%, 10 min) followed by preparative HPLC (column: Waters Xbridge 150 x 25 mm x 10 μm). 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%-62%, 8 min) and 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-(1-(4-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)amino)butanoyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (25.2 mg, 26.90 μmol, 15.65% yield, 92.1% purity) as a white solid. MS (M+H) + =863.3 1H NMR (400 MHz, DMSO-d6) δ=10.79(s, 1H), 8.29-8.23(m, 3H), 8.03(s, 1H), 7.97-7.95(m, 1H), 7.64(d, J=8.8 Hz, 2H), 7.19(d, J=6.8 Hz, 1H), 6.57(d, J=8.8 Hz, 2H), 6.25(t, J=5.6 Hz, 1H), 4.85-4.79(m, 1H), 4.74-4.67(m, 1H), 4.34-4.29(m, 1H), 4.10 -3.98(m, 3H), 3.91-3.84(m, 4H), 3.27(s, 3H), 3.13-3.07(m, 3H), 2.76 -2.71(m, 1H), 2.52(s, 3H), 2.44-2.40(m, 2H), 2.13-2.03(m, 1H), 1.98 -1.91(m, 3H), 1.83-1.71(m, 5H), 1.66-1.57(m, 4H), 1.50-1.37(m, 2H).

[0041] Example 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)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (Compound 2) [ka] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (3) To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid (0.8 g, 2.61 mmol) in DMF (5 mL) was added HATU (1.09 g, 2.87 mmol) and DIPEA (675.00 mg, 5.22 mmol, 909.70 μL). The mixture was stirred at 20 °C for 10 min, and then a solution of 3-aminopiperidine-2,6-dione (515.76 mg, 3.13 mmol, HCl salt) and DIPEA (675.00 mg, 5.22 mmol, 909.70 μL) in DMF (5 mL) was added. The resulting mixture was stirred at 20 °C for 1 h. LCMS confirmed complete consumption of the starting material and the desired mass was the major peak (96%). The reaction mixture was diluted with HO (15 mL) and a large amount of white solid precipitated. The white solid was collected by filtration and dried in vacuo to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (470 mg, 1.09 mmol, 41.92% yield, 97% purity) as a white solid. MS (M+H) + =417.3

[0042] Step 2. Synthesis of N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (4) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (470 mg, 1.13 mmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 12 mL) at 20° C., and the resulting mixture was stirred at 20° C. for 30 min. LCMS confirmed complete consumption of the starting material with a major peak of the desired mass (94%). The reaction mixture was concentrated in vacuo to give N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (400 mg, crude, HCl salt) as a white solid. MS (M+H) + =317.4

[0043] Step 3. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (6) To a solution of N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (200 mg, 566.87 μmol, HCl salt) and tert-butyl N-[1-(2-chloroacetyl)-4-piperidyl]carbamate (172.57 mg, 623.56 μmol) in DMF (4 mL) was added DIPEA (219.79 mg, 1.70 mmol, 296.22 μL) and NaI (16.99 mg, 113.37 μmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 16 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (74%). The reaction mixture was diluted with HO (12 mL) and extracted with ethyl acetate (12 mL × 3). The organic phase was washed with brine (12 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (180 mg, 320.13 μmol, 56.47% yield, 99% purity) as an off-white solid. MS (M+H) + =557.3

[0044] Step 4. Synthesis of 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (7) To a solution of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (180 mg, 323.36 μmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 8 mL) at 20° C., and the resulting mixture was stirred at 20° C. for 1 h. LCMS confirmed complete consumption of the starting material with a major peak of the desired mass (95%). The reaction mixture was concentrated in vacuo to give 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (160 mg, crude, HCl salt) as an off-white solid. MS (M+H) + =457.4

[0045] 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-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (Compound 2) To a solution of 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-benzoic acid (80 mg, 178.80 μmol) in DMF (2 mL) was added HATU (74.78 mg, 196.68 μmol) and DIPEA (46.22 mg, 357.59 μmol, 62.29 μL). After the mixture was stirred at 20° C. for 10 min, a solution of 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (96.96 mg, 196.68 μmol, HCl salt) and DIPEA (46.22 mg, 357.59 μmol, 62.29 μL) in DMF (2 mL) was added, and the resulting mixture was stirred at 20° C. for an additional 1 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (64%). The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL × 6). The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 29%-59%, 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-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (24.3 mg, 27.15 μmol, 15.19% yield, 99% purity) as a white solid. MS (M+H) + =886.3 1H NMR (400 MHz, DMSO-d6) δ=10.82(s, 1H), 8.47(d, J=8.3 Hz, 1H), 8.23(s, 1H), 8.14(d, J=8.2 Hz, 1H), 7.99(s, 1H), 7.81-7.68(m, 3H), 7.06-6.92(m, 4H), 4.80-4.64(m, 2H), 4.47-4.18(m, 1H), 4.13-3.80(m, 7H), 3.32(br s, 7H), 3.19-2.91(m, 4H), 2.84-2.73(m, 1H), 2.57(br d, J=4.3 Hz, 5H), 2.11(dq, J=4.2, 12.7 Hz, 1H), 1.99-1.85(m, 3H), 1.82-1.70(m, 2H), 1.68(br s, 2H), 1.62-1.41(m, 6H).

[0046] Example 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-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (Compound 3) [ka] Step 1. Synthesis of tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2)

[0047] A mixture of methyl 3-bromobenzoate (2 g, 9.30 mmol), tert-butyl piperazine-1-carboxylate (2.00 g, 10.74 mmol), Pd(OAc) (250.00 mg, 1.11 mmol), BINAP (600.00 mg, 963.59 μmol), and CsCO (6.50 g, 19.95 mmol) in toluene (50 mL) was degassed and purged with N three times. The mixture was then stirred at 100 °C under N for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate:petroleum ether gradient, 60 mL / min) to give tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.4 g, 7.49 mmol, 80.55% yield) as a light yellow oil. MS (M+H) + =321.3

[0048] Step 2. Synthesis of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (3) To a solution of tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.4 g, 7.49 mmol) in methanol (30 mL) was added LiOH (500 mg, 20.88 mmol) in HO (30 mL) at 20 °C. The mixture was stirred at 20 °C for 12 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with HO (30 mL) and slowly adjusted to pH = 7 with HCl (1 M) at 0 °C. The resulting mixture was extracted with ethyl acetate (60 mL × 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (2.2 g, crude) as a bright yellow solid. MS (M-56+H) + =251.2

[0049] Step 3. Synthesis of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (4) To a solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (2.1 g, 6.85 mmol) in DMF (20 mL) was added EDCI (2.10 g, 10.95 mmol), DIPEA (4.96 g, 38.36 mmol, 6.68 mL), HOBt (1.15 g, 8.48 mmol), and 3-aminopiperidine-2,6-dione (1.40 g, 8.51 mmol, HCl salt) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic phase was washed with brine (60 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was obtained in 25 °C. o The mixture was triturated with MTBE (30 mL) at 37°C for 30 minutes, followed by filtration. The filter cake was diluted with MTBE (10 mL x 2) and dried under reduced pressure to give tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (2.8 g, 6.72 mmol, 98.08% yield) as a white solid. MS (M+H) + =417.4 1 H NMR (400 MHz, DMSO-d6) δ=10.87(s, 1H), 8.70(d, J=8.4 Hz, 1H), 7.43(d, J=1.1 Hz, 1H), 7.38-7.28(m, 2H), 7.17-7.11(m, 1H), 4.92-4.65(m, 1H), 3.54-3.41(m, 4H), 3.22-3.09 (m, 4H), 2.86-2.76(m, 1H), 2.59-2.53(m, 1H), 2.19-2.07(m, 1H), 2.02-1.94(m, 1H), 1.43(s, 9H)

[0050] Step 4. Synthesis of N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (5) To a solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (2.8 g, 6.72 mmol) in dioxane (30 mL) was added HCl / dioxane (4 M, 30 mL). The mixture was stirred at 25° C. for 48 hours. LCMS showed a major peak of the desired mass (95%). The reaction mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (2.30 g, crude, HCl salt) as a white solid. MS (M+H) + =317.3 1 H NMR (400 MHz, DMSO-d6) δ=10.86(s, 1H), 9.48(br s, 2H), 8.83(d, J=8.3 Hz, 1H), 7.47(s, 1H), 7.42-7.33(m, 2H), 7.21-7.15(m 1H), 4.80-4.73(m, 1H), 3.47-3.38(m, 4H), 3.27-3.15(m, 4H), 2.86-2.75(m, 1H), 2.59-2.52(m, 1H), 2.21-2.08(m, 1H), 2.01-1.93(m, 1H).

[0051] Step 5. Synthesis of tert-butyl (1-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (6) To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (450 mg, 1.28 mmol, HCl salt) in DMF (8 mL) was added KI (45.00 mg, 271.08 μmol), DIPEA (890.40 mg, 6.89 mmol, 1.2 mL), and tert-butyl (1-(2-chloroacetyl)piperidin-4-yl)carbamate (560 mg, 2.02 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phase was washed with brine (30 mL × 3), dried over sodium sulfate, 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 0-20% methanol:ethyl acetate gradient, 60 mL / min) to afford tert-butyl (1-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (500 mg, 898.23 μmol, 70.42% yield) as a bright yellow solid. MS (M+H) + =557.5 1 H NMR (400 MHz, DMSO-d6) δ=10.87(s, 1H), 8.69(d, J=8.3 Hz, 1H), 7.70(d, J=8.2 Hz, 1H), 7.40(s, 1H), 7.34-7.25(m, 2H), 7.15-7.09(m, 1H), 4.89-4.65(m, 1H), 3.91-3.74(m, 3H), 3.23(br s, 4H), 2.97(s, 2H), 2.86-2.77(m, 2H), 2.64-2.51(m, 6H), 2.21-2.05(m, 1 H), 2.00-1.94(m, 1H), 1.71-1.63(m, 2H), 1.39(s, 9H), 1.37-1.28(m, 2H).

[0052] Step 6. Synthesis of 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (7) To a solution of tert-butyl (1-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)carbamate (250 mg, 449.11 μmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 3 hours. LCMS confirmed a major peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (200 mg, crude, diHCl salt) as a bright yellow solid. MS (M+H) + =457.5

[0053] 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-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (compound 3) 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 (60 mg, 134.10 μmol) in DMF (2 mL) was added HATU (76 mg, 199.88 μmol), DIPEA (89.04 mg, 688.93 μmol, 120 μL), and 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (80 mg, 151.10 μmol, diHCl salt) at 25° C. The mixture was stirred at 25° C. under N2 atmosphere for 16 h. The desired mass peak (78%) was confirmed by LCMS. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 11% to 41%, 7 min; column temperature: 30 °C). After repurification using a column (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20% to 60%, 9 min; column temperature: 30 °C), 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-(1-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (73.4 mg, 80.36 μmol, 59.93% yield, 97% purity) as a white solid. MS (M+H) + =886.7 1H NMR (400 MHz, DMSO-d6) δ=10.87(s, 1H), 8.69(d, J=8.3 Hz, 1H), 8.24(s, 1H), 8.15(d, J=8.1 Hz, 1H), 8.00(s, 1H), 7.72(d, J=8.1 Hz, 1H), 7.41(s, 1H), 7.36-7.27(m, 2H), 7.16-7.09(m, 1H), 7.03(s, 1H), 6.96(d, J=8.2 Hz, 1H), 4.82-4.67(m, 2H), 4.40-4.16(m, 1H), 4.16-4.00(m, 2H), 4.00-3.90(m, 2H), 3.89(s, 3H), 3.33-3.20(m, 7H), 3.13-2.88(m, 4H) , 2.85-2.76(m, 1H), 2.66-2.59(m, 4H), 2.58-2.55(m, 1H), 2.19-2.06(m, 1H), 2.05-1.88(m, 3H), 1.87-1.66(m, 4H), 1.61-1.44(m, 6H).

[0054] Example 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 4) [ka] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (3) To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid (2 g, 6.53 mmol) in DMF (20 mL) was added HATU (3.72 g, 9.79 mmol) and DIPEA (1.69 g, 13.06 mmol, 2.27 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min, and a solution of 3-aminopiperidine-2,6-dione (1.40 g, 8.49 mmol, HCl) in DMF (15 mL) was added along with DIPEA (1.69 g, 13.06 mmol, 2.27 mL). The mixture was stirred at 25 °C for 14 h. TLC (petroleum ether:ethyl acetate = 3:1) showed complete consumption of the starting material and the formation of a new spot. The mixture was diluted with HO (30 mL) and ethyl acetate (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with HO (20 mL) and concentrated under reduced pressure. The crude product (crude) was diluted with MTBE (50 mL) and the mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filter cake was washed with MTBE (10 mL). The collected filter cake was dried under reduced pressure to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (2.48 g, 5.84 mmol, 89.39% yield, 98% purity) as a white solid. MS (M+H) + =417.3

[0055] Step 2. Synthesis of N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (4) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazine-1-carboxylate (1 g, 2.40 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 20 mL) at 25° C. The mixture was stirred at 25° C. for 1 h. The desired mass was observed by LCMS. The reaction mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (850 mg, crude, HCl) as a white solid. MS (M+H) + =317.1

[0056] Step 3. Synthesis of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (5) To a solution of N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (600 mg, 1.70 mmol, HCl) and tert-butyl N-[1-(3-chloropropanoyl)-4-piperidyl]carbamate (716.96 mg, 2.47 mmol) in DMF (8 mL) was added DIPEA (659.37 mg, 5.10 mmol, 888.65 μL) and KI (62.97 mg, 379.33 μmol). The mixture was stirred at 80 °C for 12 h. LCMS confirmed 26% N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide remaining and the desired mass peak (46%). The mixture was diluted with HO (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL x 2). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to 0-10% methanol / ethyl acetate gradient @ 100 mL / min) to afford tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (320 mg, 560.74 μmol, 32.97% yield) as a yellow solid. MS (M+H) + =571.4

[0057] Step 4. Synthesis of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (6) To a solution of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (320 mg, 560.74 μmol) in dioxane (3 mL) was added HCl / dioxane (4 M, 9 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. LCMS confirmed consumption of the starting material and the desired mass peak (91%). The mixture was concentrated under reduced pressure to give 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (280 mg, crude, HCl salt) as a yellow solid. MS (M+H) + =471.2

[0058] 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (compound 4) 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 (70 mg, 156.45 μmol) in DMF (1 mL) was added HATU (89.23 mg, 234.67 μmol) and DIPEA (44.52 mg, 344.47 μmol, 60 μL), and the mixture was stirred at 25° C. for 15 min. A solution of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (100 mg, 197.23 μmol, HCl salt) and DIPEA (44.52 mg, 344.47 μmol, 60 μL) in DMF (1 mL) was added, and the mixture was stirred at 25° C. for 1 h. LCMS confirmed the desired mass. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with brine (10 mL×3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product (crude) was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 33% to 63%, 9 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (22 mg, 22.98 μmol, 14.69% yield, 94% purity) as a white solid. MS (M+H) + =900.1 1H NMR (400 MHz, DMSO-d6) δ=10.82(s, 1H), 8.46(d, J=8.3 Hz, 1H), 8.30-8.25(m, 2H), 8.15(br d, J=7.8 Hz, 1H), 7.97(s, 1H), 7.75(d, J=8.9 Hz, 2H), 7.51-7.46(m, 2H), 6.98(d, J=8.9 Hz, 2H), 4.80-4.70(m, 2H), 4.43-4.34(m, 1H), 4.10-3.90(m, 7H), 3.30(s, 3H), 3.28-3.24(m, 4H), 3.18-3.09(m, 1H) , 2.84-2.73(m, 1H), 2.62-2.53(m, 11H), 2.17-2.04(m, 1H), 1.99-1.78(m, 5H), 1.73-1.66(m, 1H), 1.65-1.34(m, 6H).

[0059] Example 5. Synthesis of 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Compound 5) [ka] Step 1. Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3) To a solution of methyl 4-bromo-2-fluorobenzoate (1.5 g, 6.44 mmol) and tert-butyl piperazine-1-carboxylate (1.20 g, 6.44 mmol) in toluene (20 mL) was added Pd(OAc) (144.51 mg, 643.68 μmol), BINAP (801.61 mg, 1.29 mmol), and CsCO (6.29 g, 19.31 mmol). The mixture was stirred at 100 °C under N for 16 h. LCMS confirmed complete consumption of methyl 4-bromo-2-fluorobenzoate and the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20-50%) to give tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (1.8 g, 3.40 mmol, 52.89% yield, 64% purity) as a white solid. MS (M+H-56) + =283.0

[0060] Step 2. Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (4) To a solution of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (1 g, 2.96 mmol) in THF (8 mL) and HO (4 mL) was added LiOH (353.87 mg, 14.78 mmol). The mixture was stirred at 25 °C for 1 h. LCMS confirmed one major peak of the desired mass. The reaction mixture was adjusted to pH = 5 and then extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (850 mg, 2.62 mmol, 88.68% yield) as a white solid, which was used directly in the next step. MS (M+H -56) + =269.1

[0061] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (6) To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (400 mg, 1.23 mmol) and 3-aminopiperidine-2,6-dione (158.01 mg, 1.23 mmol) in DMF (7 mL) was added HATU (703.38 mg, 1.85 mmol) and DIPEA (478.17 mg, 3.70 mmol, 644.43 μL). The mixture was stirred at 25 °C for 2 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, methanol / ethyl acetate = 0-10%) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (450 mg, 1.02 mmol, 82.31% yield, 98% purity) as a bright yellow solid. MS (M+H) + =435.3

[0062] Step 4. Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (7) A solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (450 mg, 1.04 mmol) and HCl / dioxane (4 M, 3 mL) in DCM (3 mL) was stirred at 25° C. for 1 h. LCMS showed complete consumption of the reactant. The reaction mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (450 mg, crude, HCl salt) as a bright yellow solid, which was used directly in the next step. MS (M+H) + =335.2

[0063] Step 5. Synthesis of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (9) To a solution of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (200 mg, 611.16 μmol, HCl salt) and tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (226.62 mg, 677.81 μmol) in DMF (8 mL) was added DIPEA (236.96 mg, 1.83 mmol, 319.36 μL) and KI (101.45 mg, 611.16 μmol). The mixture was stirred at 80° C. for 3 hours. LCMS confirmed complete consumption and the desired mass of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, methanol / ethyl acetate = 0-10%) to give tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (130 mg, 172.25 μmol, 28.18% yield, 78% purity) as a bright yellow solid. MS (M+H) + =589.2

[0064] Step 6. Synthesis of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (10) A mixture of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (130 mg, 220.84 μmol) and HCl / dioxane (4 M, 2 mL) in DCM (2 mL) was stirred at 25° C. for 30 minutes. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide as a bright yellow solid, which was used directly in the next step. MS (M+H) + =489.3

[0065] Step 7. Synthesis of 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (compound 5) To a solution of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (130 mg, 247.61 μmol, HCl salt) and 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 (110.79 mg, 247.61 μmol) in DMF (4 mL) was added HATU (141.22 mg, 371.42 μmol) and DIPEA (96.01 mg, 742.84 μmol, 129.39 μL). The mixture was stirred at 25° C. for 2 hours. LCMS confirmed complete consumption of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide and one major peak of the desired mass. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the filtrate. The residue was purified by column chromatography (SiO2, methanol / ethyl acetate = 0-10%). The residue was then purified by preparative HPLC (neutral conditions: column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%, 10 min), and the eluate was lyophilized to give 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (53.3 mg, 56.90 μmol, 22.98% yield, 98% purity) as a white solid. MS(M+H) + =918.4 1H NMR (400 M Hz, DMSO-d6) δ=10.85(s, 1H), 8.33-8.25(m, 2H), 8.16(d, J=7.8 Hz, 1H), 8.08-8.01(m, 1H), 7.98(s, 1H), 7.64(t, J=9.0 Hz, 1H), 7.53-7.46(m, 2H), 6.87-6.74(m, 2H), 4.81-4.69(m, 2H), 4.41-4.32(m, 1H), 4.07-4.03(m, 3H), 4.02-3.96(m, 1H), 3.94(s, 3H), 3.34(s, 3H), 3.32-3.28( m, 4H), 3.15-3.06(m, 1H), 2.83-2.73(m, 1H), 2.64-2.53(m, 11H), 2.13-2.06(m, 1H), 2.05-1.80(m, 5H), 1.77-1.66(m, 1H), 1.65-1.56(m, 4H), 1.53-1.36(m, 2H).

[0066] Example 6. Synthesis of 3-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Compound 6) [ka] Step 1. Synthesis of tert-butyl 4-(2-fluoro-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3) To a solution of methyl 3-bromo-2-fluorobenzoate (1 g, 4.29 mmol) and tert-butyl piperazine-1-carboxylate (879 mg, 4.72 mmol) in toluene (15 mL) was added CsCO (4.19 g, 12.87 mmol), BINAP (267.20 mg, 429.12 μmol), and Pd(OAc) (48.17 mg, 214.56 μmol), and the mixture was stirred at 100 °C for 14 h. LCMS confirmed consumption of starting material and after workup, a 76% peak of the desired mass was observed. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether @ 50 mL / min) to give tert-butyl 4-(2-fluoro-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (0.97 g, 2.18 mmol, 50.77% yield, 76% purity) as a white solid. MS (M+H) + =338.4

[0067] Step 2. Synthesis of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (4)

[0068] To a solution of tert-butyl 4-(2-fluoro-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (0.97 g, 2.87 mmol) in methanol (10 mL) and THF (10 mL) was added NaOH (3 M, 1.43 mL). The mixture was stirred at 25° C. for 14 h. LCMS confirmed consumption of the starting material and a peak of 85% of the desired mass. The mixture was concentrated under reduced pressure to give 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1 g, crude) as a white solid. MS (M+H) + =347.1

[0069] Step 3. Synthesis of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (6) To a solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (1 g, 2.89 mmol), 3-aminopiperidine-2,6-dione (570.29 mg, 3.46 mmol, HCl), EDCI (830.29 mg, 4.33 mmol), and HOBt (780.32 mg, 5.77 mmol) in DMF (10 mL) was added DIPEA (1.12 g, 8.66 mmol, 1.51 mL), and the mixture was stirred at 25 °C for 14 h. LCMS confirmed the consumption of the starting material and a peak of 88% of the desired mass. The mixture was diluted with HO (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether @ 50 mL / min) to give tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (1.06 g, 2.44 mmol, 84.50% yield, 100% purity) as a white solid. MS (M+H) + =434.8

[0070] Step 4. Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-3-(piperazin-1-yl)benzamide (7) To a solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (1 g, 2.30 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 9 mL) and the mixture was stirred at 25° C. for 1 h. LCMS showed consumption of the starting material and a peak of 96% of the desired mass. The mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-2-fluoro-3-(piperazin-1-yl)benzamide (910 mg, crude, HCl) as a white solid. MS (M+H) + =335.0

[0071] Step 5. Synthesis of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (9) To a solution of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-3-(piperazin-1-yl)benzamide (910 mg, crude, HCl) and tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (927.71 mg, 3.19 mmol) in DMF (10 mL) was added DIPEA (964.60 mg, 7.46 mmol, 1.30 mL) and KI (20.40 mg, 122.89 μmol). The mixture was stirred at 80 °C for 14 h. LCMS confirmed that the starting material was consumed. The mixture was diluted with HO (15 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether to 0-30% methanol / ethyl acetate gradient @ 100 mL / min) to afford tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (0.53 g, 900.34 μmol, 36.69% yield) as a brown solid. MS (M+H) + =589.3

[0072] Step 6. Synthesis of 3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (10) To a solution of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (0.53 g, 900.34 μmol) in dioxane (5 mL) was added HCl / dioxane (4 M, 8 mL). The mixture was stirred at 25° C. for 1 hour. LCMS confirmed consumption of the starting material and a 96% peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (470 mg, crude, HCl) as a brown solid. MS (M+H) + =489.2

[0073] Step 7. Synthesis of 3-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (compound 6) 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 (60 mg, 134.10 μmol) in DMF (0.8 mL) was added HATU (76 mg, 199.88 μmol) and DIPEA (14.84 mg, 114.82 μmol, 20 μL), and the mixture was stirred at 25° C. for 15 min. A solution of 3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (120 mg, crude, HCl) and DIPEA (14.84 mg, 114.82 μmol, 20 μL) in DMF (0.7 mL) was added, and the mixture was stirred at 25 °C for 1 h. After workup, LCMS confirmed that the desired mass peak (94%) was detected. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 10 min), and the eluate was lyophilized to give 3-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (35.2 mg, 35.28 μmol, 26.31% yield, 92% purity) as a white solid. MS (M+H) + =918.2 1H NMR (400 MHz, DMSO-d6) δ=10.86(s, 1H), 8.62-8.56(m, 1H), 8.31-8.24(m, 2H), 8.15(d, J=7.6 Hz, 1H), 7.97(s, 1H), 7.51-7.46(m, 2H), 7.20-7.11(m, 3H), 4.82-4.71(m, 2H), 4. 44-4.35(m, 1H), 4.10-4.00(m, 3H), 3.98-3.91(m, 4H), 3.31-3.28(s, 3H), 3.17-3. 09(m, 1H), 3.07-2.97(m, 4H), 2.84-2.74(m, 1H), 2.71-2.53(m, 11H), 2.12-2.02(m , 1H), 2.01-1.80(m, 4H), 1.75-1.66(m, 2H), 1.65-1.53(m, 4H), 1.52-1.33(m, 2H).

[0074] Example 7. Synthesis of 5-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 7) [ka] Step 1. Synthesis of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (2) To a solution of methyl 5-bromopicolinate (1 g, 4.63 mmol) and tert-butyl piperazine-1-carboxylate (862.14 mg, 4.63 mmol) in toluene (20 mL) was added Pd(dba) (105.97 mg, 115.72 μmol), RuPhos (216.00 mg, 462.89 μmol), and CsCO (4.52 g, 13.89 mmol) under N, and the mixture was stirred at 100 °C for 16 h. LCMS confirmed the desired mass as a major peak. The mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (1.5 g, crude) as a yellow solid, which was used directly in the next step. MS (M+H) + =322.0

[0075] Step 2. Synthesis of methyl 5-(piperazin-1-yl)picolinate (3) To a solution of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (1 g, 3.11 mmol) in dioxane (6 mL) was added HCl / dioxane (4 M, 6 mL), and the mixture was stirred at 25° C. for 1 h. LCMS confirmed complete consumption of the starting material and the desired mass. The mixture was filtered, and the filter cake was diluted with methanol (10 mL) to give methyl 5-(piperazin-1-yl)picolinate (1 g, crude, HCl) as a yellow solid. MS (M+H) + =221.9

[0076] Step 3. Synthesis of methyl 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (4) To a solution of methyl 5-(piperazin-1-yl)picolinate (1 g, 3.88 mmol, HCl) and tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (3.38 g, 11.64 mmol) in DMF (20 mL) was added DIPEA (1.50 g, 11.64 mmol, 2.03 mL) and NaI (58.16 mg, 388.02 μmol), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-100% ethyl acetate / petroleum ether gradient @ 45 mL / min) to give methyl 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (580 mg, 1.21 mmol, 31.12% yield, 99% purity) as a yellow powder. MS (M+H) + =476.

[0077] Step 4. Synthesis of 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (5) To a solution of methyl 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (300 mg, 630.81 μmol) in THF (10 mL) and HO (5 mL) was added LiOH (30.21 mg, 1.26 mmol) at 0° C., and the mixture was stirred at 25° C. for 4 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated and lyophilized to give 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (280 mg, crude) as a yellow powder, which was used directly. MS (M+H) + =462.0

[0078] Step 5. Synthesis of tert-butyl (1-(3-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (6) To a solution of 5-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (100 mg, 213.45 μmol Li) in DMF (2 mL) was added HATU (121.74 mg, 320.17 μmol) and DIPEA (82.76 mg, 640.35 μmol, 111.54 μL). After stirring for 1 min, 3-aminopiperidine-2,6-dione (42.16 mg, 256.14 μmol, HCl) was added. The mixture was stirred at 25° C. for 2 h. LCMS confirmed the desired mass as a major peak. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-50% methanol / ethyl acetate gradient @ 25 mL / min) to afford tert-butyl (1-(3-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (110 mg, 153.94 μmol, 72.12% yield, 80% purity) as a yellow powder. MS (M+H) + =572.1

[0079] Step 6. Synthesis of 5-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (7) To a solution of tert-butyl (1-(3-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (110 mg, 192.42 μmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 4 mL, 83.15) and the reaction mixture was stirred at 25° C. for 1 h. LCMS confirmed complete consumption of starting material and the desired mass. The mixture was concentrated in vacuo to give 5-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (110 mg, crude, HCl) as a white powder. MS (M+H) + =472.0

[0080] Step 7. Synthesis of 5-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 7) 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 (60 mg, 134.10 μmol) in DMF (2 mL) was added HATU (76.48 mg, 201.15 μmol) and DIPEA (51.99 mg, 402.29 μmol, 70.07 μL). The mixture was stirred at 25 °C for 1 minute, and then 5-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (68.12 mg, 134.10 μmol, HCl) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS confirmed the desired mass. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 μm; mobile phase: [water (TFA)-ACN]; B%: 28%-48%, 7 min) and preparative HPLC (column: Waters Xbridge Purification by chromatography (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25% to 58%, 8 min) and lyophilization afforded 5-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (47.2 mg, 51.55 μmol, 38.44% yield, 98.4% purity) as a white powder. MS (M+H) + =901.3 1H NMR (400 MHz, DMSO-d6) δ=10.85(s, 1 H), 8.73(d, J=8.31 ​​Hz, 1 H), 8.33(d, J=2.69 Hz, 1 H), 8.26-8.30(m, 2 H), 8.16(d, J=7.70 Hz, 1 H), 7.97(s, 1 H), 7.87(d, J=8.80 Hz, 1 H), 7.47-7.51(m, 2 H), 7.43(dd, J=8.93, 2.81 Hz, 1 H), 4.70-4.82(m, 2 H), 4.40(d, J=12.23 Hz, 1 H), 3.95-4.12(m, 4 H), 3.94(s, 3 H), 3.34-3.37(m, 4 H), 3.31(s, 3 H), 3.14(t, J=12.29 Hz, 1 H), 2.74-2.84(m, 1 H), 2.66-2.74(m, 1 H), 2.53-2.66(m, 10 H), 2.12-2.19(m, 1 H), 1.87-2.06(m, 4 H), 1.72-1.85(m, 2 H), 1.61-1.70(m, 2 H), 1.49-1.58(m, 2 H), 1.36-1.53(m, 2 H).

[0081] Example 8. Synthesis of 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 8) [ka] Step 1. Synthesis of tert-butyl 4-(2-(methoxycarbonyl)pyridin-4-yl)piperazine-1-carboxylate (2) To a solution of methyl 4-bromopicolinate (1 g, 4.63 mmol) and tert-butyl piperazine-1-carboxylate (862.14 mg, 4.63 mmol) in toluene (20 mL) was added Pd(dba) (105.97 mg, 115.72 μmol), RuPhos (216.00 mg, 462.89 μmol), and CsCO (4.52 g, 13.89 mmol) under N, and the mixture was stirred at 100 °C for 16 h. LCMS confirmed the desired mass as a major peak. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-100% ethyl acetate / petroleum ether gradient @ 40 mL / min) to afford tert-butyl 4-(2-(methoxycarbonyl)pyridin-4-yl)piperazine-1-carboxylate (780 mg, 1.53 mmol, 33.03% yield, 63% purity) as a yellow oil. MS (M+H) + =322.0

[0082] Step 2. Synthesis of methyl 4-(piperazin-1-yl)picolinate (3) To a solution of tert-butyl 4-(2-(methoxycarbonyl)pyridin-4-yl)piperazine-1-carboxylate (780 mg, 2.43 mmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 4 mL). The mixture was stirred at 25° C. for 2 hours. LCMS confirmed complete consumption of the starting material and the desired mass. The mixture was filtered. The filter cake was concentrated to give methyl 4-(piperazin-1-yl)picolinate (540 mg, crude, HCl) as a yellow solid. MS (M+H) + =221.9

[0083] Step 3. Synthesis of methyl 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (4) To a solution of methyl 4-(piperazin-1-yl)picolinate (540 mg, 2.10 mmol, HCl) and tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (1.83 g, 6.29 mmol) in DMF (15 mL) was added DIPEA (812.42 mg, 6.29 mmol, 1.09 mL) and KI (69.57 mg, 419.07 μmol), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-90% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford methyl 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (150 mg, 315.40 μmol, 15.05% yield) as a yellow oil. MS (M+H) + =476.1

[0084] Step 4. Synthesis of 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (5) To a solution of methyl 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinate (150 mg, 315.40 μmol) in HO (3 mL) and THF (6 mL) was added LiOH (26.47 mg, 630.81 μmol). The mixture was stirred at 25° C. for 4 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated and lyophilized to give 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (130 mg, crude) as a yellow powder, which was used directly. MS (M+H) + =462.1

[0085] Step 5. Synthesis of tert-butyl (1-(3-(4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (6) To a solution of 4-(4-(3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)picolinic acid (130 mg, 277.48 μmol) in DMF (3 mL) was added HATU (158.26 mg, 416.23 μmol) and DIPEA (107.59 mg, 832.45 μmol, 145.00 μL), followed by 3-aminopiperidine-2,6-dione (54.81 mg, 332.98 μmol, HCl). The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL×3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (1-(3-(4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (130 mg, crude) as a yellow oil. MS (M+H) + =572.1

[0086] Step 6. Synthesis of 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (7) To a solution of tert-butyl (1-(3-(4-(2-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (130 mg, 227.41 μmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 56.85 μL) and the mixture was stirred at 25° C. for 1 h. LCMS confirmed the desired mass peak. The mixture was concentrated in vacuo to give 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (100 mg, crude, HCl) as a yellow powder. MS (M+H) + =472.0

[0087] Step 7. Synthesis of 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (compound 8) To a solution of 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-benzoic acid (85 mg, 189.97 μmol) in DMF (2 mL) was added HATU (108.35 mg, 284.96 μmol) and DIPEA (73.66 mg, 569.92 μmol, 99.27 μL), followed by 4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (96.51 mg, 189.97 μmol, HCl). The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass as a major peak. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 23% to 43%, 7 min), followed by preparative HPLC (column: Waters Xbridge Purification using a column (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) followed by lyophilization afforded 4-(4-(3-(4-(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-methoxybenzamido)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (32.9 mg, 36.33 μmol, 19.13% yield, 99.5% purity) as a white powder. MS (M+H) + =901.0 1H NMR (400 MHz, DMSO-d6) δ=10.86(s, 1 H), 8.96(d, J=8.31 ​​Hz, 1 H), 8.27-8.32(m, 2 H), 8.24(d, J=5.99 Hz, 1 H), 8.16(d, J=7.46 Hz, 1 H), 7.98(s, 1 H), 7.46-7.52(m, 3 H), 7.04(dd, J=5.99, 2.57 Hz, 1 H), 4.71-4.82(m, 2 H), 4.41(d, J=13.20 Hz, 1 H), 3.95-4.13(m, 4 H), 3.95(s, 3 H), 3.40(d, J=4.65 Hz, 4 H), 3.34(s, 3 H), 3.06-3.20(m, 1 H), 2.75-2.86(m, 1 H), 2.69(dd, J=3.61, 1.65 Hz, 1 H), 2.53-2.67(m, 10 H), 2.14-2.26(m, 1 H), 1.87-2.06(m, 4 H), 1.82-1.72(m, 2 H), 1.62-1.69(m, 2 H), 1.60-1.68(m, 2 H), 1.34-1.53(m, 2 H).

[0088] 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-(4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 9) [ka] Step 1. Synthesis of tert-butyl (4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (2) To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (300 mg, 850.30 μmol, HCl) in DCE (10 mL) was added tert-butyl (4-formylpiperidin-1-yl)carbamate (240 mg, 1.05 mmol) and NaOAc (100 mg, 1.22 mmol). The mixture was stirred at 25 °C for 1 h. NaBH(OAc) (700 mg, 3.30 mmol) was then added at 25 °C. The resulting mixture was stirred at 25 °C for 15 h. LCMS confirmed the desired mass peak (78%). The reaction mixture was diluted with HO (10 mL) at 0 °C, adjusted to pH 9 with saturated sodium bicarbonate at 0 °C, and extracted with 60 mL of ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 0-25% methanol:ethyl acetate gradient, 60 mL / min) to afford tert-butyl (4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (160 mg, 302.66 μmol, 35.59% yield) as a bright yellow solid. MS (M+H) + =529.3 1 H NMR (400 MHz, DMSO-d6) δ=10.89(s, 1H), 8.70(d, J=8.4 Hz, 1H), 7.98-7.74(m, 1H), 7.43-7.34(m, 1H), 7.32-7.22(m, 2H), 7.10(d, J=7.3 Hz, 1H), 4.82-4.73(m, 1H), 3.56-3.33(m, 4H), 3.23-3.17(m, 4H), 2.90-2.83(m, 2H), 2.82-2.74(m, 1H), 2.59-2.53(m, 1H), 2.46-2. 41(m, 2H), 2.18-2.13(m, 2H), 2.03-1.96(m, 1H), 1.86-1.85(m, 1H), 1.73-1.65(m, 2H), 1.42(s, 1H), 1.38(s, 9H), 1.21-1.11(m, 2H).

[0089] Step 2. Synthesis of 3-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (3) To a solution of tert-butyl (4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (150 mg, 283.75 μmol) in DCM (6 mL) was added TFA (8 mL). The mixture was stirred at 25° C. for 2 h. LCMS confirmed a major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to give 3-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (150 mg, crude, 2% TFA) as a yellow oil. MS (M+H) + =429.2

[0090] 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-(4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 9)

[0091] 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 (60 mg, 134.10 μmol) in DMF (2 mL) was added EDCI (50 mg, 260.82 μmol), HOBt (30 mg, 222.02 μmol), DIPEA (148.40 mg, 1.15 mmol, 200 μL) and 3-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (100 mg, 152.31 μmol, 2 TFA salt) at 25 °C. The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass peak (58%). The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP). Purification was carried out using a column (100 × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 27% to 47%, 7 min; column temperature: 30 °C), 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-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (45.7 mg, 45.61 μmol, 34.01% yield, 97% purity, TFA salt) as a white solid. MS (M+H) + =858.4 1H NMR (400 MHz, CD3OD) δ=8.16(s, 1H), 8.13(d, J=8.4 Hz, 1H), 7.59(d, J=1.8 Hz, 1H), 7.55-7.51(m, 2H), 7.47-7.41(m, 2H), 7.29-7.23(m, 1H), 5.11-5.03(m, 1H), 4.92-4.90(m, 1H), 4.18(t, J=12.2 Hz, 2H), 4.03(s, 3H), 4.00-3.84(m, 2H), 3.83-3.66(m, 2H), 3.42(s, 3H), 3.28-3.17(m, 6H), 2 .87-2.70(m, 4H), 2.27-2.20(m, 2H), 2.14-2.01(m, 3H), 2.01-1.81(m, 5H), 1.81-1.55(m, 7H).

[0092] 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-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 10) [ka] Step 1. Synthesis of tert-butyl (4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2) To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (400 mg, 1.13 mmol, HCl) in DMF (8 mL) was added DIPEA (890.43 mg, 6.89 mmol, 1.20 mL), KI (100 mg, 602.40 μmol), and 2-(1-((tert-butoxycarbonyl)amino)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (600.02 mg, 1.51 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h. LCMS confirmed the desired mass peak (30%). The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, 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 0-25% methanol:ethyl acetate gradient, 60 mL / min) to afford tert-butyl (4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (200 mg, 368.55 μmol, 32.51% yield) as a bright yellow solid. MS (M+H) + =543.5 1 H NMR (400 MHz, DMSO-d6) δ=10.89(s, 1H), 8.70(d, J=8.3 Hz, 1H), 7.99-7.76(m, 1H), 7.39(s, 1H), 7.34-7.25(m, 2H), 7.17-7.05(m, 1H), 4 .85-4.69(m, 1H), 3.36-3.35(m, 4H), 3.19-3.16(m, 4H), 2.89-2.75(m, 3H), 2.59 -2.55(m, 1H), 2.45-2.38(m, 2H), 2.36-2.30(m, 2H), 2.17-2.06(m, 1H), 2.01-1. 94(m, 1H), 1.68-1.60(m, 2H), 1.44-1.39(m, 2H), 1.37(s, 9H), 1.24-1.15(m, 3H).

[0093] Step 2. Synthesis of 3-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (3) To a solution of tert-butyl (4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (180 mg, 331.69 μmol) in dioxane (5 mL) was added HCl / dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass peak (84%). The reaction mixture was concentrated under reduced pressure to give 3-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (160 mg, crude, diHCl salt) as a bright yellow solid. MS (M+H) + =443.4 1 H NMR (400 MHz, DMSO-d6) δ=10.86(s, 1H), 10.84-10.70(m, 1H), 8.76(d, J=8.4 Hz, 1H), 7.46(s, 1H), 7.38(d, J=4.9 Hz, 2H), 7.23-7.17(m, 1H), 4.80-4.72(m, 1H), 3.97-3.79(m, 3H), 3.24-2.99(m, 8H), 2.91-2.73(m, 2H), 2.59-2.56(m, 1H), 2.19-2.11(m, 1H), 2.05-1.93(m, 2H), 1.87-1.66(m, 4H), 1.50-1.22(m, 3H).

[0094] 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-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 10)

[0095] 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 (60 mg, 134.10 μmol) in DMF (2 mL) was added HATU (70 mg, 184.10 μmol), DIPEA (111.30 mg, 861.17 μmol, 150 μL), and 3-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (80 mg, 155.20 μmol, diHCl salt) at 25° C. The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass peak (40%). The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 28% to 48%, 7 min; column temperature: 30 °C) and purified by preparative HPLC (column: Waters Xbridge The column was re-purified using a column chromatography (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-66%, 9 min; column temperature: 30 °C) 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-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (30.7 mg, 33.80 μmol, 25.20% yield, 96% purity) as a white solid. MS (M+H) + =872.7 1H NMR(400 MHz, DMSO-d6)δ=10.87(s, 1H), 9.39-9.19(m, 1H), 8.77-8.60(m, 1H), 8.36-8.16(m, 2H), 7.97(s, 1H), 7.49-7.36(m, 3H), 7.34-7.27(m, 2H), 7.15-7.09(m, 1H), 4.83-4.72(m, 2H), 4.12-4.00(m, 2H), 3.93(s, 3H), 3.33-3.32(m, 3H), 3.24-3.17(m 4H), 3.06-2.98(m, 2H), 2.84-2.73(m, 3H), 2.58-2.53(m, 5H), 2.42-2.35(m, 2H) ), 2.18-2.09(m, 1H), 2.01-1.90(m, 3H), 1.76-1.57(m, 8H), 1.48-1.26(m, 5H).

[0096] Example 11. 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-(3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)-3-methoxybenzamide (Compound 11) [ka] Step 1. Synthesis of tert-butyl (4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (2A) and tert-butyl (3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)carbamate (2B) To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(piperazin-1-yl)benzamide (500 mg, 1.42 mmol, HCl) in DMF (8 mL) was added KI (60 mg, 361.44 μmol), DIPEA (1.04 g, 8.04 mmol, 1.4 mL), and (1-((tert-butoxycarbonyl)amino)piperidin-4-yl)methyl 4-methylbenzenesulfonate (500.00 mg, 1.30 mmol) at 25 °C. The mixture was stirred at 60 °C under N2 gas for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (30 mL × 3), dried over sodium sulfate, 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 0 to 25% methanol:ethyl acetate gradient, 60 mL / min) to give tert-butyl (4-((4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (130 mg, 245.91 μmol, 17.35% purity) as a bright yellow solid and tert-butyl (3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)carbamate (260 mg, 491.83 μmol, 34.70% yield) as a bright yellow solid, confirmed by 2D NMR. MS(M+H) + =529.5 1H NMR (400 MHz, DMSO-d6) δ=10.87(s, 1H), 8.69(d, J=8.3 Hz, 1H), 7.88(s, 1H), 7.39(s, 1H), 7.33-7.22(m, 2H), 7.13-7.07(m, 1H) , 4.82-4.70(m, 1H), 3.40-3.35(m, 4H), 3.19-3.16(m, 4H), 2.93(t, J=8.1 Hz, 1H), 2.87-2.77(m, 2H), 2.77-2.72(m, 1H), 2.58-2.53(m, 1H), 2.49-2.44(m, 2H), 2.35-2.24( m, 2H), 2.16-2.01(m, 2H), 1.96-1.90(m, 1H), 1.54-1.46(m, 2H), 1.37(s, 9H), 1.34-1.24(m, 1H).

[0097] Step 2. Synthesis of 3-(4-(2-(1-aminopyrrolidin-3-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (3) To a solution of tert-butyl (3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)carbamate (150 mg, 283.75 μmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 3 hours. LCMS confirmed a major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to give 3-(4-(2-(1-aminopyrrolidin-3-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (130 mg, crude, diHCl salt) as a bright yellow solid. MS (M+H) + =429.2

[0098] 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-(3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)-3-methoxybenzamide (Compound 11) 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 (80 mg, 178.80 μmol) in DMF (2 mL) was added EDCI (60 mg, 312.99 μmol), HOBt (30 mg, 222.02 μmol), and 3-(4-(2-(1-aminopyrrolidin-3-yl)ethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (100.00 mg, 199.43 μmol, diHCl salt) at 25° C. The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass peak (57%). The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 28% to 48%, 7 min; column temperature: 30 °C) 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-(3-(2-(4-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)-3-methoxybenzamide (78.5 mg, 77.53 μmol, 43.36% yield, 96% purity, TFA salt) as a white solid. MS(M+H) + =858.4 1H NMR(400 MHz, MeOD)δ=8.24-8.11(m, 2H), 7.61-7.50(m, 3H), 7.49-7.39(m, 2H), 7.31-7.23(m, 1H), 5.10-5.01(m, 1H), 4.98-4.91(m, 1H), 4.23-4.12(m 2H), 4.02(s, 3H), 3.99-3.61(m, 4H), 3.42(s, 3H), 3.38-3.33(m, 4H), 3.32-3.26(m, 4H), 3.25-3.15(m, 2H), 3.09-3.00(m, 1H), 2.9 2-2.81(m, 1H), 2.78-2.70(m, 1H), 2.53-2.41(m, 1H), 2.31-2.18(m, 3H), 2.09-1.97(m, 4H), 1.89-1.79(m, 2H), 1.77-1.68(m, 4H).

[0099] Example 12. 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-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 12) [ka] Step 1. Synthesis of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3) To a solution of methyl 3,4-difluorobenzoate (2 g, 11.62 mmol) and tert-butyl piperazine-1-carboxylate (2.60 g, 13.94 mmol) in DMSO (20 mL) was added K2CO3 (3.21 g, 23.24 mmol), and the mixture was stirred at 100 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with brine (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 10–65% ethyl acetate / petroleum ether @ 40 mL / min) to give tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3 g, 8.69 mmol, 74.78% yield, 98% purity) as a white solid. MS (M+H) + =338.8

[0100] Step 2. Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (4) To a solution of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3 g, 8.87 mmol) in THF (30 mL) and HO (10 mL) was added LiOH·HO (744.09 mg, 17.73 mmol), and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak (97%). The mixture was diluted with water (30 mL). The aqueous phase was adjusted to pH = 6 with HCl (1N) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (2.8 g, crude) as a white solid. MS (M-100+H) + =225.1

[0101] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (6) To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (2.6 g, 8.02 mmol), 3-aminopiperidine-2,6-dione (1.45 g, 8.82 mmol, HCl salt) in DMF (40 mL) was added EDCI (2.31 g, 12.02 mmol), HOBt (1.62 g, 12.02 mmol), and DIPEA (3.11 g, 24.05 mmol, 4.19 mL), and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with MTBE (20 mL) to give 20% methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (2.6 g, 8.02 mmol), 3-aminopiperidine-2,6-dione (1.45 g, 8.82 mmol, HCl salt). The mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with MTBE (20 mL) to give 20% methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (2.6 g, 8.02 mmol), 3-aminopiperidine-2,6-dione (1.45 g, 8. o C for 10 min to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (3 g, 6.70 mmol, 83.56% yield, 97% purity) as a white solid. MS (M+H) + =435.2

[0102] Step 4. Synthesis of N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (7) To a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]-2-fluoro-phenyl]piperazine-1-carboxylate (200 mg, 460.34 μmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL), and the mixture was stirred at 20° C. for 1 hour. LCMS confirmed the desired mass as a major peak. The mixture was concentrated under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (150 mg, crude) as a white solid, which was used directly in the next step. MS (M+H) + =335.1

[0103] Step 5. Synthesis of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (9) A mixture of N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (150 mg, 404.52 μmol, HCl salt) and tert-butyl (4-formylpiperidin-1-yl)carbamate (92.35 mg, 404.52 μmol), AcOH (12.15 mg, 202.26 μmol, 11.57 μL) in DCM (4 mL) was stirred at 20 °C for 1 h. NaBH(OAc) (257.21 mg, 1.21 mmol) was added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass peak (27%). The reaction mixture was diluted with HO (10 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (20 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 5-20% ethyl acetate / methanol @ 100 mL / min) to afford tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (130 mg, 195.01 μmol, 48.21% yield, 82% purity) as a yellow solid. MS (M+H) + =547.4

[0104] Step 6. Synthesis of 4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (10) To a solution of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (130 mg, 237.82 μmol) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL) and the mixture was stirred at 20° C. for 30 min. LCMS confirmed a major peak of the desired mass. The reaction mixture was concentrated in vacuo to give 4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (100 mg, crude, TFA salt) as a brown solid. MS (M+H) + =447.3

[0105] 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-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (compound 12) 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 (79.82 mg, 178.40 μmol) in DMF (2 mL) was added HATU (101.75 mg, 267.60 μmol) and DIPEA (69.17 mg, 535.20 μmol, 93.22 μL), and the mixture was stirred at 20° C. for 1 h. 4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (100 mg, 178.40 μmol, TFA salt) was added, and the resulting mixture was stirred at 20 °C for 2 h. LCMS confirmed a major peak of the desired mass. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, DCM:methanol = 10:1) and re-purified by reverse-phase HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NHHCO)-ACN]; B%: 37% to 67%, 9 min). 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-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (41 mg, 42.13 μmol, 23.61% yield, 90% purity) as a white solid. MS (M+H) + =876.5 1H NMR (400 MHz, DMSO-d6) δ=10.85(s, 1H), 9.31(s, 1H), 8.66(d, J=8.4 Hz, 1H), 8.31-8.23(m, 2H), 7.96(s, 1H), 7.69-7.59(m, 2H), 7.46-7.38(m, 2H), 7.09(t, J=8.7 Hz, 1H), 4.82-4.70(m, 2H), 4.04(t, J=14.1 Hz, 2H), 3.93(s, 3H), 3.33(s, 3H), 3.18-3.09(m, 4H), 3.06-2.98(m, 2H), 2.88-2.72(m, 3H), 2.58-2.52(m, 5H), 2 .27-2.18(m, 2H), 2.16-2.04(m, 1H), 2.01-1.88(m, 3H), 1.82-1.66(m, 4H), 1.65-1.51(m, 5H), 1.34-1.16(m, 2H).

[0106] Example 13. 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-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 13) [ka] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (2) To a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1 g, 3.61 mmol) in DMF (10 mL) was added 3-bromopiperidine-2,6-dione (761.50 mg, 3.97 mmol) and DIPEA (1.40 g, 10.82 mmol, 1.88 mL), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass as a major peak. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-80% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (0.96 g, 2.08 mmol, 57.58% yield, 84% purity) as a brown powder. MS (M+H) + =388.9

[0107] Step 2. Synthesis of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (500 mg, 1.29 mmol) in dioxane (8 mL) was added HCl / dioxane (4 M, 321.78 μL) and the mixture was stirred at 25° C. for 2 h. LCMS showed complete consumption of the starting material and a major peak of the desired mass. The mixture was concentrated in vacuo to give 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (550 mg, crude) as a brown powder. MS (M+H) + =288.9

[0108] Step 3. Synthesis of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (4) To a solution of 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (550 mg, 1.69 mmol, HCl) in DMF (15 mL) was added tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (541.63 mg, 1.86 mmol), DIPEA (656.55 mg, 5.08 mmol, 884.84 μL), and KI (56.22 mg, 338.66 μmol), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass peak (40%). The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-80% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (260 mg, 354.54 μmol, 20.94% yield, 74% purity) as a brown powder. MS (M+H) + =543.1

[0109] Step 4. Synthesis of 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (5) To a solution of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (260 mg, 479.11 μmol) in dioxane (6 mL) was added HCl / dioxane (4 M, 6 mL) and the mixture was stirred at 25° C. for 1 h. LCMS confirmed a major peak of the desired mass and the mixture was concentrated in vacuo to give 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (300 mg, crude, HCl) as a green powder. MS (M+H)+ =443.0

[0110] 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (compound 13) 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 (100 mg, 223.50 μmol) in DMF (2 mL) was added HATU (127.47 mg, 335.24 μmol) and DIPEA (86.66 mg, 670.49 μmol, 116.79 μL), followed by 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (128.47 mg, 268.20 μmol, HCl salt), and the resulting mixture was stirred at 25° C. for 16 h. LCMS confirmed the major peak of the desired mass. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [water (TFA)-ACN]; B%: 26%-46%, 7 min) and preparative HPLC (column: Waters Xbridge The mixture was purified by HPLC (150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 8 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (40.4 mg, 44.15 μmol, 19.76% yield, 95.3% purity) as a red powder. MS (M+H) + =872.1 1H NMR (400 MHz, DMSO-d6) δ=10.74(s, 1 H), 8.33-8.20(m, 2 H), 8.15(d, J=6.75 Hz, 1 H), 7.96(s, 1 H), 7.56-7.43(m, 2 H), 6.75(d, J=7.75 Hz, 2 H), 6.60(d, J=8.13 Hz, 2 H), 5.37(d, J=7.00 Hz, 1 H), 4.83-4.70(m, 1 H), 4.39(d, J=10.01 Hz, 1 H), 4.18(s, 1 H), 4.04(t, J=13.82 Hz, 3 H), 3.99-3.93(m, 4 H), 3.31(s, 3 H), 3.22-3.04(m, 2 H), 2.98-2.93(m, 4 H), 2.69(d, J=12.76 Hz, 3 H), 2.63-2.56(m, 5 H), 2.14-2.06(m, 1 H), 2.00-1.77(m, 6 H), 1.76-1.52(m, 7) H)1.52-1.35(m, 2H).

[0111] 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-(1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 14) [ka] Step 1. Synthesis of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (3) To a solution of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1 g, 3.61 mmol) in DMF (10 mL) was added DIPEA (1.40 g, 10.82 mmol, 1.88 mL) and 3-bromopiperidine-2,6-dione (692.28 mg, 3.61 mmol), and the mixture was stirred at 50 °C for 16 h. LCMS showed 42% starting material remaining and the desired mass peak (48%). The reaction mixture was diluted with HO (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (60 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 10-65% ethyl acetate / petroleum ether @ 40 mL / min) to give tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (450 mg, 1.11 mmol, 30.84% ​​yield, 96% purity) as a yellow solid. MS (M+H) + =389.0

[0112] Step 2. Synthesis of 3-((3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (4) To a solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (450 mg, 1.16 mmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 4 mL) and the mixture was stirred at 20° C. for 10 minutes. LCMS confirmed a major peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-((3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (380 mg, crude, HCl salt) as a white solid, which was used directly in the next step. MS (M+H) + =289.0

[0113] Step 3. Synthesis of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (6) To a solution of 3-((3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, 615.75 μmol, HCl salt) in DMF (5 mL) was added tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (268.58 mg, 923.63 μmol), DIPEA (238.75 mg, 1.85 mmol, 321.76 μL), and NaI (9.23 mg, 61.58 μmol), and the mixture was stirred at 60 °C for 24 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over sodium sulfate, 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 50-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 60 mL / min) to afford tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (100 mg, 178.75 μmol, 29.03% yield, 97% purity) as a yellow oil. MS (M+H) + =543.3

[0114] Step 4. Synthesis of 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7) To a solution of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (100 mg, 184.27 μmol) in dioxane (4 mL) was added HCl / dioxane (4 M, 4 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (88 mg, crude, HCl salt) as a white solid. MS (M+H) + =443.1

[0115] 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-(1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (compound 14) 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 (74.73 mg, 167.01 μmol) in DMF (2 mL) was added HATU (95.25 mg, 250.51 μmol) and DIPEA (64.75 mg, 501.03 μmol, 87.27 μL), and the mixture was stirred at 20° C. for 30 minutes. Then, 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (80 mg, 167.01 μmol, HCl salt) was added, and the mixture was stirred at 20° C. for 16 hours. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:methanol = 10:1) and repurified by reverse-phase HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 32% to 62%, 8 min). 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-(1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (50 mg, 55.05 μmol, 32.96% yield, 96% purity) as a white solid. MS (M+H) + =872.1 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 8.31-8.24(m, 2H), 8.17(d, J=7.8 Hz, 1H), 7.98(s, 1H), 7.53-7.45(m, 2H), 6.91(t, J=8.1 Hz, 1H), 6.31-6.10(m, 3H), 5.63(d, J=7.6 Hz, 1H), 4.84-4.69(m, 1H), 4.45-4.27(m, 2H), 4.13-4.00(m, 3H), 4.00-3.90(m, 4H), 3.33(s, 3H), 3.18-3.02(m, 5H) , 2.81-2.53(m, 11H), 2.15-2.04(m, 1H), 2.00-1.79(m, 5H), 1.76-1.67(m, 2H), 1.66-1.55(m, 4H), 1.54-1.34(m, 2H).

[0116] Example 15. 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-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 15) [ka] Step 1. Synthesis of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carboxylate (2) To a solution of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1 g, 3.61 mmol) in DMF (10 mL) was added DIPEA (1.40 g, 10.82 mmol, 1.88 mL) and tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1.09 g, 5.70 mmol). The mixture was stirred at 50 °C for 16 h. LCMS confirmed the desired mass peak. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 20-30% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carboxylate (500 mg, 1.29 mmol, 35.70% yield) as a yellow solid. MS (M+H) + =389.3

[0117] Step 2. Synthesis of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)-methyl-amino]phenyl]piperazine-1-carboxylate (3) To a solution of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carboxylate (500 mg, 1.29 mmol) and HCHO (193.24 mg, 1.93 mmol, 177.28 μL, 37% purity) in methanol (5 mL) was added HOAc (7.73 mg, 128.71 μmol, 7.36 μL) and sodium cyanoborohydride (121.33 mg, 1.93 mmol). The mixture was stirred at 25 °C for 2 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was concentrated under reduced pressure to remove the methanol. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 40-70% ethyl acetate / petroleum ether gradient @ 60 mL / min) to afford tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)-methyl-amino]phenyl]piperazine-1-carboxylate (300 mg, 693.19 μmol, 53.86% yield, 93% purity) as a white solid. MS (M+H) + =403.3

[0118] Step 3. Synthesis of 3-(methyl(3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (4)

[0119] To a solution of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)-methyl-amino]phenyl]piperazine-1-carboxylate (250 mg, 621.14 μmol) in dioxane (1 mL) was added HCl / dioxane (4 M, 10.00 mL). The mixture was stirred at 25° C. for 16 hours. LCMS confirmed the desired mass peak. The reaction mixture was concentrated to give 3-(methyl(3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, crude, HCl salt) as a white solid. MS (M+H) + =303.3

[0120] Step 4. Synthesis of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (7) To a solution of 3-(methyl(3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, 661.44 μmol, HCl salt) in DMF (2 mL) was added NaI (99.15 mg, 661.44 μmol), DIPEA (427.43 mg, 3.31 mmol, 576.05 μL), and tert-butyl N-[1-(3-chloropropanoyl)-4-piperidyl]carbamate (192.34 mg, 661.44 μmol), and the reaction mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass peak. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (TFA)-ACN]; B%: 13% to 43%, 10 min), and the eluate was lyophilized to give tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (160 mg, 287.41 μmol, 43.45% yield) as a white solid. MS (M+H) + =557.1

[0121] Step 5. Synthesis of 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl (1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (80 mg, 143.71 μmol) in DCM (1 mL) was added TFA (262.17 mg, 2.30 mmol, 170.24 μL). The mixture was stirred at 25° C. for 1 h. LCMS confirmed the desired mass peak. The reaction mixture was concentrated under reduced pressure to give 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (65 mg, crude, TFA salt) as a yellow solid. MS (M+H) + =457.1

[0122] 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-(1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 15) To a solution of 3-((3-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (65 mg, 142.36 μmol, TFA) in DMF (1 mL) was added HATU (64.96 mg, 170.84 μmol), DIPEA (92.00 mg, 711.81 μmol, 123.99 μL), and 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 (63.70 mg, 142.36 μmol). The mixture was stirred at 25° C. for 1 hour. The desired mass peak was confirmed by LCMS. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 36% to 66%, 8 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-(1-(3-(4-(3-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (32 mg, 33.95 μmol, 23.85% yield, 94% purity) as a white solid. MS(M+H) + =886.6 1H NMR (400 MHz, DMSO-d6) δ=10.76(s, 1H), 8.32-8.24(m, 2H), 8.15(br d, J=7.70 Hz, 1H), 7.96(s, 1H), 7.53-7.44(m, 2H), 6.99(t, J=8.13 Hz, 1H), 6.36-6.22(m, 3H), 4.99-4.72(m, 1H), 4.81-4.71(m, 1H), 4.39(br d, J=12.23 Hz, 1H), 4.04(br t, J=14.00 Hz, 3H), 3.98-3.90(m, 4H), 3.27(s, 3H), 3.17-3.08(m, 5H), 2.91-2.77(m, 1H), 2.77-2.55(m, 13H) ), 2.31-2.22(m, 1H), 2.02-1.81(m, 5H) 1.77-1.66(m, 2H), 1.65-1.55(m, 4H), 1.51-1.33(m, 2H).

[0123] Example 16. 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-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 16) [ka] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (2) To a stirred solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (1 g, 3.39 mmol) in DMF (20 mL) was added 3-bromopiperidine-2,6-dione (1.95 g, 10.16 mmol) and NaHCO3 (2.84 g, 33.86 mmol, 1.32 mL), and the mixture was stirred at 85 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was washed with brine (60 mL) and extracted with ethyl acetate (50 mL × 5). The combined organic phase was washed with brine (200 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent: 20-70% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (670 mg, 1.57 mmol, 46.25% yield, 95% purity) as a blue solid. MS (M+H) + =406.9

[0124] 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 (620 mg, 1.53 mmol) and formaldehyde (185.68 mg, 2.29 mmol, 170.35 μL, 37% purity) in methanol (10 mL) was added acetic acid (9.16 mg, 152.54 μmol, 8.72 μL), and the reaction was stirred at 20 °C for 30 min. NaBH CN (143.79 mg, 2.29 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The resulting mixture was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 20-70% ethyl acetate / petroleum ether @ 40 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (200 mg, 437.60 μmol, 28.69% yield, 92% purity) as a blue solid. MS (M+H) + =420.8

[0125] Step 3. Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (4) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (100 mg, 237.83 μmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL) and the mixture was stirred at 20° C. for 30 minutes. LCMS confirmed a major peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (80 mg, crude, HCl salt) as a blue solid. MS (M+H) + =321.1

[0126] Step 4. Synthesis of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (6) To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (80 mg, 224.20 μmol, HCl salt) in DMF (1 mL) was added tert-butyl (1-(3-chloropropanoyl)piperidin-4-yl)carbamate (97.79 mg, 336.30 μmol) and DIPEA (86.93 mg, 672.60 μmol, 117.16 μL), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (3 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic phase was washed with brine (10 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent: 20-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) to afford tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (100 mg, 161.83 μmol, 72.18% yield, 93% purity) as a brown solid. MS (M+H) + =575.4

[0127] Step 5. Synthesis of 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (7) To a solution of tert-butyl (1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)carbamate (100 mg, 174.01 μmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 43.50 μL), and the mixture was stirred at 20° C. for 1 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (80 mg, 156.55 μmol, 89.96% yield, HCl salt) as a white solid, which was used directly in the next step. MS(M+H) + =475.3

[0128] 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (Compound 16) 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 (70.04 mg, 156.55 μmol) in DMF (2 mL) was added HATU (89.29 mg, 234.82 μmol) and DIPEA (60.70 mg, 469.64 μmol, 81.80 μL), and the mixture was stirred at 20° C. for 30 min. 3-((4-(4-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (80 mg, 156.55 μmol, HCl salt) was added, and the resulting mixture was stirred at 20 °C for 1 h. LCMS confirmed a major peak of the desired mass. The reaction mixture was diluted with brine (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, DCM:methanol = 10:1) and repurified by reverse-phase HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NHHCO)-ACN]; B%: 30% to 63%, 9 min). 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-(1-(3-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)propanoyl)piperidin-4-yl)-3-methoxybenzamide (51.2 mg, 54.94 μmol, 35.09% yield, 97% purity) as a white solid. MS (M+H) + =904.5 1H NMR (400 MHz, DMSO-d6) δ=10.78(s, 1H), 8.32-8.24(m, 2H), 8.15(d, J=7.6 Hz, 1H), 7.97(s, 1H), 7.53-7.45(m, 2H), 6.88(t, J=9.6 Hz, 1H), 6.72-6.63(m, 1H), 6.57-6.48(m, 1H), 4.85-4.71(m, 2H), 4.43-4.35(m, 1H), 4.04(t, J=13.9 Hz, 3H), 3.98-3.89(m, 4H), 3.31(s, 3H), 3.19-3.08(m, 1H), 2.93-2.77(m, 5H), 2.73-2.63(m, 5H) , 2.59-2.54(m, 7H), 2.31-2.20(m, 1H), 1.98-1.80(m, 5H), 1.77-1.52(m, 7H), 1.51-1.34(m, 2H).

[0129] Example 17. 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 17) [ka] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (3) To a mixture of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (2 g, 6.77 mmol) in DMF (40 mL) was added 3-bromopiperidine-2,6-dione (2.60 g, 13.54 mmol) and NaHCO3 (2.84 g, 33.86 mmol, 1.32 mL) and stirred at 85 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with brine (120 mL), and the aqueous phase was extracted with ethyl acetate (120 mL × 3). The combined organic phase was washed with brine (200 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1 g, 2.46 mmol, 36.33% yield, 100% purity) as a blue solid. MS (M+H) + =407.0

[0130] Step 2. Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (4) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1 g, 2.46 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 10 mL) and the mixture was stirred at 20° C. for 2 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated in vacuo to give 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (800 mg, crude, HCl salt) as a blue solid. MS (M+H) + =306.9

[0131] Step 3. Synthesis of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (6) To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (800 mg, crude, HCl salt) and tert-butyl (4-formylpiperidin-1-yl)carbamate (532.77 mg, 2.33 mmol) in methanol (20 mL) was added NaOAc (382.89 mg, 4.67 mmol), and the mixture was stirred at 20 °C for 30 min. NaBH CN (439.97 mg, 7.00 mmol) was added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass peak (10%). The reaction mixture was diluted with HO (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified twice by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) and re-purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (FA)-ACN]; B%: 8%-38%, 10 min), and the eluate was lyophilized to give tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (350 mg, 661.37 μmol, 28.34% yield, 98% purity) as a brown solid. MS (M+H) + =519.4

[0132] Step 4. Synthesis of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (7) To a solution of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (350 mg, 674.86 μmol) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed the major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to give 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (350 mg, crude, TFA salt) as a yellow oil. MS (M+H) + =419.2

[0133] 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-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 17) 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 (276.96 mg, 657.24 μmol) in DMF (10 mL) were added HATU (374.85 mg, 985.86 μmol), DIPEA (254.83 mg, 1.97 mmol, 343.44 μL), and the mixture was stirred at 20° C. for 30 min. 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (350 mg, crude, TFA salt) was added, and the resulting mixture was stirred at 20° C. for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent: 20-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) and repurified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 10 min). The eluate was lyophilized to give 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (207.1 mg, 249.46 μmol, 37.96% yield, 99% purity) as a yellow solid. MS (M+H) + =822.4 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.27(s, 1H), 8.33-8.27(m, 1H), 8.22(s, 1H), 7.87(s, 1H), 7.48-7.39(m, 2H), 6.83(t, J=9.4 Hz, 1H), 6.54-6.47(m, 1H), 6.45-6.39(m, 1H), 5.80(d, J=7.6 Hz, 1H), 4.93-4.83(m, 1H), 4.31-4.21(m, 1H), 4.03(t, J=13.5 Hz, 2H), 3.93(s, 3H), 3.30(s, 3H), 3.05-2.98(m, 2H), 2.90-2.80(m, 4H), 2.80-2.68(m, 3H), 2.60-2.51(m, 5H), 2 .23-2.16(m, 2H), 2.14-2.03(m, 1H), 1.92-1.81(m, 1H), 1.80-1.71(m, 2H), 1.60-1.46(m, 1H), 1.31-1.18(m, 8H).

[0134] Example 18. 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 18) [ka] Step 1. Synthesis of tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3) To a solution of tert-butyl piperazine-1-carboxylate (6.29 g, 28.24 mmol) and 1,2,3-trifluoro-5-nitrobenzene (5 g, 28.24 mmol) in ACN (50 mL) was added K2CO3 (7.80 g, 56.47 mmol). The resulting mixture was heated to 50 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was 20 o Trituration with MTBE (40 mL) at RT for 10 min afforded tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (9.5 g, 27.67 mmol, 98.00% yield) as a yellow solid. MS (M-56+H) + =288.0

[0135] Step 2. Synthesis of tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (4) A mixture of tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (9.5 g, 27.67 mmol) and Pd / C (1 g, 10% purity) in methanol (200 mL) was degassed and purged with H three times. It was then stirred at 20 °C under H gas (15 Psi) for 20 h. TLC confirmed complete consumption of the starting material and the appearance of a new major spot with a more polar character. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give tert-butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (8 g, crude) as a yellow solid. MS (M+H) + =314.2

[0136] Step 3. Synthesis of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (6) A mixture of tert-butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (1 g, 3.19 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.54 g, 4.15 mmol), and CsCO (3.12 g, 9.57 mmol) in dioxane (40 mL) was degassed with nitrogen for 15 minutes. XPhos (152.14 mg, 319.14 μmol) and Pd(dba) (292.24 mg, 319.14 μmol) were added, and the mixture was degassed with nitrogen for 5 minutes. The resulting mixture was heated to 100 °C under N gas for 16 hours. LCMS confirmed the desired mass as a major peak. The mixture was filtered through a pad of Celite. The filtrate was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash® silica flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient @ 40 mL / min) to afford tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (1.9 g, 3.06 mmol, 95.82% yield, 97% purity) as a yellow solid. MS (M+H) + =603.2

[0137] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (7)

[0138] A mixture of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (1.9 g, 3.15 mmol) and Pd / C (200 mg, 10% purity) in CF3CH2OH (20 mL) was degassed and purged with H2 three times. The mixture was stirred at 20 °C under H2 gas (15 Psi) for 16 h. LCMS confirmed a major peak of the desired mass. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-1-carboxylate (1.3 g, crude) as a blue solid. MS (M+H) + =425.2

[0139] Step 5. Synthesis of 3-((3,5-difluoro-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)-2,6-difluorophenyl)piperazine-1-carboxylate (300 mg, 706.81 μmol) in dioxane (3 mL) was added HCl / dioxane (4 M, 3 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed a major peak of the desired mass. The mixture was concentrated in vacuo to give 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (250 mg, crude, HCl salt) as a blue solid, which was used directly in the next step. MS (M+H) + =325.1

[0140] Step 6. Synthesis of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (10) To a solution of 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (250 mg, 692.93 μmol, HCl salt), tert-butyl (4-formylpiperidin-1-yl)carbamate (158.19 mg, 692.93 μmol) in methanol (4 mL) was added NaOAc (113.69 mg, 1.39 mmol), and the mixture was stirred at 20 °C for 1 h. After that, NaBH CN (130.64 mg, 2.08 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 20-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) to afford tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (66 mg, 120.53 μmol, 17.39% yield, 98% purity) as a yellow solid. MS (M+H) + =537.3

[0141] Step 7. Synthesis of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (11) To a solution of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (66 mg, 122.99 μmol) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at 20° C. for 2 h. LCMS confirmed a major peak of the desired mass. The reaction mixture was concentrated under reduced pressure to give 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (65 mg, crude, TFA salt) as a yellow oil, which was used directly in the next step. MS (M+H) + =437.3

[0142] 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (compound 18) 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 (49.75 mg, 118.07 μmol) in DMF (2 mL) was added HATU (67.34 mg, 177.11 μmol), DIPEA (45.78 mg, 354.21 μmol, 61.70 μL), and the mixture was stirred at 20° C. for 30 minutes, after which 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (65 mg, 118.07 μmol, TFA salt) was added and stirred at 20° C. for 16 hours. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM:methanol = 10:1) and repurified by reverse-phase HPLC (Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 39%-69%, 9 min). The eluate was lyophilized to give 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (16.4 mg, 18.94 μmol, 16.04% yield, 97% purity) as a white solid. MS (M+H) + =840.4 1H NMR (400 MHz, CD3CN) δ=8.73(s, 1H), 8.47(d, J=8.3 Hz, 1H), 8.07(s, 1H), 7.80-7.61(m, 2H), 7.46-7.30(m, 2H), 6.33-6.21(m, 2H), 5 .07-4.89(m, 2H), 4.18-4.09(m, 1H), 4.02-3.89(m, 5H), 3.33(s, 3H), 3.15-3.08 (m, 2H), 3.06-2.99(m, 4H), 2.77-2.57(m, 4H), 2.51-2.42(m, 4H), 2.27-2.22(m, 3H), 1.90-1.86(m, 1H), 1.84-1.78(m, 2H), 1.64-1.49(m, 1H), 1.36-1.24(m, 8H).

[0143] Example 19. Synthesis of N-(4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-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-methoxybenzamide (Compound 19) [ka] Step 1. Synthesis of tert-butyl 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (3) To a solution of 2-chloro-1-fluoro-4-nitrobenzene (5 g, 28.48 mmol) and tert-butyl piperazine-1-carboxylate (5.84 g, 31.33 mmol) in DMF (50 mL) was added K2CO3 (7.87 g, 56.97 mmol), and the mixture was stirred at 100 °C for 16 h. LCMS confirmed complete consumption of 2-chloro-1-fluoro-4-nitrobenzene and 88% of the desired mass. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with brine (200 mL × 5), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with MTBE (20 mL) for 10 min, the suspension was filtered, and the filter cake was washed with MTBE (20 mL). The filter cake was collected and dried to give tert-butyl 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (9.18 g, 26.86 mmol, 94.30% yield) as a gray solid. MS (M-56+H). + =286.1

[0144] Step 2. Synthesis of tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (4) To a solution of tert-butyl 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (9.18 g, 26.86 mmol) in methanol (90 mL) were added Fe (7.50 g, 134.29 mmol), NH4Cl (7.18 g, 134.29 mmol), and HO (9 mL), and the mixture was stirred at 70 °C for 16 h. LCMS confirmed complete consumption of the starting material and 91% of the desired mass. The reaction mixture was poured into HCl solution (1 M, 200 mL). K2CO3 was added to the resulting mixture to adjust the pH to >12. The suspension was filtered, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated in vacuo to remove most of the methanol. The residue was diluted with HO (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.91 g, 9.33 mmol, 34.75% yield) as a black solid, which was used directly in the next step. MS (M+H) + =312.1

[0145] Step 3. Synthesis of tert-butyl 4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (5) To a solution of tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (500 mg, 1.60 mmol) and 3-bromopiperidine-2,6-dione (923.70 mg, 4.81 mmol) in DMF (8 mL) was added NaHCO (1.35 g, 16.04 mmol, 623.66 μL), and the mixture was stirred at 80 °C for 16 h. LCMS confirmed 39% tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate remaining and 59% of the desired mass. The reaction mixture was diluted with HO (120 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (150 mL × 5), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 12-26% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl 4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (300 mg, 709.38 μmol, 44.24% yield) as a blue solid. MS (M+H) + =423.2

[0146] Step 4. Synthesis of 3-((3-chloro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (6) To a solution of tert-butyl 4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate (300 mg, 709.38 μmol) in dioxane (5 mL) was added HCl / dioxane (4 M, 10 mL) and the mixture was stirred at 15° C. for 2 hours. LCMS confirmed 88% of the desired mass. The mixture was concentrated in vacuo to give 3-((3-chloro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (420 mg, HCl salt) as a blue solid. MS (M+H) + =323.2

[0147] Step 5. Synthesis of tert-butyl (4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (8) A mixture of 3-((3-chloro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (270 mg, 751.57 μmol, HCl salt), tert-butyl (4-formylpiperidin-1-yl)carbamate (240.20 mg, 1.05 mmol), and NaOAc (184.96 mg, 2.25 mmol) in methanol (5 mL) was stirred at 15° C. for 30 minutes, after which NaBH3CN (283.38 mg, 4.51 mmol) was added and the resulting mixture was stirred at 15° C. for 12 hours. LCMS confirmed 76% of the desired mass. The reaction mixture was combined with another batch (150 mg scale), and the combined mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (FA)-ACN]; B%: 10% to 40%, 10 min), and the eluate was lyophilized to give tert-butyl (4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (55 mg, 71.95 μmol, 9.57% yield, 70% purity) as a brown solid. MS (M+H) + =535.3

[0148] Step 6. Synthesis of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-chlorophenyl)amino)piperidine-2,6-dione (9) To a solution of tert-butyl (4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (50.00 mg, 65.41 μmol, 70% purity) in DCM (3 mL) was added TFA (74.58 mg, 654.11 μmol, 48.43 μL) at 0° C. and stirred at 15° C. for 4 h. LCMS confirmed 42% starting material remaining and 32% desired mass. Additional TFA (74.58 mg, 654.11 μmol, 48.43 μL) was added and the resulting mixture was stirred at 15° C. for an additional 4 h, after which LCMS confirmed complete consumption of the starting material. The reaction mixture was concentrated in vacuo to give 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-chlorophenyl)amino)piperidine-2,6-dione (50 mg, TFA salt) as a brown oil. MS (M+H) + =435.0

[0149] Step 7. Synthesis of N-(4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-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-methoxybenzamide (Compound 19) 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 (25 mg, 59.33 μmol) in DMF (0.5 mL) was diluted with HATU (33.84 mg, 88.99 μmol) and DIPEA (115.01 mg, 889 μmol). After 15 minutes of stirring at 15° C., a solution of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-chlorophenyl)amino)piperidine-2,6-dione (50 mg, 91.08 μmol, TFA salt) in DMF (1.5 mL) was added and the resulting mixture was stirred at 15° C. for 1 hour. LCMS confirmed the desired mass peak (90%). The reaction mixture was diluted with HO (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (40 mL×5), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 41% to 71%, 8 min), and the eluate was lyophilized to give N-(4-((4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-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-methoxybenzamide (15.0 mg, 16.64 μmol, 28.05% yield, 93% purity) as an off-white solid. MS (M+H) + =838.2 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 9.34-9.16(m, 1H), 8.36-8.26(m, 1H), 8.22(s, 1H), 7.87(s, 1H), 7.52-7.38(m, 2H), 6.96(d, J=8.8 Hz, 1H), 6.75(d, J=2.5 Hz, 1H), 6.60(dd, J=2.5, 8.6 Hz, 1H), 5.86(d, J=7.9 Hz, 1H), 4.96-4.79(m, 1H), 4.36-4.19(m, 1H), 4.03(br t, J=13.5 Hz, 2H), 3.93(s, 3H), 3.30(s, 3H), 3.01(br d, J=10.4 Hz, 2H), 2.84(br s, 4H), 2.75(br dd, J=5.2, 11.8 Hz, 2H), 2.72-2.68(m, 1H), 2.61-2.51(m, 5H), 2.21(br d, J=6.6 Hz, 2H), 2.07(dt, J=5.0, 8.5 Hz, 1H), 1.93-1.82(m, 1H), 1.76(br d, J=11.0 Hz, 2H), 1.57-1.46(m, 1H), 1.24(d, J=6.8 Hz, 8H).

[0150] Example 20. 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)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)-3-methoxybenzamide (Compound 20) [ka] Step 1. Synthesis of tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (2) To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (5 g, 26.70 mmol) in DCM (50 mL) was added TEA (8.11 g, 80.11 mmol) and TosCl (7.13 g, 37.39 mmol) at 20 °C and stirred for 12 h. LCMS confirmed the desired mass (76%). The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (7.5 g, 21.75 mmol, 81.44% yield, 99% purity) as a yellow oil. MS (M-56+H) + =286.2

[0151] Step 2. Synthesis of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate (3) To a solution of tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (5 g, 14.64 mmol) and benzyl piperidin-4-ylcarbamate (4.46 g, 19.04 mmol) in DMF (50 mL) was added NaI (439.03 mg, 2.93 mmol) and DIPEA (5.68 g, 43.93 mmol, 7.65 mL) at 20 °C, and the resulting mixture was stirred at 80 °C for 16 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (78%). The reaction mixture was diluted with HO (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with brine (200 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give two batches of the title compound. Batch 1: tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate (4.9 g, 12.14 mmol, 82.92% yield) as a yellow oil, and Batch 2: tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate (1.7 g, 4.21 mmol, 28.77% yield) as a yellow oil. MS (M+H) + =404.4

[0152] Step 3. Synthesis of benzyl (1-(azetidin-3-ylmethyl)piperidin-4-yl)carbamate (4) To a solution of tert-butyl 3-((4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)azetidine-1-carboxylate (4.9 g, 12.14 mmol) in DCM (10 mL) was added TFA (4.15 g, 36.43 mmol, 2.70 mL) at 20° C. and the resulting mixture was stirred at 20° C. for 1 h. No reaction was observed by LCMS, so additional TFA (5.54 g, 48.57 mmol, 3.60 mL) was added and the reaction mixture was stirred at 20° C. for an additional 16 h. LCMS showed 56% starting material remaining with a 29% peak of the desired mass, and the reaction mixture was stirred at 20° C. for an additional 32 h. LCMS showed complete consumption of the starting material. The reaction mixture was combined with another batch (1.7 g scale) for workup. The combined reaction mixture was concentrated in vacuo to give benzyl (1-(azetidin-3-ylmethyl)piperidin-4-yl)carbamate (13.9 g, crude, TFA salt) as an orange oil. MS (M+H) + =304.4

[0153] Step 4. Synthesis of benzyl (1-((1-(2-fluoro-4-nitrophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (5) To a solution of benzyl (1-(azetidin-3-ylmethyl)piperidin-4-yl)carbamate (3.94 g, 9.43 mmol, TFA salt) in DMSO (15 mL) was added K2CO3 (2.61 g, 18.86 mmol) and 1,2-difluoro-4-nitrobenzene (1 g, 6.29 mmol, 694.44 μL) at 20 °C, and the resulting mixture was stirred at 40 °C for 1 h. TLC (SiO2, petroleum ether:ethyl acetate = 10:1) confirmed the presence of 1,2-difluoro-4-nitrobenzene and the formation of one new spot. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (25 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford benzyl (1-((1-(2-fluoro-4-nitrophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (1.1 g, 2.49 mmol, 39.55% yield) as a yellow solid. MS (M+H) + =443.3

[0154] Step 5. Synthesis of benzyl (1-((1-(4-amino-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (6) To a solution of benzyl (1-((1-(2-fluoro-4-nitrophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (1.1 g, 2.49 mmol) in ethanol (10 mL) and HO (5 mL) was added Fe (832.98 mg, 14.92 mmol) and NH4Cl (797.87 mg, 14.92 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (70%). The pH of the mixture was adjusted to pH = 10 with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give benzyl (1-((1-(4-amino-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (926 mg, 2.24 mmol, 90.30% yield) as an orange solid. MS (M+H) + =413.2

[0155] Step 6. Synthesis of benzyl (1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (7) To a solution of benzyl (1-((1-(4-amino-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (926 mg, 2.24 mmol) and 3-bromopiperidine-2,6-dione (1.29 g, 6.73 mmol) in DMF (15 mL) was added NaHCO (1.89 g, 22.45 mmol, 873.07 μL) at 20 °C, and the resulting mixture was stirred at 85 °C for 16 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (39%). The reaction mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was diluted with HO (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford benzyl (1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (545 mg, 1.04 mmol, 46.37% yield) as a green solid. MS (M+H) + =524.2

[0156] Step 7. Synthesis of 3-((4-(3-((4-aminopiperidin-1-yl)methyl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (8) To a solution of benzyl (1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)carbamate (200 mg, 381.97 μmol) in CF3CH2OH (5 mL) was added Pd / C (0.1 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C under H2 atmosphere (15 Psi) for 16 h. LCMS showed complete consumption of the starting material and the desired mass peak. The reaction mixture was diluted with CF3CH2OH (20 mL) and filtered. The filtrate was concentrated in vacuo to give 3-((4-(3-((4-aminopiperidin-1-yl)methyl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (201 mg, crude) as a blue solid. MS (M+H) + =390.2

[0157] 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-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)-3-methoxybenzamide (Compound 20) 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 (80 mg, 189.84 μmol) in DMF (2 mL) was added HATU (79.40 mg, 208.83 μmol) and DIPEA (73.61 mg, 569.53 μmol, 99.20 μL). The mixture was stirred at 20°C for 10 minutes, and then a solution of 3-((4-(3-((4-aminopiperidin-1-yl)methyl)azetidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (147.88 mg, 379.69 μmol) in DMF (2 mL) was added, and the resulting mixture was stirred at 20°C for 1 hour. LCMS confirmed complete consumption of the starting material and the desired mass peak. The reaction mixture was diluted with H2O (12 mL) and extracted with ethyl acetate (12 mL x 3). The organic phase was washed with brine (12 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, DCM:methanol = 10:1) followed by preparative HPLC (column: Unisil 3-100 C18 Ultra The mixture was purified using a 150 x 50 mm x 3 μm column chromatography (mobile phase: [water (FA)-ACN]; B%: 10% to 40%, 7 min) and the eluate was lyophilized to give 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)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)-3-methoxybenzamide (32 mg, 34.52 μmol, 18.18% yield, 88% purity, 0.5% FA salt) as a gray solid. MS (M+H) + =793.2 1H NMR(400 MHz, DMSO-d6)δ=10.75(s, 1H), 8.34-8.27(m, 1H), 8.22(s, 1H), 8.15-8.10(br, 1H ), 7.87(s, 1H), 7.54-7.45(m, 2H), 6.52-6.44(m, 1H), 6.43-6.32(m, 2H), 5.53(br d, J=7.1 Hz, 1H), 4.93-4.82(m, 1H), 4.23-4.14(m, 1H), 4.04(br t, J=13.5 Hz, 2H), 3.94(s, 3H), 3.86(br t, J=6.7 Hz, 2H), 3.82-3.71(m, 1H), 3.42-3.34(m, 5H), 2.91-2.79(m, 3H), 2.77-2.68(m, 1H), 2.58(br d, J=5.1 Hz, 3H), 2.12-2.01(m, 3H), 1.89-1.74(m, 3H), 1.65-1.52(m, 2H), 1.24(d, J=6.7 Hz, 6H).

[0158] 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21) [ka] Step 1. Synthesis of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (3) To a solution of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol, 3.29 mL) and tert-butyl piperazine-1-carboxylate (4.90 g, 26.30 mmol) in DMF (50 mL) was added K2CO3 (6.61 g, 47.82 mmol), and the mixture was stirred at 50 °C for 16 h. LCMS confirmed the desired mass peak (70%). The reaction mixture was diluted with HO (250 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with brine (200 mL × 5), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g SepaFlash® silica flash column, eluent 6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (7.1 g, 18.92 mmol, 79.11% yield) as a yellow solid. MS (M-56+H) + =320.1

[0159] Step 2. Synthesis of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (4) To a solution of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (7.1 g, 18.92 mmol) in CF3CH2OH (80 mL) was added Pd / C (1 g, 10% purity) under N2, and the suspension was degassed and purged with H2 several times. The mixture was stirred at 15 °C under H2 (15 Psi) for 16 h. LCMS confirmed complete consumption of the starting material and a major peak of the desired mass (99%). The reaction mixture was filtered, the filter cake was washed with CF3CH2OH (100 mL), and the filtrate was concentrated in vacuo to give tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (6.08 g, 17.60 mmol, 93.07% yield) as a gray solid. MS (M+H) + =346.1

[0160] Step 3. Synthesis of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (6) To a solution of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (800 mg, 2.32 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (1.11 g, 3.01 mmol) in dioxane (20 mL) was added CsCO (2.26 g, 6.95 mmol), Pd(dba) (212.12 mg, 231.64 μmol), and XPhos (110.43 mg, 231.64 μmol), and the mixture was stirred at 100 °C under N for 16 h. LCMS confirmed complete consumption of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate and the desired mass peak (56%). The reaction mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1.43 g, 2.25 mmol, 97.27% yield) as a yellow oil. MS (M+H) + =635.2

[0161] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (7) To a solution of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (930 mg, 1.47 mmol) and CHCOOH (8.80 mg, 146.53 μmol, 8.38 μL) in CFCHOH (30 mL) was added Pd(OH) / C (200 mg, 10% purity) under N, and the suspension was degassed and purged with H several times. The mixture was stirred at 15 °C under H (15 Psi) for 16 h. LCMS confirmed complete consumption of the starting material and the desired mass peak (55%). The reaction mixture was filtered, and the filter cake was washed with CFCHOH (50 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (590 mg) as a blue solid. MS (M+H) + =457.2

[0162] Step 5. Synthesis of 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (590 mg, 1.29 mmol) in dioxane (6 mL) was added HCl / dioxane (4 M, 12 mL) and the mixture was stirred at 15° C. for 2 h. LCMS showed complete consumption of starting material and the desired mass peak (69%). The residue was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; B%: 1% to 23%, 11 min), and the eluate was lyophilized to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (240 mg, 610.99 μmol, 47.27% yield, HCl salt) as a light brown solid. MS (M+H) + =357.0 1H NMR (400 MHz, DMSO-d6) δ=11.22-10.41(m, 1H), 8.33(s, 1H), 7.27(d, J=8.6 Hz, 1H), 7.01-6.79(m, 2H), 6.24(br d, J=8.0 Hz, 1H), 4.43-4.34(m, 1H), 2.93(br s, 4H), 2.84-2.75(m, 4H), 2.75-2.68(m, 1H), 2.58(td, J=4.0, 17.4 Hz, 1H), 2.13-2.01(m, 1H), 1.90(dq, J=4.6, 12.2 Hz, 1H).

[0163] Step 6. Synthesis of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (10) A solution of 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (240 mg, 610.99 μmol, HCl salt), tert-butyl (4-formylpiperidin-1-yl)carbamate (488.19 mg, 2.14 mmol), and NaOAc (150.37 mg, 1.83 mmol) in methanol (8 mL) was stirred at 15° C. for 30 minutes, after which NaBHCN (153.58 mg, 2.44 mmol) was added and the resulting mixture was stirred at 15° C. for 16 hours. LCMS confirmed complete consumption of 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione and the desired mass. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Shim-pack C18 150 x 25 x 10 μm; mobile phase: [water (TFA)-ACN]; B%: 15% to 45%, 10 min), and the eluate was lyophilized to give tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (160 mg, 234.38 μmol, 38.36% yield, TFA salt) as a brown solid. MS (M+H) + =569.3

[0164] Step 7. Synthesis of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (11) To a solution of tert-butyl (4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)carbamate (150 mg, 219.73 μmol, TFA salt) in DCM (2 mL) was added TFA (250.54 mg, 2.20 mmol, 162.69 μL) and the mixture was stirred at 15 °C for 5 h. LCMS showed traces of starting material remaining and the desired mass peak (53%). N was bubbled through the reaction mixture to remove most of the solvent and give 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (130 mg, TFA salt) as a brown oil. MS(M+H) + =469.2

[0165] 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21) 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 (85 mg, 201.71 μmol) in DMF (2 mL) was diluted with HATU (115.04 mg, 302.56 μmol) and DIPEA (338.90 mg, 2 After adding 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione (129.25 mg, 221.88 μmol, TFA salt) and stirring the mixture at 15° C. for 15 minutes, 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione was added and the resulting mixture was stirred at 15° C. for 1 hour. LCMS confirmed complete consumption of 3-((4-(4-((1-aminopiperidin-4-yl)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione and the desired mass peak (62%). CH3COOH was added to the mixture, the pH was adjusted to <7, and the resulting mixture was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex C18 Purification by chromatography (75 × 30 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 18% to 48%, 7 min) and lyophilization of the eluate gave 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-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (12.1 mg, 12.77 μmol, 6.33% yield, 93% purity, 0.2% FA salt) as a brown solid. MS (M+H) + =872.1 1H NMR (400 MHz, DMSO-d6) δ=10.80(s, 1H), 9.29(s, 1H), 8.34-8.26(m, 1H), 8.22(s, 1H), 7.88(s, 1H), 7.50-7.39(m, 2H), 7.33(br d, J=8.8 Hz, 1H), 6.99-6.84(m, 2H), 6.35-6.12(m, 1H), 4.96-4.79(m, 1H), 4.45-4.32(m, 1H), 4.04(br t, J=13.5 Hz, 2H), 3.94(s, 3H), 3.31(br s, 3H), 3.03(br d, J=9.9 Hz, 2H), 2.90-2.69(m, 7H), 2.61(br d, J=3.8 Hz, 2H), 2.57-2.52(m, 5H), 2.11-2.05(m, 1H), 1.97-1.89(m, 1H), 1.78(br d, J=10.8 Hz, 2H), 1.67-1.50(m, 1H), 1.25(d, J=6.7 Hz, 8H).

[0166] Example 22. 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-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 22) [ka] Step 1. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2) To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.25 g, 729.30 μmol, HCl salt) and 2-(1-((tert-butoxycarbonyl)amino)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (290.64 mg, 729.30 μmol) in DMF (1 mL) at 25° C. was added DIPEA (282.76 mg, 2.19 mmol, 381.08 μL) and NaI (21.86 mg, 145.86 μmol). The reaction mixture was heated to 60° C. and stirred for 2 h. LCMS showed complete consumption of the starting material, with the main peak of the desired mass being detected. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150x40mmx15um; mobile phase: [water (FA)-ACN]; B%: 3%-35%, 9 min) and then lyophilized to give tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.1 g, crude) as a brown solid. MS (M+H) + =533.3

[0167] Step 2. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (3) To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.1 g, 187.74 μmol) in DCM (2 mL) at 25° C. was added TFA (1.26 g, 11.09 mmol, 821.07 μL). The resulting mixture was stirred at 25° C. for 30 minutes. LCMS confirmed complete consumption of the starting material, and a main peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (0.1 g, crude, TFA salt) as a brown solid. MS (M+H) + =433.2

[0168] 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-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 22) 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 (0.1 g, 223.50 μmol) in DMF (1 mL) was added HATU (101.98 mg, 268.20 μmol) and DIPEA (115.54 mg, 893.99 μmol, 155.71 μL). The mixture was stirred at 25° C. for 10 min. 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (97.72 mg, 178.80 μmol, TFA salt) was then added, and the resulting mixture was stirred at 25° C. for 1 hour. LCMS confirmed complete consumption of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, with the desired mass peak (41%) detected. The reaction mixture was filtered. The filtered material was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150x50mmx3um; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 7 min), and then purified by preparative HPLC (column: Waters Xbridge 150x25mmx The mixture was re-purified by 5 μm elution (5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 37%-67%, 8 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-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (36 mg, 40.51 μmol, 18.13% yield, 97% purity) as a white solid. MS (M+H) + =862.5 1H NMR (400 MHz, DMSO-d6) δ=10.78(s, 1H), 9.28(s, 1H), 8.35-8.20(m, 2H), 7.96(s, 1H), 7.51-7.37(m, 2H), 6.91-6.77(m, 1H), 6.52(dd, J=1.8, 15.0 Hz, 1H), 6.43(dd, J=1.7, 8.8 Hz, 1H), 5.80(d, J=7.8 Hz, 1H), 4.88-4.70(m, 1H), 4.26(td, J=5.5, 11.3 Hz, 1H), 4.05(br t, J=14.1 Hz, 2H), 3.94(s, 3H), 3.30(s, 3H), 3.00(br d, J=9.6 Hz, 2H), 2.86(br s, 4H), 2.80-2.66(m, 3H), 2.59(br d, J=4.1 Hz, 5H), 2.38-2.32(m, 2H), 2.14-2.04(m, 1H), 2.00-1.80(m, 3H), 1.77-1.54(m, 8H), 1.48-1.21(m, 5H).

[0169] Example 23. 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)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 23) [ka] Step 1. Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (2) A mixture of 1,2-difluoro-4-nitrobenzene (6.3 g, 39.60 mmol, 4.37 mL), tert-butyl piperazine-1-carboxylate (7.38 g, 39.60 mmol), and K2CO3 (16.42 g, 118.80 mmol) in DMSO (80 mL) was stirred at 60 °C for 4 h. A major peak of the desired mass was detected by LCMS. The mixture was poured into water (300 mL) and extracted with ethyl acetate (80 mL × 5). The combined organic phase was washed with brine (80 mL × 3), dried over sodium sulfate, filtered, and concentrated to give tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (13.7 g, crude) as a yellow solid. MS (M-100+H) + =226.0

[0170] Step 2. Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (3) To a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (13 g, 39.96 mmol) in THF (300 mL) and methanol (300 mL) was added Pd / C (1 g, 10% purity) under nitrogen N2 gas at 25 °C. The reaction mixture was degassed and purged three times under H2. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 h. LCMS confirmed complete consumption of the starting material, and a main peak of the desired mass was detected. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to give tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (12 g, crude) as a brown solid. MS (M+H) + =296.1

[0171] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (4) A mixture of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (0.5 g, 1.69 mmol), 3-bromopiperidine-2,6-dione (650.11 mg, 3.39 mmol), and NaHCO (711.07 mg, 8.46 mmol, 329.20 μL) in ACN (20 mL) was stirred at 80° C. for 12 hours. LCMS showed most of the starting material still remaining, with a peak of the desired mass (14%). Additional 3-bromopiperidine-2,6-dione (325.05 mg, 1.69 mmol) and NaHCO (426.64 mg, 5.08 mmol, 197.52 μL) were added at 25° C., and the resulting mixture was stirred at 80° C. for 12 hours. LCMS showed starting material still remaining, with a peak of the desired mass (44%). Further 3-bromopiperidine-2,6-dione (487.58 mg, 2.54 mmol) and NaHCO3 (426.64 mg, 5.08 mmol, 197.52 μL) were added at 25 °C, and the mixture was further stirred at 80 °C for 12 h. LCMS showed that starting material still remained and a peak of the desired mass (65%) was detected. The reaction mixture filter cake was washed with ethyl acetate (30 mL). The combined filtrates were concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-35% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.5 g, crude) as a green solid. MS (M+H) + =407.2

[0172] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (5) A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.4 g, 984.13 μmol), HCHO (159.73 mg, 1.97 mmol, 146.54 μL, 37% purity), and AcOH (59.10 mg, 984.13 μmol, 56.28 μL) in methanol (5 mL) was stirred at 25° C. for 30 minutes. NaBHCN (185.53 mg, 2.95 mmol) was added at 25° C., and the resulting mixture was stirred at 25° C. for 1 hour. LCMS showed a peak for the mass of the starting material (50%) and a peak for the desired mass (43%). Further HCHO (159.73 mg, 1.97 mmol, 146.54 μL, 37% purity) was added to the reaction mixture at 25° C., and after stirring for an additional 10 minutes at 25° C., NaBH3CN (123.69 mg, 1.97 mmol) was added at 25° C., and the resulting mixture was stirred at 25° C. for 12 hours. LCMS showed a peak mass for the starting material (9%) and a peak mass for the desired material (86%). The reaction solution was concentrated, and the organic phase was removed. The crude product was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.6 g, crude) as a blue solid. MS (M+H) + =421.0

[0173] Step 5. Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (6) To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.6 g, 1.43 mmol) in dioxane (2 mL) at 25° C. was added HCl / dioxane (4 M, 36.62 mL). The resulting mixture was stirred at 25° C. for 30 minutes. LCMS confirmed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (0.7 g, crude) as a blue solid. MS (M+H) + =321.4

[0174] Step 6. 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 (7) To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (200 mg, 560.50 μmol, HCl salt) and 2-(1-((tert)-butoxycarbonyl)amino)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (223.37 mg, 560.50 μmol) in DMF (1 mL) was added DIPEA (217.32 mg, 1.68 mmol, 292.88 μL) and NaI (16.80 mg, 112.10 μmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred for 4 h. LCMS confirmed complete consumption of the starting material, and the main peak of the desired mass was detected. The mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic phase was washed with brine (15 mL x 3), then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 μm; mobile phase: [HO(TFA)-ACN]; B%: 21% to 41%, 7 min), and the eluate was lyophilized to give tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (50 mg, crude) as a brown solid. MS (M+H) + =547.4

[0175] Step 7. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (50 mg, 91.46 μmol) in DCM (2 mL) at 25° C. was added TFA (616.00 mg, 5.40 mmol, 0.4 mL). The resulting mixture was stirred at 25° C. for 30 minutes. LCMS confirmed complete consumption of the starting material, and a main peak of the desired mass was detected. The reaction mixture was concentrated under reduced pressure to afford 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (55 mg, crude, TFA salt) as a yellow oil. MS (M+H) + =447.3

[0176] 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)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (compound 23) 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 (50 mg, 111.75 μmol) in DMF (1 mL) was added HATU (50.99 mg, 134.10 μmol) and DIPEA (57.77 mg, 446.99 μmol, 77.86 μL). The mixture was stirred at 25° C. for 10 min. 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (50.12 mg, 89.40 μmol, TFA salt) was added, and the resulting mixture was stirred at 25° C. for 1 hour. LCMS confirmed complete consumption of the starting material, and a peak of the desired mass (34%) was detected. The mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL×5). The combined organic phase was washed with brine (10 mL×3), then dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150x50mmx3um; mobile phase: [HO(FA)-ACN]; B%: 15%-45%, 7 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)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (35.6 mg, 37.39 μmol, 33.46% yield, 92% purity) as a white solid. MS(M+H) + =876.5 1H NMR (400 MHz, CD3CN) δ=8.78-8.65(m, 1H), 8.46(d, J=8.4 Hz, 1H), 8.10(s, 1H), 7.92-7.77(m, 1H), 7.73(s, 1H), 7.46-7.30(m, 2H), 7. 01-6.89(m, 1H), 6.70-6.52(m, 2H), 4.95-4.81(m, 1H), 4.60(dd, J=5.1, 12.8 Hz, 1H), 4.03-3.91(m, 5H), 3.66-3.49(m, 2H), 3.44-3.35(m, 2H), 3.33(s, 3H), 3.21-3.13(m, 5H), 3. 10-2.99(m, 2H), 2.77-2.74(m, 3H), 2.73-2.64(m, 3H), 2.40-2.26(m, 2H), 2.02(dd, J=2.5, 5.0, 10.1 Hz, 3H), 1.83-1.55(m, 11H), 1.51-1.33(m, 3H).

[0177] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 24) [ka] Step 1. Synthesis of tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (2) To a solution of tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 4.16 mmol) in THF (10 mL) and HO (5 mL) was added NaHCO (1.05 g, 12.48 mmol, 485.46 μL) at 0 °C. CbzCl (922.73 mg, 5.41 mmol, 768.94 μL) was then added dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 2 h. LCMS confirmed complete consumption of the starting material, and the desired mass peak (35%) was detected. The reaction mixture was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.74 mmol, 89.85% yield) as a white solid. MS (M-100+H) + =275.4

[0178] Step 2. Synthesis of benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (3) To a solution of tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.74 mmol) in DCM (5 mL) at 20 °C was added TFA (2.13 g, 18.69 mmol, 1.38 mL), and the mixture was stirred at 20 °C for 12 h. LCMS confirmed complete consumption of the starting material, with a peak of the desired mass (70%). The reaction mixture was concentrated in vacuo to give benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (3 g, crude, TFA salt) as a yellow oil. MS (M+H) + =275.5

[0179] Step 3. Synthesis of tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (4) To a solution of benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (2 g, 5.15 mmol, TFA salt) in DMF (10 mL) at 20 °C, DIPEA (3.33 g, 25.75 mmol, 4.48 mL) and tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (1.34 g, 4.12 mmol) were added, and the resulting mixture was stirred at 60 °C for 16 h. LCMS showed the remaining starting material and the desired mass peak (21%). The reaction mixture was stirred at 80 °C for 16 h. LCMS showed the remaining trace of starting material and the desired mass peak (28%). The reaction mixture was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (1.6 g, 3.39 mmol, 65.88% yield) as a yellow oil. MS (M+H) + =472.3

[0180] Step 4. Synthesis of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5) To a solution of tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (1.6 g, 3.39 mmol) in DCM (5 mL) at 20° C. was added TFA (1.93 g, 16.96 mmol, 1.26 mL), and the resulting mixture was stirred at 20° C. for 12 h. LCMS confirmed complete consumption of the starting material, and a peak of the desired mass (56%) was detected. The reaction mixture was concentrated in vacuo to afford benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.1 g, crude, TFA salt) as a yellow oil. MS (M+H) + =372.4

[0181] Step 5. Synthesis of benzyl (7-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) To a solution of 1,2-difluoro-4-nitro-benzene (1 g, 6.29 mmol, 694.44 μL) in DMSO (10 mL) at 20 °C, K2CO3 (2.61 g, 18.86 mmol) and benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.05 g, 6.29 mmol, TFA) were added, and the resulting mixture was stirred at 40 °C for 1 h. LCMS showed the presence of 1,2-difluoro-4-nitro-benzene remaining and the desired mass peak (52%). The reaction mixture was diluted with HO (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (30 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give two batches of the title compound. Batch 1: benzyl (7-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (896 mg, 1.60 mmol, 25.40% yield, 91% purity) was obtained as a yellow solid, and Batch 2: benzyl (7-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (490 mg, 921.27 μmol, 14.66% yield, 96% purity) was obtained as a yellow solid. Carbamate MS (M+H) + =511.3

[0182] Step 6. Synthesis of benzyl (7-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) To a solution of benzyl (7-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (490 mg, 959.66 μmol) in ethanol (6 mL) and HO (3 mL) was added Fe (321.55 mg, 5.76 mmol) and NH Cl (308.00 mg, 5.76 mmol) at 20 °C, and the resulting mixture was stirred at 80 °C for 12 h. LCMS confirmed complete consumption of the starting material, and a peak of the desired mass (91%) was detected. The reaction mixture was combined with another batch (896 mg scale) for workup. NaHCO (20 mL) was added to this reaction mixture, adjusting the pH to 10, and then extracted with ethyl acetate (40 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give benzyl (7-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.1 g, crude) as an orange oil. MS (M+H) + =481.4

[0183] Step 7. Synthesis of (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8) To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (600 mg, 1.62 mmol) and benzyl (7-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (934.65 mg, 1.94 mmol) in dioxane (10 mL) at 20 °C under N was added Pd-PEPPSI-IHeptCl (78.82 mg, 81.03 μmol) and CsCO (1.58 g, 4.86 mmol), and the resulting mixture was stirred at 100 °C for 16 h. LCMS confirmed complete consumption of all starting material, with the desired mass peak (54%) detected. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (25 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give two batches of the title compound. Batch 1: (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (742 mg, 963.71 μmol, 59.47% yield) was obtained as a green oil, and Batch 2: (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (246 mg, 319.50 μmol, 19.72% yield) was obtained as a green oil. MS (M+H) + =770.1

[0184] Step 8. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (9) To a solution of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (400 mg, 519.52 μmol) in CF3CH2OH (10 mL) was added Pd / C (0.1 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged under H2 three times. The mixture was stirred at 20 °C under H2 (15 Psi) for 16 h. LCMS showed complete consumption of the starting material and a peak with the desired mass was detected. The reaction mixture was combined with another batch (246 mg scale) for workup. The reaction mixture was diluted with ethyl acetate (15 mL) and filtered. After concentration of the filtrate in vacuo, 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (219 mg, 478.60 μmol, 92.12% yield) was obtained as a green oil. MS (M+H) + =458.1

[0185] Step 9. 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-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (compound 24) 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 (100 mg, 237.31 μmol) in DMF (2 mL) was added HATU (99.25 mg, 261.04 μmol) and DIPEA (92.01 mg, 711.92 μmol, 124.00 μL). After the mixture was stirred at 20° C. for 10 minutes, a solution of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (217.17 mg, 474.61 μmol) in DMF (2 mL) was added, and the resulting mixture was stirred at 20° C. for 1 hour. LCMS confirmed complete consumption of the starting material, and the desired mass peak (68%) was detected. The reaction mixture was diluted with HO (15 mL) and extracted with ethyl acetate (15 mL×3). The organic phase was washed with brine (15 mL×3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150*40 mm* The mixture was purified by HPLC using a 15 μm column; mobile phase: [water (FA)-ACN]; B%: 13%-43%, 10 min.) and the eluate was lyophilized to give 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-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (119.5 mg, 126.42 μmol, 53.27% yield, 94% purity, 0.6% FA salt) as a gray solid. MS (M+H) + =861.1 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 8.42(br d, J=7.2 Hz, 1H), 8.30(d, J=8.3 Hz, 1H), 8.22(s, 1H), 8.16(s, 1H), 7.88(s, 1H), 7.54-7.45(m, 2H), 6.82(br t, J=9.3 Hz, 1H), 6.49(dd, J=2.0, 15.0 Hz, 1H), 6.41(br d, J=8.7 Hz, 1H), 5.77(br d, J=7.3 Hz, 1H), 4.94-4.82(m, 1H), 4.47-4.34(m, 1H), 4.30-4.19(m, 1H), 4.04(br t, J=13.5 Hz, 2H), 3.94(s, 3H), 3.32(s, 3H), 3.10(br d, J=11.1 Hz, 2H), 2.78-2.67(m, 1H), 2.61-2.54(m, 2H), 2.54-2.50(m, 2H), 2.50-2.23(m, 2H), 2.22-2.03(m, 6H), 1.90-1.78(m, 3H), 1.74(br d, J=11.7 Hz, 2H), 1.59(br d, J=19.2 Hz, 5H), 1.27-1.17(m, 8H).

[0186] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 25) [ka] Step 1. Synthesis of tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (2) To a solution of tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 4.16 mmol) in THF (10 mL) and HO (5 mL) was added NaHCO (1.05 g, 12.48 mmol) at 0 °C. CbzCl (922.73 mg, 5.41 mmol) was then added dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 2 h. LCMS confirmed complete consumption of the starting material, and a peak of the desired mass (35%) was detected. The reaction mixture was diluted with HO (20 mL) and then extracted with ethyl acetate (20 mL × 3). The organic phase was washed with sodium sulfate. The mixture was dried at 77°C, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 0-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.74 mmol, 89.85% yield) as a white solid. MS (M-100+H) + =275.4

[0187] Step 2. Synthesis of benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (3) To a solution of tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (6 g, 16.02 mmol) in dioxane (30 mL) was added HCl / dioxane (4 M, 30 mL), and the mixture was stirred at 20° C. for 2 hours. LCMS confirmed complete consumption of the starting material, and a peak of the desired mass was detected. After concentrating the mixture in vacuo, benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (6 g, crude) was obtained as a white solid, which was used directly in the next reaction. MS (M+H) + =275.2

[0188] Step 3. Synthesis of tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (4) A solution of benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (5 g, 16.09 mmol, HCl salt), tert-butyl 4-formylpiperidine-1-carboxylate (3.43 g, 16.09 mmol), and AcOH (966.03 mg, 16.09 mmol) in DCE (60 mL) was stirred at 20 °C for 30 min. NaBH(OAc) (6.82 g, 32.17 mmol) was then added, and the resulting mixture was stirred at 20 °C for 1 h. The main peak of the desired mass was detected by LCMS. The reaction mixture was poured into NaHCO solution (100 mL). The layers were separated. The aqueous phase was extracted with DCM (30 mL × 3). The combined organic phase was washed with sodium sulfate. Drying at 40°C and concentration gave tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (7.5 g, 15.90 mmol, 98.85% yield) as a white solid. MS (M+H) + =472.4

[0189] Step 4. Synthesis of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5) To a solution of tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (6 g, 12.72 mmol) in ethyl acetate (25 mL) was added HCl / dioxane (4 M, 30.00 mL) and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the desired mass was detected. The reaction mixture was concentrated to give benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5 g, crude, diHCl salt) as a white solid. MS (M+H) + =372.2

[0190] Step 5. Synthesis of benzyl (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) To a solution of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.5 g, 5.63 mmol, diHCl salt) and 1,2,3-trifluoro-5-nitro-benzene (996.10 mg, 5.63 mmol) in MeCN (20 mL) at 20 °C was added EtN (2.85 g, 28.13 mmol). The resulting mixture was stirred at 80 °C for 1 h. LCMS confirmed complete consumption of the starting material and the desired mass was detected. The reaction mixture was concentrated. The crude product was purified by flash silica gel chromatography (25 g silica gel column, ethyl acetate / petroleum ether = 10-60%, 80 mL / min) to give benzyl (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 1.89 mmol, 33.63% yield) as a yellow solid. MS (M+H) + =529.3

[0191] Step 6. Synthesis of benzyl (7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) To a mixture of benzyl (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 1.89 mmol) and NH4Cl (607.18 mg, 11.35 mmol) in ethanol (20 mL) and HO (10 mL) was added Fe (633.89 mg, 11.35 mmol) at 20 °C. The resulting mixture was stirred at 80 °C for 1 h. LCMS confirmed complete consumption of the starting material, and the desired mass was detected. The reaction mixture was poured into NaHCO3 solution (200 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give benzyl (7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (900 mg, crude) as a yellow solid which was used directly in the next reaction. MS (M+H) + =499.5

[0192] Step 7. Synthesis of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8) Benzyl (7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (900 mg, 1.81 mmol), 2,6-dibenzyloxy-3-bromo-pyridine (801.95 mg, 2.17 mmol) and CsCO in dioxane (15 mL). 3(To a mixture of Pd-PEPPSI-IHeptCl (1.76 g, 5.42 mmol) was added Pd-PEPPSI-IHeptCl (87.79 mg, 90.25 μmol) at 20° C. The resulting mixture was purged with N2, degassed, and then heated to 100° C. and stirred for 14 hours. LCMS confirmed complete consumption of the starting material, and the desired mass was detected. The reaction mixture was diluted with ethyl acetate (50 mL) and then filtered. The filtrate was concentrated. The crude product was purified by flash silica gel chromatography (12 g silica gel column, ethyl acetate / petroleum ether = 10-40%, 80 mL / min) to give benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (900 mg, 959.47 μmol, 53.16% yield, 84% purity) as a brown solid. MS (M+H) + =788.8

[0193] Step 8. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (9) To a solution of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (800 mg, 1.02 mmol) in THF (15 mL) at 20 °C under N was added Pd / C (200 mg, 10% purity). The mixture was purged with H three times, degassed, and then stirred at 20 °C under H (15 Psi) for 2 h. LCMS showed that most of the starting material remained. The reaction mixture was further stirred at 20 °C under H (15 Psi) for 12 h. LCMS showed that starting material remained and the desired mass was detected. The reaction mixture was filtered through a pad of Celite. To the filtrate was added Pd / C (100 mg, 10% purity) at 20 °C under N. The mixture was purged with H three times, degassed, and then stirred at 20 °C under H (15 Psi) for 4 h. LCMS confirmed complete consumption of the starting material, and the desired mass was detected. The reaction product was filtered through a pad of Celite and dissolved in THF to give 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (400 mg, crude), which was used directly in the next reaction. MS (M+H) + =476.3

[0194] Step 9. 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)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (compound 25) To a solution of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (400 mg, 841.09 μmol), 4-[(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-benzoic acid (248.10 mg, 588.76 μmol) and DIPEA (543.53 mg, 4.21 mmol) in THF (20 mL) was added HATU (319.81 mg, 841.09 μmol) at 20° C. The resulting mixture was stirred at 20° C. for 13 hours. LCMS confirmed that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated. The crude product was purified by flash silica gel chromatography (4 g silica gel column, ethyl acetate / petroleum ether = 30 to 100%, then methanol / ethyl acetate = 10 to 20%, 40 mL / min) to give the crude product, which was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra Further purification with a 150*50 mm*3 μm column (mobile phase: [HO(FA)-ACN]; B%: 13%-43%, 7 min) and lyophilization of the eluate gave 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)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (40.6 mg, 45.54 μmol, 5.41% yield, 98.6% purity) as a white solid. MS (M+H) + =879.4 1H NMR (400 MHz, DMSO-d6) δ=10.82(s, 1H), 8.45(br d, J=6.7 Hz, 1H), 8.31(d, J=8.2 Hz, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.53-7.46(m, 2H), 6.31(br d, J=12.3 Hz, 2H), 6.24(br d, J=7.8 Hz, 1H), 4.88(td, J=6.6, 13.2 Hz, 1H), 4.45-4.37(m, 1H), 4.35-4.27(m, 1H), 4.04(br t, J=13.6 Hz, 2H), 3.94(s, 3H), 3.32(br s, 3H), 2.98-2.90(m, 4H), 2.75-2.71(m, 1H), 2.40-2.35(m, 2H), 2.25-2.1 5(m, 4H), 2.10-2.01(m, 2H), 1.90-1.80(m, 4H), 1.74-1.63(m, 7H), 1.24(br d, J=6.7 Hz, 8H).

[0195] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 26) [ka] Step 1. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2) To a solution of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (500 mg, 649.40 μmol) in THF (20 mL) was added BocO (500 mg, 2.29 mmol, 526.32 μL) and Pd / C (200 mg, 10% purity) under N atmosphere. The suspension was degassed and purged with H several times and stirred at 20 °C under H (15 Psi) for 16 h. LCMS showed complete consumption of starting material and the desired mass peak. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 0-20% methanol:DCM gradient, 60 mL / min) to afford tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (300 mg, 537.93 μmol, 82.83% yield) as a brown solid. MS (M+H) + =558.3

[0196] Step 2. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (300 mg, 537.93 μmol) in methanol (20 mL) was added HOAc (32.30 mg, 537.93 μmol, 30.77 μL) and HCHO (750.00 mg, 9.24 mmol, 688.07 μL, 37% purity). The mixture was stirred at 20 °C for 1 h. NaBHCN (375.00 mg, 5.97 mmol) was then added at 0 °C, and the resulting mixture was stirred at 20 °C for 15 h. LCMS confirmed complete consumption of the starting material and one major peak of the desired mass. The reaction mixture was diluted with HO (15 mL) and concentrated. The residue was dissolved in ethyl acetate (30 mL), and saturated sodium bicarbonate was added to adjust the pH to 9. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (30 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 0-20% methanol:dichloromethane gradient, 60 mL / min) to afford tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (280 mg, 489.75 μmol, 91.04% yield) as a bright yellow solid. MS (M+H) + =572.3

[0197] Step 3. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (4) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (280 mg, 489.75 μmol) in DCM (5 mL) was added TFA (4.52 g, 39.67 mmol, 2.94 mL) under N atmosphere and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the desired mass peak (65%). The reaction mixture was concentrated to give 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (286 mg, crude, TFA salt) as a yellow oil. MS (M+H) + =472.3

[0198] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 26) 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 (220 mg, 522.07 μmol) in DMF (4 mL) was added HATU (280 mg, 736.40 μmol), DIPEA (544.12 mg, 4.21 mmol, 733.32 μL) and 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (286 mg, 488.36 μmol, TFA salt) at 20 °C. The mixture was stirred at 20°C under N2 gas for 16 hours. LCMS confirmed complete consumption of the starting material and the desired mass peak (40%). The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with 60 mL of brine (20 mL x 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g SepaFlash® silica flash column, eluent 0-25% methanol:DCM gradient, 60 mL / min) and preparative HPLC (column: Unisil 3-100 C18 Ultra The column was re-purified using a column chromatography (150 × 50 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 13% to 43%, 7 min; column temperature: 30 °C) and the eluate was lyophilized to give 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)(methyl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (109.6 mg, 124.01 μmol, 23.75% yield, 99% purity) as a white solid. MS (M+H) + =875.2 1H NMR (400 MHz, DMSO-d6) δ=10.80(s, 1H), 8.44(d, J=7.5 Hz, 1H), 8.35-8.28(m, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.55-7.44(m, 2H), 6.89(t, J=9.6 Hz, 1H), 6.70-6.62(m, 1H), 6.56-6.48(m, 1H), 4.95-4.87(m, 1H), 4.84-4.76(m, 1H), 4.45-4.33(m, 1H), 4.04(t, J=13.8 Hz, 2H), 3.94(s, 3H), 3.34(s, 3H), 3.18-3.10(m, 2H), 2.89-2.76(m, 1H), 2.67(s, 3H), 2.56-2.51(m, 6H), 2.28-2.13(m, 6H), 1.87-1.78(m, 3H), 1.78-1.71(m, 2H), 1.65-1.53(m, 5H), 1.29-1.18(m, 8H).

[0199] Example 27. 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)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 27) [ka] Step 1. Synthesis of benzyl (7-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2) To a solution of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2 g, 4.90 mmol, HCl salt) in DMSO (15 mL) was added K2CO3 (2.03 g, 14.71 mmol) and 1-fluoro-4-nitrobenzene (1.04 g, 7.35 mmol, 780.12 μL) and stirred at 20 °C for 12 h. LCMS confirmed the desired mass peak (~45%). The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30% petroleum ether: (ethyl acetate / ethanol = 2 / 1) gradient @ 80 mL / min) to afford benzyl (7-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.41 mmol, 49.10% yield, 98.8% purity) as a yellow solid. MS (M+H) + =493.2.

[0200] Step 2. Synthesis of benzyl (7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) To a solution of benzyl (7-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.44 mmol) in ethanol (8 mL) was added Fe (544.16 mg, 9.74 mmol) and a solution of NH4Cl (521.22 mg, 9.74 mmol) in HO (8 mL). The mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass peak (87%). The mixture was diluted with saturated sodium bicarbonate solution (100 mL) and filtered to remove insoluble solids. The filtrate was extracted with ethyl acetate (50 mL × 4), and the combined organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give benzyl (7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 1.53 mmol, 62.65% yield, 70.6% purity) as a gray solid. MS (M+H) + =463.3.

[0201] Step 3. Synthesis of benzyl(7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5) To a solution of benzyl (7-((1-(4-aminophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 2.16 mmol) in dioxane (10 mL) was added 2,6-bis(benzyloxy)-3-bromopyridine (880.33 mg, 2.38 mmol), CsCO (2.11 g, 6.48 mmol), and Pd-PEPPSI-IHeptCl (210.27 mg, 216.16 μmol). The mixture was stirred at 100 °C under N gas for 12 h. LCMS confirmed the desired mass peak (54%). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-35% petroleum ether: (ethyl acetate / ethanol = 2 / 1) gradient @ 80 mL / min) to afford benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.45 g, 1.93 mmol, 89.21% yield) as a brown oil. MS (M+H) + =752.4. 1 H NMR (400 MHz, DMSO-d6) δ=7.56-7.49(m, 1H), 7.42-7.29(m, 15H), 6.79(s, 4H), 6.34(d, J=8.3 Hz, 1H), 5.38(s, 2H), 5.25(s, 2H), 4.98(s, 2H), 3.98-3.89(m, 1H), 3.45(d, J=11.9 Hz, 2H), 3.33-3.29(m, 4H), 2.56-2.52(m, 4H), 2.0-2.06(m, 2H), 1.80-1.44(m, 11H), 1.24 - 1.21(m, 2H).

[0202] Step 4. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6) To a solution of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (0.5 g, 664.94 μmol) and BocO (435.36 mg, 1.99 mmol, 458.27 μL) in THF (5 mL) was added Pd / C (50 mg, 66.49 μmol, 10% purity) under N atmosphere. The mixture was stirred at 20 °C under H (15 Psi) for 16 h. LCMS confirmed the desired mass peak (~20%). The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-40% petroleum ether: (ethyl acetate / methanol = 1 / 2) gradient @ 60 mL / min) to afford tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (160 mg, 278.67 μmol, 41.91% yield, 94% purity) as a gray solid. MS (M+H) + =540.3

[0203] Step 5. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (160 mg, 296.46 μmol) in methanol (5 mL) was added HCHO (433.04 mg, 5.34 mmol, 397.29 μL, 37% purity), HOAc (8.90 mg, 148.23 μmol, 8.48 μL) at 20 °C. After stirring for 1 h, NaBHCN (335.34 mg, 5.34 mmol) was added and the resulting mixture was stirred at 20 °C for 12 h. LCMS confirmed the desired mass as a major peak (90%). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (160 mg, 288.95 μmol, 97.47% yield) as a brown oil. MS (M+H) + =554.4

[0204] Step 6. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (8) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (160 mg, 288.95 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 20° C. for 1 h. TLC (methanol:dichloromethane=2:1) ​​confirmed complete consumption of the starting material. The mixture was concentrated under reduced pressure to give 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (180 mg, crude, TFA salt) as a yellow oil. MS (M+H) + =454.2

[0205] 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)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 27) 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 (133.63 mg, 317.10 μmol) in DMF (3 mL) was added HATU (180.86 mg, 475.65 μmol) and DIPEA (122.95 mg, 951.30 μmol, 165.70 μL) and stirred for 30 minutes, followed by the addition of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (180 mg, 317.10 μmol, TFA salt). The mixture was stirred at 20°C for 12 hours. LCMS confirmed the desired mass peak (40%). The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-80% petroleum ether / (ethyl acetate / ethanol; v / v=1:2) gradient @ 60 mL / min) followed by preparative HPLC (column: Waters Xbridge The mixture was re-purified using a column (150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) and the eluate was lyophilized to give 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)(methyl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (21.4 mg, 24.10 μmol, 7.60% yield, 96.5% purity) as a white solid. MS (M+H) + =857.4 1H NMR (400 MHz, DMSO-d6) δ=10.72(s, 1H), 8.41(d, J=7.6 Hz, 1H), 8.33-8.28(m, 1H), 8.22(s, 1H), 7.88(s, 1H), 7.53-7.46(m, 2H), 6. 83-6.78(m, 2H), 6.73-6.71(m, 2H), 4.91-4.84(m, 1H), 4.71(dd, J=4.8, 12.3 Hz, 1H), 4.45-4.34(m, 1H), 4.04(t, J=13.6 Hz, 2H), 3.94(s, 3H), 3.42(d, J=11.6 Hz, 2H), 3.29(s, 3H), 2.85-2.77(m, 1H), 2.67(s, 3H), 2.57-2.52(m, 3H) , 2.29-2.09(m, 8H), 1.89-1.71(m, 6H), 1.63-1.51(m, 5H), 1.24(d, J=6.8 Hz, 6H), 1.22-1.14(m, 2H).

[0206] Example 28. 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)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 28) [ka] Step 1. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (2) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (160 mg, 296.46 μmol) in DCM (2 mL) was added TFA (33.80 mg, 296.46 μmol, 21.95 μL). The mixture was stirred at 20° C. for 1 hour. TLC (methanol:dichloromethane=2:1) ​​confirmed the formation of a new spot. The mixture was concentrated under reduced pressure to give 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (0.2 g, crude, TFA salt) as a green oil. MS (M+H) + =440.4.

[0207] 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)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 28) 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 (160 mg, 379.69 μmol) in DMF (3 mL) was added HATU (216.55 mg, 569.53 μmol) and DIPEA (245.36 mg, 1.90 mmol, 330.68 μL) and stirred for 30 min. Then, 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (199.69 mg, 360.70 μmol, TFA salt) was added, and the resulting mixture was stirred at 20° C. for 12 hours. LCMS confirmed the desired mass peak (~50%). The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 10 min) followed by preparative HPLC (column: Waters Xbridge Purification by chromatography (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 8 min) and lyophilization afforded 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)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (41.5 mg, 43.96 μmol, 11.58% yield, 89.3% purity) as a gray solid. MS (M+H) + =843.2. 1H NMR (400 MHz, DMSO-d6) δ=10.76(s, 1H), 8.43(d, J=7.2 Hz, 1H), 8.30(d, J=8.4 Hz, 1H), 8.22(s, 1H), 7.88(s, 1H), 7.53-7.46(m, 2H), 6.75 - 6.73(m, 2H), 6.60 - 6.57(m, 2H), 5.36(d, J=7.2 Hz, 1H), 4.91-4.84(m, 1H), 4.42-4.35(m, 1H), 4.21-4.14(m, 1H), 4.04(t, J=13.8 Hz, 2H), 3.94(s, 3H), 3.41-3.40(m, 2H), 3.32(s, 3H), 2.75-2.67(m, 1H), 2.60-2. 57(m, 3H), 2.27-2.06(m, 8H), 1.91-1.68(m, 6H), 1.64-1.51(m, 5H), 1.24(d, J=6.6 Hz, 6H), 1.21-1.13(m, 2H).

[0208] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 29) [ka] Step 1. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2) To a solution of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (500 mg, 634.57 μmol) and BocO (415.48 mg, 1.90 mmol) in THF (20 mL) was added Pd / C (100 mg, 10% purity) under N gas. The resulting mixture was degassed and purged with H three times, and the suspension was stirred at 20 °C under H (15 Psi) for 16 h. LCMS confirmed the intermediate and the desired mass. The mixture was filtered. To the filtrate was added Pd / C (200 mg, 10% purity). The resulting mixture was stirred at 20 °C under H (15 Psi) for an additional 18 h. LCMS confirmed complete consumption of the intermediate with a major peak of the desired mass. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (360 mg, crude) as a dark green solid. The crude product was used directly in the next step. MS (M+H) + =576.5

[0209] Step 2. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3) A solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (360 mg, 625.34 μmol), HCHO (1.01 g, 12.51 mmol, 37% purity), and AcOH (37.55 mg, 625.34 μmol) in methanol (10 mL) was stirred at 20° C. for 1 h. NaBHCN (785.95 mg, 12.51 mmol) was then added, and the resulting mixture was stirred at 20° C. for 14 h. LCMS confirmed the remaining starting material and the desired mass peak. Another portion of HCHO (507.47 mg, 6.25 mmol, 465.57 μL, 37% purity) was added to the mixture, and the mixture was stirred at 20 °C for 1 h. Then, NaBHCN (392.97 mg, 6.25 mmol) was added, and the resulting mixture was stirred at 20 °C for 15 h. LCMS confirmed the remaining starting material and a peak with the desired mass. The reaction mixture was concentrated to remove methanol. The residue was dissolved in ethyl acetate (20 mL), washed with NaHCO solution (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative TLC (DCM:methanol = 10:1, Rf = 0.6) to give the crude product. The crude product was dissolved in methanol (6 mL) and then HCHO (405.98 mg, 5.00 mmol, 372.46 μL, 37% purity) and AcOH (37.55 mg, 625.34 μmol, 35.80 μL) were added. The mixture was stirred at 20 °C for 1 h. NaBHCN (314.38 mg, 5.00 mmol) was added. The resulting mixture was stirred at 20 °C for 13 h. LCMS showed traces of starting material remaining and a peak of the desired mass. The reaction mixture was concentrated to remove the methanol.The residue was dissolved in ethyl acetate (20 mL), washed with NaHCO solution (10 mL), dried over sodium sulfate, filtered, and concentrated to give tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (150 mg, crude) as a yellow oil. MS (M+H). + =590.5

[0210] Step 3. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)(methyl)amino)piperidine-2,6-dione (4) To a solution of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (150 mg, 254.36 μmol) in DCM (4 mL) was added TFA (1.54 g, 13.51 mmol) at 20° C. The resulting solution was stirred at 20° C. for 30 min. LCMS confirmed complete consumption of the starting material with a major peak of the desired mass. The reaction mixture was concentrated to give 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)(methyl)amino)piperidine-2,6-dione (150 mg, crude, TFA salt) as a brown oil. MS (M+H) + =490.4

[0211] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 29) To a mixture of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)(methyl)amino)piperidine-2,6-dione (150 mg, 248.50 μmol, TFA salt), 4-[(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-benzoic acid (73.30 mg, 173.95 μmol) and DIPEA (192.70 mg, 1.49 mmol) in DMF (3 mL) was added HATU (94.49 mg, 248.50 μmol) at 20° C. The resulting mixture was stirred at 20° C. for 30 minutes. LCMS confirmed complete consumption of the starting material and the desired mass. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra Purification using a column (150 × 50 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 18% to 48%, 7 min) and lyophilization of the eluate gave 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)(methyl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (10.3 mg, 9.93 μmol, 3.99% yield, 90.5% purity, FA salt) as a white solid. MS (M+H) + =893.5 1H NMR (400 MHz, DMSO-d6) δ=10.84(br s, 1H), 8.44(br d, J=7.5 Hz, 1H), 8.30(d, J=8.4 Hz, 1H), 8.26(s, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.53-7.46(m, 2H), 6.49(s, 1H), 6.45(s, 1H), 4.92-4.80(m, 2H), 4.45-4.35(m, 1H), 4.04(br t, J=13.9 Hz, 2H), 3.94(s, 3H), 3.32(br s, 3H), 2.98-2.92(m, 4H), 2.84-2.77(m, 1H), 2.67(s, 3H), 2.582.55(m, 1H), 2.32-2.20(m, 5H) ), 2.17-2.10(m, 4H), 1.87-1.77(m, 3H), 1.74-1.65(m, 2H), 1.63-1.51(m, 5H), 1.24(d, J=6.6 Hz, 6H), 1.20-1.13(m, 2H).

[0212] Example 30. 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)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-3-methoxybenzamide (Compound 30) [ka] Step 1. Synthesis of tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (2) To a solution of tert-butyl 2-cyano-7-azaspiro[3.5]nonane-7-carboxylate (1.5 g, 5.99 mmol) in methanol (30 mL) was added NH3.HO (2.73 g, 21.81 mmol, 3 mL, 28% purity) and Raney-Ni (300.00 mg, 3.50 mmol) under N2. H2 was bubbled through the mixture, and the mixture was stirred at 20 °C under H2 (45 Psi) for 16 h. LCMS confirmed the desired mass as a major peak, and the mixture was filtered. The filtrate was concentrated in vacuo to give tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.5 g, crude) as a yellow oil. MS (M+H) + =255.1.

[0213] Step 2. Synthesis of tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (3) To a solution of tert-butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, crude) in THF (28 mL) and HO (7 mL) was added CbzCl (1.13 g, 6.60 mmol, 938.92 μL) and NaCO (1.17 g, 11.01 mmol), and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak, and the mixture was diluted with water (30 mL) and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (2.6 g, crude) as a white powder. MS (M+H) + =389.1

[0214] Step 3. Synthesis of benzyl ((7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (4) To a solution of tert-butyl 2-((((benzyloxy)carbonyl)amino)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, crude) in dioxane (2 mL) was added HCl / dioxane (4 M, 1.00 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed consumption of starting material and the desired mass. The mixture was concentrated in vacuo to give benzyl ((7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (110 mg, crude) as a yellow oil. MS (M+H) + =289.1

[0215] Step 4. Synthesis of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2,6-difluoro-4-nitrophenyl)piperidine (6) To a solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (505.16 mg, 1.43 mmol) in DMSO (10 mL) was added 1,2,3-trifluoro-5-nitrobenzene (230 mg, 1.30 mmol) and K2CO3 (538.52 mg, 3.90 mmol), and the mixture was stirred at 20 °C for 16 h. The desired mass was confirmed by LCMS, and the mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-60% ethyl acetate / petroleum ether gradient @ 15 mL / min) to afford 4-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2,6-difluoro-4-nitrophenyl)piperidine (420 mg, 822.49 μmol, 63.32% yield, 100% purity) as a yellow oil. MS (M+H) + =511.2.

[0216] Step 5. Synthesis of (1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methanol (7) To a solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2,6-difluoro-4-nitrophenyl)piperidine (420 mg, 822.49 μmol) in DMSO (10 mL) was added CsF (187.40 mg, 1.23 mmol), and the mixture was stirred at 20° C. for 16 h. LCMS confirmed the desired mass as a major peak, and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL×3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give (1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methanol (450 mg, crude) as a yellow oil. MS (M+H) + =273.0

[0217] Step 6. Synthesis of 1-(2,6-difluoro-4-nitrophenyl)piperidine-4-carbaldehyde (8) To a solution of DMSO (717.45 mg, 9.18 mmol, 717.45 μL) in DCM (6 mL) was added oxalyl chloride (233.12 mg, 1.84 mmol, 160.77 μL) at −70° C. and stirred for 10 min. A solution of (1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methanol (250 mg, crude) in DCM (2 mL) was added over 20 min at −65° C. TEA (464.60 mg, 4.59 mmol, 639.07 μL) was added dropwise at −65° C., followed by warming to 20° C. and stirring for 30 min. TLC (ethyl acetate / petroleum ether=1 / 1) confirmed the consumption of the starting material. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3), and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-(2,6-difluoro-4-nitrophenyl)piperidine-4-carbaldehyde (200 mg, crude) as a yellow oil, which was used directly in the next step. MS (M+H) + =271.2.

[0218] Step 7. Synthesis of benzyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (9) To a solution of benzyl ((7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (200 mg, crude) in DCE (2 mL) was added 1-(2,6-difluoro-4-nitrophenyl)piperidine-4-carbaldehyde (96.17 mg, 296.04 μmol, HCl), NaOAc (60.71 mg, 740.11 μmol), and AcOH (4.44 mg, 74.01 μmol, 4.23 μL). The mixture was stirred at 20 °C for 30 min. NaBH(OAc) (188.23 mg, 888.13 μmol) was added, and the mixture was stirred at 20 °C for 15.5 h. LCMS confirmed the desired mass peak, and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-98% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford benzyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (700 mg, crude) as a yellow oil. MS (M+H) + =543.3.

[0219] Step 8. Synthesis of (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methanamine (10) A mixture of benzyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (700 mg, crude) in TFA (3 mL) was stirred at 40° C. for 16 h. LCMS confirmed the desired mass and the mixture was concentrated in vacuo to give (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methanamine (500 mg, crude) as a brown oil. MS (M+H) + =409.2.

[0220] Step 9. Synthesis of tert-butyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (11) To a solution of (7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methanamine (500 mg, crude) in dioxane (10 mL) was added TEA (1.24 g, 12.24 mmol, 1.70 mL), the pH was adjusted to 8, BocO (534.29 mg, 2.45 mmol, 562.41 μL) was added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass, and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3), and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-77% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford tert-butyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (140 mg, 261.50 μmol, 21.36% yield, 95% purity) as a yellow oil. MS (M+H) + =509.2

[0221] Step 10. Synthesis of tert-butyl ((7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (12) To a solution of tert-butyl ((7-((1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (140 mg, 275.27 μmol) in ethanol (5 mL) and HO (5 mL) were added Fe (153.72 mg, 2.75 mmol) and NHCl (147.24 mg, 2.75 mmol) at 80° C., and the mixture was stirred at 80° C. for 2 h. LCMS confirmed a major peak of the desired mass, and the mixture was diluted with aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl ((7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (140 mg, crude) as a yellow oil, which was used directly in the next step. MS (M+H) + =479.2

[0222] Step 11. Synthesis of tert-butyl ((7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (13) To a solution of tert-butyl ((7-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (120 mg, crude) in DMF (0.2 mL) was added 3-bromopiperidine-2,6-dione (481.41 mg, 2.51 mmol) and NaHCO3 (421.25 mg, 5.01 mmol, 195.02 μL), and the mixture was stirred at 80 °C for 72 h. LCMS confirmed the desired mass, and the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-70% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford tert-butyl ((7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (80 mg, 135.66 μmol, 54.11% yield, 100% purity) as a yellow oil. MS (M+H) + =590.1

[0223] Step 12. Synthesis of 3-((4-(4-((2-(aminomethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (14) To a solution of tert-butyl ((7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)carbamate (70 mg, 118.70 μmol) in DCM (2.5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed the desired mass and the mixture was concentrated in vacuo to give 3-((4-(4-((2-(aminomethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (100 mg, crude, TFA) as a brown oil which was used directly in the next step. MS (M+H) + =490.3

[0224] Step 13. 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)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-3-methoxybenzamide (compound 30) 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 (50 mg, 118.65 μmol) in DMF (2 mL) was added HATU (67.67 mg, 177.98 μmol) and DIPEA (46.01 mg, 355.96 μmol, 62.00 μL), 3-((4-(4-((2-(aminomethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (71.62 mg, crude, TFA) was added, and the mixture was stirred at 25° C. for 16 h. LCMS confirmed the desired mass peak (46%), and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent: 4-15% ethyl acetate / methanol gradient @ 20 mL / min) and preparative HPLC (column: Waters Xbridge) The mixture was purified again by chromatography (150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 8 min) and lyophilized to give 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)-2,6-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-3-methoxybenzamide (9.3 mg, 9.48 μmol, 7.99% yield, 91.0% purity) as a white powder. MS (M+H) + =893.5 1H NMR (400 MHz, DMSO-d6) δ=10.81(s, 1H), 8.38-8.28(m, 2H), 8.22(s, 1H), 7.89(s, 1H), 7.54-7.47(m, 2H), 6.31(d, J=12.2 Hz, 2H), 6.22(d, J=7.8 Hz, 1H), 4.88(td, J=6.6, 13.5 Hz, 1H), 4.35-4.27(m, 1H), 4.04(t, J=13.6 Hz, 2H), 3.94(s, 3H), 3.51-3.46(m, 3H), 3.38(s, 3H), 2.92(d, J=6.7 Hz, 4H), 2.82-2.72(m, 2H), 2.30-2.02(m, 7H), 1.88-1.76(m, 3H), 1.68(d, J=11.7 Hz, 2H), 1.58-1.43(m, 7H), 1.25(d, J=6.7 Hz, 6H), 1.20-1.10(m, 2H).

[0225] 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-(4-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 31) [ka] Step 1. Synthesis of tert-butyl 7-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3) To a solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol, 751.88 μL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.5 g, 6.63 mmol) in DMSO (10 mL) was added K2CO3 (2.75 g, 19.88 mmol), and the mixture was stirred at 60 °C for 5 h. LCMS showed the main peak of the desired mass (100%). The mixture was diluted with water (30 mL) and then filtered. The filter cake was washed with water (50 mL), collected, and dried under vacuum to give tert-butyl 7-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.1 g, crude) as a yellow solid. MS (M+H) + =348.1

[0226] Step 2. Synthesis of tert-butyl 7-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (4) To a solution of tert-butyl 7-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.1 g, 6.04 mmol) in ethanol (40 mL) was added Pd / C (0.2 g, 10% purity) under N2 gas. The mixture was then degassed and purged under H2 three times. The mixture was then stirred under H2 (15 Psi) at 20 °C for 14 h. LCMS showed the desired mass as the main peak (100%). The mixture was filtered. The filter cake was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 7-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.9 g, crude) as a gray solid. MS (M+H) + =318.2

[0227] Step 3. Synthesis of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (5) To a solution of tert-butyl 7-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, 3.15 mmol) and 3-bromopiperidine-2,6-dione (1.31 g, 6.84 mmol) in MeCN (10 mL) was added NaHCO (1.44 g, 17.11 mmol, 665.33 μL), and the mixture was stirred at 80 °C for 14 h. HPLC showed the desired mass (92%). The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL) and THF (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 70-100% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, 1.87 mmol, 59.26% yield, 80% purity) as a dark brown solid. MS (M+H) + =429.2

[0228] Step 4. Synthesis of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (6) To a solution of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, 1.87 mmol, 80% purity) in methanol (20 mL) was added HCHO (196.20 mg, 2.42 mmol, 180 μL, 37% purity) and AcOH (105.00 mg, 1.75 mmol, 0.1 mL), and the mixture was stirred at 20 °C for 30 min. NaBHCN (352 mg, 5.60 mmol) was added, and the mixture was further stirred at 20 °C for 3 h. A peak of the desired mass (70%) was detected by LCMS. Additional HCHO (109.00 mg, 1.34 mmol, 0.1 mL, 37% purity) was added, and the mixture was stirred at 20 °C for 30 min. Then, NaBHCN (351.95 mg, 5.60 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The desired mass was detected by LCMS, and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was diluted with HO (30 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with water (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, crude) as a gray solid. MS (M+H) + =443.4

[0229] Step 5. Synthesis of 3-((4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)(methyl)amino)piperidine-2,6-dione (7) To a solution of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.1 g, 225.96 μmol) in DCM (0.5 mL) at 0° C. was added TFA (246.40 mg, 2.16 mmol, 160 μL), and the mixture was stirred at 20° C. for 1 h. LCMS showed traces of starting material remaining and the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)(methyl)amino)piperidine-2,6-dione (0.1 g, crude, TFA salt) as a dark brown oil. MS (M+H) + =343.4

[0230] 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-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (compound 31) To a solution of 3-((4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)(methyl)amino)piperidine-2,6-dione (0.3 g, 657.24 μmol, TFA salt) in DCE (10 mL) was added TEA (392.58 mg, 3.88 mmol, 540 μL) and 4A MS (0.3 g) followed by 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-(4-oxopiperidin-1-yl)benzamide (450 mg, 869.52 μmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. NaBH(OAc)3 (417.59 mg, 1.97 mmol) was then added, and the mixture was stirred at 20 °C for 3 h. The desired mass was detected by LCMS. The mixture was filtered, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 25–100% methanol / ethyl acetate gradient @ 80 mL / min). The crude product was triturated with MTBE (10 mL) for 30 min at 20 °C. The mixture was filtered, and the filter cake was washed with MTBE (20 mL). The filtrate was diluted with DCM / methanol = 10 / 1 (20 mL) and HO (10 mL) and then extracted with DCM / methanol = 10 / 1 (10 mL × 2). The combined organic phase was washed with water (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The product was washed with ACN (6 mL), methanol (2 mL), and deionized water (40 mL) and then lyophilized to give the product (214.6 mg, 221.22 μmol, 33.66% yield, 87% purity) as a blue solid. 80 mg of the product (87% purity) was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [HO(TFA)-ACN]; B%: 19%-39%, 7 min), and the eluate was lyophilized.70 mg of the product water (87% purity) was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 um; mobile phase: [HO(TFA)-ACN]; B%: 20%~40%, 7 min). The combined eluates were lyophilized to give 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-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (140.4 mg, 133.37 μmol, 75.04% yield, 91% purity, 2% TFA) as a gray solid. MS (M+H). + =844.2 1 H NMR(400 MHz, DMSO-d6)δ=10.85-10.80(m, 1H), 9.55-9.48(m, 1H), 8.31-8.20(m, 2H), 8.14-8.02 (m, 1H), 7.46-7.40(m, 2H), 7.39-7.15(m, 2H), 6.94-6.83(m, 2H), 4.95-4.83(m, 2H), 4.1 1-4.04(m, 6H), 3.93(s, 3H), 3.38-3.31(m, 6H), 3.15-3.07(m, 2H), 2.93-2.70(m, 5H), 2. 62-2.52(m, 4H), 2.20-2.04(m, 4H), 2.00-1.83(m, 4H), 1.56-1.42(m, 2H), 1.24(d, J=6.7 Hz, 6H).

[0231] Example 32. 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-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 32) [ka] Step 1. Synthesis of tert-butyl 7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3) To a solution of 1,2-difluoro-4-nitrobenzene (1.5 g, 9.43 mmol, 1.04 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2 g, 8.84 mmol) in DMSO (20 mL) was added K2CO3 (3.66 g, 26.51 mmol), and the mixture was stirred at 60 °C for 5 h. TLC (petroleum ether:ethyl acetate = 5:1) confirmed the formation of a new spot. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give tert-butyl 7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.93 g, 7.30 mmol, 82.57% yield, 91% purity) as a yellow solid. MS (M+H) + =366.2

[0232] Step 2. Synthesis of tert-butyl 7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (4) To a solution of tert-butyl 7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.93 g, 8.02 mmol) in ethanol (50 mL) under N2 gas, Pd / C (300 mg, 10% purity) was added. The reaction mixture was degassed and purged under H2 three times. The mixture was then stirred under H2 (15 Psi) at 20 °C for 14 h. LCMS showed the desired mass as the main peak (99%). The mixture was filtered, and the filter cake was washed with methanol (100 mL) and THF (30 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.6 g, crude) as a gray solid. MS (M+H) + =336.1

[0233] Step 3. Synthesis of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (5) To a solution of tert-butyl 7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1 g, 2.98 mmol) and 3-bromopiperidine-2,6-dione (1.24 g, 6.47 mmol) in MeCN (15 mL) was added NaHCO (1.36 g, 16.19 mmol, 629.64 μL), and the mixture was stirred at 80 °C for 14 h. LCMS showed starting material remaining and 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 40-60% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (610 mg, 1.35 mmol, 45.36% yield, 99% purity) as a gray solid. MS (M+H) + =447.2

[0234] Step 4. Synthesis of 3-((3-fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione (6) To a solution of tert-butyl 7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3 g, 671.87 μmol) in DCM (1.5 mL) at 0° C. was added TFA (770.00 mg, 6.75 mmol, 0.5 mL), and the mixture was stirred for 2 h at 0° C. LCMS showed 26% starting material remaining and 59% of the desired mass. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated under reduced pressure to give 3-((3-fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione (0.3 g, crude, TFA salt) as a dark brown oil. MS (M+H) + =347.3

[0235] 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-(4-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (compound 32) To a solution of 3-((3-fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)piperidine-2,6-dione (0.3 g, 651.58 μmol, TFA salt) in DCE (10 mL) was added TEA (399.85 mg, 3.95 mmol, 550 μL) and 4A MS (0.5 g) followed by 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-(4-oxopiperidin-1-yl)benzamide (0.5 g, 966.13 μmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, NaBH(OAc)3 (414 mg, 1.95 mmol) was added, and the mixture was stirred at 20°C for 3 hours. A peak of the desired mass (73%) was detected by LCMS. The mixture was filtered, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent: 30% methanol / ethyl acetate gradient @ 80 mL / min). The product was diluted with MTBE (20 mL) and stirred at 20°C for 30 minutes. The mixture was filtered, and the filter cake was washed with MTBE (30 mL). The filtrate was collected and dried under reduced pressure. The product was diluted with ACN (5 mL) and deionized water (40 mL) and then lyophilized to give 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-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (406.1 mg, 464.57 μmol, 71.30% yield, 97% purity) as a gray solid. MS (M+H) + =848.2 1H NMR (400 MHz, DMSO-d6) δ=10.79(s, 1H), 9.43(br s, 1H), 8.31(br d, J=8.2 Hz, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.46-7.40(m, 2H), 6.83(t, J=9.3 Hz, 1H), 6.54-6.48(m, 1H), 6.44-6.39(m, 1H), 5.83(br d, J=7.7 Hz, 1H), 4.92-4.84(m, 1H), 4.31-4.22(m, 1H), 4.04(br t, J=13.6 Hz, 2H), 3.94(s, 3H), 3.33-3.29(m, 8H), 3.12-3.02(m, 3H), 2.88-2.66(m, 7 H), 2.12-2.04(m, 1H), 1.97-1.79(m, 7H), 1.52-1.37(m, 2H), 1.25(d, J=6.7 Hz, 6H).

[0236] 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-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 33) [ka] Step 1. Synthesis of benzyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (3) To a solution of benzyl (4-(2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (1.6 g, 4.05 mmol, HCl salt) and 1,2-difluoro-4-nitrobenzene (800.00 mg, 5.03 mmol, 555.56 μL) in DMSO (15 mL) was added K2CO3 (1.68 g, 12.15 mmol), and the mixture was stirred at 20 °C for 14 h. LCMS confirmed the desired mass. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent 0-30% methanol / ethyl acetate gradient @ 70 mL / min) to afford benzyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (1.19 g, 2.39 mmol, 59.03% yield) as a yellow oil. MS (M+H) + =498.3

[0237] Step 2. Synthesis of 4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-amine (4)

[0238] A solution of benzyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (2.28 g, 4.58 mmol) in TFA (20 mL) was stirred at 60° C. for 3 h. LCMS showed 13% starting material remaining with the desired mass peak (62%). The mixture was stirred at 60° C. for 2 h. LCMS showed 6% starting material remaining with the desired mass peak (67%). The mixture was concentrated under reduced pressure to give 4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-amine (2.2 g, crude, TFA salt) as a yellow oil. MS (M+H) + =364.0

[0239] Step 3. Synthesis of tert-butyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (5) To a solution of 4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-amine (2.2 g, 4.61 mmol, TFA salt) in THF (20 mL) was added NaOH (1 M, 7 mL) and BocO (2.01 g, 9.22 mmol, 2.12 mL) at 0 °C, and the mixture was stirred at 20 °C for 14 h. LCMS confirmed the desired mass peak. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with H2O (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give residue A. The aqueous phase was concentrated under reduced pressure. The crude product was diluted with saturated sodium bicarbonate (10 mL) and THF (10 mL), and then BocO (1.01 g, 4.61 mmol, 1.06 mL) was added, and the mixture was stirred at 20 °C for 14 hours. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with HO (10 mL × 2), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give residue B. Residues A and B were combined and purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent 20% methanol / ethyl acetate gradient @ 50 mL / min) to give tert-butyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (1.17 g, 2.27 mmol, 49.30% yield, 90% purity) as a yellow oil. MS(M-100+H) + =364.3

[0240] Step 4. Synthesis of tert-butyl (4-(7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (6) To a solution of tert-butyl (4-(7-(2-fluoro-4-nitrophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (1.17 g, 2.52 mmol) in ethanol (20 mL) and HO (20 mL) were added Fe (845.80 mg, 15.14 mmol) and NH Cl (810.06 mg, 15.14 mmol), and the mixture was stirred at 80 °C for 2 h. TLC (dichloromethane:methanol = 10:1) confirmed the formation of a new spot. The mixture was filtered, and the filter cake was washed with DMF (20 mL) and ethanol (20 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with HO (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with water (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4-(7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (460 mg, 1.06 mmol, 42.04% yield) as a brown oil. MS (M+H) + =434.3

[0241] Step 5. Synthesis of tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (8) To a solution of tert-butyl (4-(7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (460 mg, 1.06 mmol) and 3-bromopiperidine-2,6-dione (442.07 mg, 2.30 mmol) in ACN (10 mL) was added NaHCO (483.71 mg, 5.76 mmol, 223.94 μL), and the mixture was stirred at 80° C. for 14 h. LCMS confirmed the remaining tert-butyl (4-(7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate and the desired mass. Additional 3-bromopiperidine-2,6-dione (407.44 mg, 2.12 mmol) and NaHCO3 (445.65 mg, 5.30 mmol, 206.32 μL) were added, and the mixture was stirred at 80 °C for 14 h. LCMS confirmed complete consumption of tert-butyl (4-(7-(4-amino-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate. The mixture was filtered, and the filter cake was washed with DCM (20 mL) and THF (20 mL). The filter cake was collected and dried under vacuum. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent 30-50% methanol / ethyl acetate gradient @ 50 mL / min) to afford tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (190 mg, 289.54 μmol, 27.29% yield, 83% purity) as a brown solid. MS (M+H) + =545.2

[0242] Step 6. Synthesis of tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (9) To a solution of tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (100.29 mg, 184.14 μmol) and formaldehyde (21.80 mg, 268.63 μmol, 20 μL, 37% purity) in methanol (2 mL) was added AcOH (10.41 mg, 173.31 μmol, 9.91 μL) and the mixture was stirred at 20° C. for 30 minutes. NaBH3CN (32.67 mg, 519.94 μmol) was added and the mixture was stirred at 20° C. for 3 hours. LCMS confirmed the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent 30% methanol / ethyl acetate gradient @ 50 mL / min) to afford tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (80 mg, 143.19 μmol, 82.62% yield) as a brown solid. MS (M+H) + =559.3

[0243] Step 7. Synthesis of 3-((4-(2-(1-aminopiperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (10) To a solution of tert-butyl (4-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)carbamate (80 mg, 143.19 μmol) in DCM (1 mL) was added TFA (246.40 mg, 2.16 mmol, 160 μL) and the mixture was stirred at 20° C. for 1 h. LCMS showed 16% starting material remaining with the desired mass peak (54%). The mixture was concentrated under reduced pressure to give 3-((4-(2-(1-aminopiperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (80 mg, crude, TFA salt) as a brown oil. MS (M+H) + =459.1

[0244] 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-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (compound 33) 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 (45 mg, 106.79 μmol) and HATU (50.60 mg, 133.07 μmol) in DMF (1 mL) was added DIPEA (29.79 mg, 230.53 μmol, 40.15 μL), and the mixture was stirred at 20° C. for 15 min. Then, a solution of 3-((4-(2-(1-aminopiperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (80.00 mg, 139.72 μmol, TFA salt) and DIPEA (148.97 mg, 1.15 mmol, 200.77 μL) in DMF (1 mL) was added, and the mixture was stirred at 20 °C for 1 h. TLC (dichloromethane:methanol = 10:1) confirmed the formation of a new spot. The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (dichloromethane:methanol = 10:1) and then purified by preparative HPLC (column: Phenomenex Synergi Polar-RP The mixture was re-purified using a 100 x 25 mm x 4 μm column; mobile phase: [water (TFA)-ACN]; B%: 28%-48%, 7 min.) and the eluate was lyophilized to give 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-(7-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (31.6 mg, 25.41 μmol, 22.91% yield, 96.8% purity, 3% TFA) as a blue solid. MS (M+H) + =862.4 1H NMR(400 MHz, DMSO-d6)δ=10.77-10.75(m, 1H), 10.01-9.63(m, 1H), 9.54-9.42(m, 1H), 8.31-8.17(m, 2H), 7.47-7.41(m , 2H), 6.73-6.62(m, 2H), 6.57-6.50(m, 1H), 4.92-4.84(m, 1H), 4.77-4.70(m, 1H), 4.13-4.02(m, 2H), 3.92(s, 3) H), 3.69-3.56(m, 2H), 3.40-3.18(m, 9H), 3.13-3.05(m, 2H), 2.90-2.77(m, 2H), 2.66(s, 3H), 2.57-2.50(m, 3H) , 2.30-2.20(m, 1H), 2.17-2.07(m, 3H), 2.04-1.90(m, 3H), 1.89-1.82(m, 1H), 1.79-1.65(m, 2H), 1.24(d, J=6.7 Hz, 6H).

[0245] 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-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 34) [ka] Step 1. Synthesis of benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)methyl)piperidine-1-carboxylate (3) A mixture of benzyl 4-formylpiperidine-1-carboxylate (2 g, 8.09 mmol), tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (1.73 g, 8.09 mmol), and AcOH (485.68 mg, 8.09 mmol, 462.55 μL) in methanol (20 mL) was stirred at 20 °C for 30 min. After that, NaBHCN (1.52 g, 24.26 mmol) was added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the major peak of the desired mass. The reaction mixture was concentrated in vacuo, quenched with NaHCO (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 100 mL / min) to give benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)methyl)piperidine-1-carboxylate (3.6 g, 8.08 mmol, 99.89% yield) as a colorless oil. MS (M+H) + =446.3

[0246] Step 2. Synthesis of benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidine-1-carboxylate (4) A mixture of benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)methyl)piperidine-1-carboxylate (3.6 g, 8.08 mmol), formaldehyde (1.31 g, 16.16 mmol, 1.20 mL, 37% in HO), and AcOH (485.15 mg, 8.08 mmol, 462.05 μL) in methanol (30 mL) was stirred at 20 °C for 30 min. NaBHCN (1.52 g, 24.24 mmol) was added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was concentrated in vacuo to remove most of the solvent. The mixture was quenched with NaHCO (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with brine (50 mL x 2), dried over sodium sulfate, 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 50-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 100 mL / min) to afford benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidine-1-carboxylate (3.7 g, 8.05 mmol, 99.64% yield) as a colorless oil. MS (M+H) + =460.3

[0247] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(methyl(piperidin-4-ylmethyl)amino)cyclohexyl)carbamate (5) To a mixture of benzyl 4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidine-1-carboxylate (3.7 g, 8.05 mmol) in methanol (40 mL) was added Pd / C (370 mg, 8.05 mmol, 10% purity) under N2, degassed, and purged with H2 three times, and the mixture was stirred at 20 °C for 44 h. LCMS confirmed a major peak of the desired mass. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give tert-butyl ((1r,4r)-4-(methyl(piperidin-4-ylmethyl)amino)cyclohexyl)carbamate (2.6 g, crude) as a yellow oil. MS (M+H) + =326.2

[0248] Step 4. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (7) To a solution of tert-butyl ((1r,4r)-4-(methyl(piperidin-4-ylmethyl)amino)cyclohexyl)carbamate (500 mg, crude), 1,2-difluoro-4-nitrobenzene (244.39 mg, 1.54 mmol, 169.71 μL) in DMSO (5 mL) was added K2CO3 (636.92 mg, 4.61 mmol), and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass as a major peak. The mixture was diluted with brine (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (40 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 50-100% ethyl acetate / petroleum ether to 20% methanol / ethyl acetate gradient @ 100 mL / min) to give tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (500 mg, 1.08 mmol, 70.06% yield) as a yellow solid. MS (M+H) + =465.3

[0249] Step 5. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (8) To a mixture of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (500 mg, 1.08 mmol) in CF3CH2OH (10 mL) was added Pd / C (100 mg, 1.08 mmol, 10% purity) under N2. After degassing and purging with H2 three times, the mixture was stirred at 20 °C under H2 (15 Psi) for 12 h. LCMS confirmed a major peak of the desired mass. The mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (450 mg, crude) as a brown oil. MS(M+H) + =435.3

[0250] Step 6. 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 (10) To a solution of 3-bromopiperidine-2,6-dione (309.27 mg, 1.61 mmol), tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (350 mg, crude) in ACN (5 mL) was added NaHCO3 (338.28 mg, 4.03 mmol, 156.61 μL) and the mixture was stirred at 80 °C for 16 h. LCMS confirmed the desired mass as a major peak. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 20-100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 100 mL / min) to give tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (400 mg, crude) as a gray solid. MS (M+H) + =546.4

[0251] Step 7. Synthesis of 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (11) To a solution of tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (100 mg, 183.26 μmol) in DCM (1 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL) and the mixture was stirred at 20° C. for 1 h. LCMS confirmed a major peak of the desired mass and the mixture was concentrated in vacuo to give 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (100 mg, crude, TFA) as a brown oil. MS (M+H) + =446.3

[0252] 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-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (compound 34) 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 (79.96 mg, 178.70 μmol) in DMF (2 mL) were added HATU (101.92 mg, 268.05 μmol), DIPEA (115.48 mg, 893.50 μmol, 155.63 μL), and the mixture was stirred at 20° C. for 1 h. 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (100 mg, crude, TFA) was added, and the resulting mixture was stirred at 20 °C for 15 hours. LCMS confirmed the major peak of the desired mass. The reaction mixture was diluted with brine (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (40 mL × 2), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, DCM:methanol = 10:1) and then re-purified by reverse-phase HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NHHCO)-ACN]; B%: 46%~76%, 8 min). 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-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (39.9 mg, 44.23 μmol, 24.75% yield, 97% purity) as a white solid. MS (M+H) + =875.4 1H NMR (400 MHz, DMSO-d6) δ=10.77(s, 1H), 8.30-8.21(m, 2H), 8.06(d, J=7.6 Hz, 1H), 7.95(s, 1H), 7.52-7.44(m, 2H), 6.83(t, J=9.3 Hz, 1H), 6.54-6.45(m, 1H), 6.44-6.37(m, 1H), 5.77(d, J=7.6 Hz, 1H), 4.82-4.70(m, 1H), 4.30-4.20(m, 1H), 4.04(t, J=14.1 Hz, 2H), 3.93(s, 3H), 3.78-3.67(m, 1H), 3.30(s, 3H), 3.16-3.05(m, 2H), 2 .77-2.67(m, 1H), 2.61-2.53(m, 3H), 2.35-2.32(m, 1H), 2.23-2.24(m, 2H) , 2.20(s, 3H), 2.13-2.04(m, 1H), 1.98-1.81(m, 5H), 1.80-1.67(m, 6H), 1. 66-1.54(m, 4H), 1.51-1.42(m, 1H), 1.41-1.29(m, 4H), 1.27-1.15(m, 2H).

[0253] Example 35. 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)oxy)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 35) [ka] Step 1. Synthesis of 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (2) To a solution of piperidin-4-ylmethanol (10 g, 86.83 mmol) in DCM (150 mL) was added TEA (13.18 g, 130.24 mmol, 18.13 mL) and DMAP (530.37 mg, 4.34 mmol), followed by dropwise addition of tert-butylchlorodiphenylsilane (35.80 g, 130.24 mmol, 33.46 mL). The mixture was stirred at 20 °C for 16 h. TLC (dichloromethane:methanol = 10:1) confirmed complete consumption of piperidin-4-ylmethanol and the formation of one new spot. The reaction mixture was diluted with water (100 mL) at 0 °C and extracted with dichloromethane (80 mL × 2). The combined organic phase was washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 80 mL / min) and triturated with MTBE to give 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (9.6 g, 27.15 mmol, 31.27% yield) as a white solid. MS (M+H) + =354.6

[0254] Step 2. Synthesis of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenol (4) A mixture of 4-bromo-3-fluorophenol (500 mg, 2.62 mmol), 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (1.02 g, 2.88 mmol), DavePhos (164.84 mg, 418.85 μmol), Pd(dba) (143.83 mg, 157.07 μmol), and NaOBu-t (2 M, 3.93 mL) in dioxane (12 mL) was degassed and purged with N three times, and the mixture was stirred at 100 °C under N for 16 h. LCMS showed 38% of 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine remained. LCMS showed several new peaks and the peak of the desired compound (31%). The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) at 0°C and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-16% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenol (400 mg, 819.57 μmol, 31.31% yield, 95% purity) as a yellow solid. MS (M+H) + =464.2

[0255] Step 3. Synthesis of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione (5) To a solution of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenol (200 mg, 431.35 μmol) in THF (5 mL) was added NaH (43.14 mg, 1.08 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 1 h, followed by the dropwise addition of 3-bromopiperidine-2,6-dione (91.11 mg, 474.49 μmol) in THF (2 mL) at 0° C. The resulting mixture was stirred at 20° C. for 2 h. LCMS confirmed 40% of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenol remaining and the desired mass peak (52%). The mixture was then stirred for an additional 2 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.23) confirmed the formation of one new spot with greater polarity. Saturated aqueous ammonium chloride (15 mL) was added to the reaction mixture at 0 °C, followed by quenching and extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-45% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione (190 mg, 320.66 μmol, 74.34% yield, 97% purity) as a yellow solid. MS (M+H) + =575.4

[0256] Step 4. Synthesis of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (6) To a solution of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione (140 mg, 243.58 μmol) in DMSO (1 mL) was added CsF (74.00 mg, 487.16 μmol, 17.96 μL). The mixture was stirred at 30° C. for 2.5 h. LCMS confirmed 9% of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione remaining and a peak of the desired mass (44%). The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) at 0° C. and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (50 mg, 148.65 μmol, 61.03% yield) as a yellow solid. MS (M+H) + =337.4 1 H NMR (400 MHz, CDCl3)δ=7.76(s, 1H), 6.99-6.87(m, 1H), 6.85-6.74(m, 2H), 4.77(dd, J=4.4, 7.5 Hz, 1H), 3.58(d, J=6.0 Hz, 2H), 3.44-3.33(m, 2H), 3.02-2.90(m, 1H), 2.74-2.58(m, 3H), 2.38-2.23(m, 2H), 1.91-1.78(m, 2H), 1.69-1.59(m, 1H), 1.51-1.41(m, 2H), 1.37-1.29(m, 1H).

[0257] Step 5. Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-4-carbaldehyde (7) To a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (50 mg, 148.65 μmol) in DCM (1 mL) was added DMP (75.66 mg, 178.38 μmol, 55.23 μL). The mixture was stirred at 20° C. for 2 hours. LCMS confirmed that some 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione remained. The mixture was then stirred for an additional 2 hours, and LCMS confirmed that 3-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to give 1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-4-carbaldehyde (49 mg, crude) as a yellow solid, which was used directly in the next step. MS (M+H+18). + =353.1

[0258] 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-((1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 35) To a solution of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-4-carbaldehyde (49 mg, 146.56 μmol) and 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 (76.51 mg, 131.90 μmol, HCl salt) in DCE (0.5 mL) was added NaOAc (18.03 mg, 219.84 μmol) at 20 °C. After the addition, the mixture was stirred at 20°C for 1 hour, then NaBH(OAc)3 (155.31 mg, 732.78 μmol) was added, and the resulting mixture was stirred at 20°C for 16 hours. LCMS confirmed complete consumption of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidine-4-carbaldehyde and a single peak of the desired mass (52%). Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, which was quenched at 0°C and then extracted with ethyl acetate (20 mL × 2).The combined organic phase was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, DCM:methanol=5:1) and then by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min) and purified by preparative HPLC (column: Waters Xbridge Purification using a column (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 44%–74%, 8 min) and lyophilization of the eluate gave 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)oxy)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (10.2 mg, 11.36 μmol, 7.75% yield, 96% purity) as a white solid. MS (M+H). + =862.2 1 H NMR (400 MHz, DMSO-d6) δ=10.92(s, 1H), 8.42(d, J=7.5 Hz, 1H), 8.35-8.27(m, 1H), 8.22(s, 1H), 7.88(s, 1H), 7.54-7.46(m, 2H), 6.96(t, J=9.4 Hz, 1H), 6.88(dd, J=2.7, 13.9 Hz, 1H), 6.77-6.74(m, 1H), 5.13-5.09(m 1H), 4.93-4.83(m, 1H), 4.46-4.32(m, 1H), 4.04(t, J=13.6 Hz, 2H), 3.94(s, 3H), 3.30(s, 3H), 3.21-3.18(m, 2H), 2.66-2.59(m, 2H), 2.57-2.56(m, 2H), 2.32-2. 26(m, 2H), 2.26-2.19(m, 2H), 2.19-2.08(m, 6H), 1.85-1.72(m, 4H), 1.64-1.52(m, 5H), 1.24(d, J=6.6 Hz, 8H).

[0259] Example 36. 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)oxy)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 36) [ka] Step 1. Synthesis of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenol (3) A mixture of 4-bromophenol (450 mg, 2.60 mmol), 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine (1.01 g, 2.86 mmol), DavePhos (204.73 mg, 520.21 μmol), Pd(dba) (142.91 mg, 156.06 μmol), and NaOBu-t (2 M, 3.90 mL) in dioxane (10 mL) was degassed and purged with N three times. The mixture was stirred at 100 °C under N for 16 h. LCMS confirmed 12% of 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine remained and a peak for the desired compound (54%) was observed. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) at 0 °C and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-18% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenol (650 mg, 1.40 mmol, 53.83% yield, 96% purity) as a yellow solid. MS (M+H) + =446.2

[0260] Step 2. Synthesis of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (5) To a solution of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenol (320 mg, 718.02 μmol) in THF (10 mL) was added NaH (71.80 mg, 1.80 mmol, 60% purity) at 0°C. After the addition, the mixture was stirred at 0°C for 1 h. Then, a solution of 3-bromopiperidine-2,6-dione (165.44 mg, 861.63 μmol) in THF (2 mL) was added dropwise at 0°C, and the resulting mixture was stirred at 20°C for 3 h. LCMS confirmed complete consumption of 4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenol and the desired mass. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) at 0°C and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (380 mg, 662.04 μmol, 92.20% yield, 97% purity) as a yellow solid. MS (M+H) + =557.3

[0261] Step 3. Synthesis of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (6) To a solution of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (380 mg, 682.51 μmol) in DMSO (2 mL) was added CsF (207.35 mg, 1.37 mmol, 50.33 μL). The mixture was stirred at 30° C. for 4 hours. LCMS confirmed complete consumption of 3-(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione and the desired mass. The reaction mixture was diluted with saturated aqueous ammonium chloride (10 mL) at 0° C. and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (120 mg, 376.92 μmol, 55.23% yield) as a yellow solid. MS (M+H) + =319.1

[0262] Step 4. Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (7) To a solution of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione (60 mg, 188.46 μmol) in DCM (2 mL) was added DMP (95.92 mg, 226.15 μmol, 70.02 μL). The mixture was stirred at 20° C. for 5 h. TLC (petroleum ether:ethyl acetate=0:1, Rf=0.7) confirmed complete consumption of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenoxy)piperidine-2,6-dione and the formation of a new, less polar spot. The reaction mixture was filtered, and the filtrate was concentrated to give 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (59 mg, crude) as a red solid, which was used directly in the next step without further purification. MS(M+H) + =317.4

[0263] 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-(7-((1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (compound 36) To a solution of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (59 mg, 186.50 μmol) and 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 (97.37 mg, 167.85 μmol, HCl salt) in DCE (2 mL) was added NaOAc (22.95 mg, 279.75 μmol) at 20 °C. After the addition, the mixture was stirred at 20 °C for 1 h. NaBH(OAc) (237.16 mg, 1.12 mmol) was added, and the resulting mixture was stirred at 20 °C for 16 h. TLC (dichloromethane:methanol = 5:1) confirmed that 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 remained and several new spots with lower polarity were formed. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (15 mL) at 0 °C and extracted with ethyl acetate (40 mL × 2). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, DCM:methanol=5:1) (column: Waters Xbridge Purification by chromatography (150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 38% to 68%, 9 min) and lyophilization of the eluate gave 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)oxy)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (10.0 mg, 10.90 μmol, 5.84% yield, 92% purity) as a white solid. MS (M+H) + =844.4 1 H NMR(400 MHz, DMSO-d6)δ=10.88(s, 1H), 8.42-8.40(m, 1H), 8.35-8.28(m, 1H), 8.22(s, 1H), 7.92-7.84(m, 1H), 7.56-7.45(m, 2H), 6 .99-6.78(m, 4H), 5.01-5.0(m, 1H), 4.94-4.83(m, 1H), 4.45-4.34(m, 1H), 4.10-3.99(m, 2H), 3.94(s, 3H), 3.50(d, J=12.0 Hz, 2H), 3.29(s, 3H), 2.73-2.63(m, 2H), 2.62-2.58(m, 2H), 2.32-2.24(m, 2H), 2.24-2. 18(m, 2H), 2.18-2.01(m, 6H), 1.86-1.72(m, 4H), 1.65-1.50(m, 5H), 1.30-1.13(m, 8H).

[0264] Example 37. 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-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 37) [ka] Step 1. Synthesis of 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (2) To a solution of 2-(piperidin-4-yl)ethan-1-ol (10 g, 77.40 mmol) in DCM (150 mL) was added TEA (15.66 g, 154.80 mmol, 21.55 mL) and DMAP (472.79 mg, 3.87 mmol), and tert-butyl-chloro-diphenyl-silane (31.91 g, 116.10 mmol, 29.82 mL) was slowly added, and the mixture was stirred at 20 °C for 16 h. LCMS confirmed the desired mass peak (33%). The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give the product, which was triturated with MTBE (20 mL) at 20° C. for 30 min and filtered to give 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (2.54 g, 6.56 mmol, 8.48% yield, 95%) as a white solid. MS (M+H) + =368.2

[0265] Step 2. Synthesis of 3-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (3) To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (450 mg, 981.88 μmol) in dioxane (10 mL) was added 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (360.94 mg, 981.88 μmol), CsCO (639.83 mg, 1.96 mmol), and Pd-PEPPSI-IHeptCl (47.76 mg, 49.09 μmol), and the mixture was stirred at 100 °C under N for 16 h. LCMS confirmed the desired mass peak, and the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent: 4-70% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give 3-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (730 mg, crude) as a yellow oil. MS (M+H) + =745.3

[0266] Step 3. Synthesis of 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (4) To a solution of 3-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (730 mg, 979.88 μmol) in DMSO (15 mL) was added CsF (223.27 mg, 1.47 mmol, 54.19 μL) and the mixture was stirred at 20° C. for 16 h. LCMS confirmed the desired mass, and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over sodium sulfate, filtered, concentrated in vacuo, and the crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-65% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 363.21 μmol, 37.07% yield, 92% purity) as a yellow oil. MS (M+H) + =507.3

[0267] Step 4. Synthesis of 2-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (5) To a solution of 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200 mg, 394.80 μmol) in DCM (2 mL) was added TEA (119.85 mg, 1.18 mmol, 164.85 μL), TosCl (112.90 mg, 592.19 μmol), and DMAP (4.82 mg, 39.48 μmol), and the mixture was stirred at 20° C. for 16 h. The desired mass was confirmed by LCMS, and the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL×2). The organic phase was dried over sodium sulfate, filtered, concentrated in vacuo, and the crude product was purified by flash silica gel chromatography (Biotage, 4 g SepaFlash® silica flash column, eluent 4-98% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford 2-(1-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (200 mg, 236.09 μmol, 59.80% yield, 78% purity) as a yellow oil. MS (M+H) + =661.2

[0268] Step 5. Synthesis of tert-butyl (1-(2-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6) To a solution of 2-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (200 mg, 302.67 μmol) and tert-butyl N-(4-piperidyl)carbamate (90.93 mg, 454.01 μmol) in DMF (8 mL) was added DIEA (117.35 mg, 908.02 μmol) and NaI (4.54 mg, 30.27 μmol) at 20 °C. The resulting mixture was stirred at 80 °C for 2 h. LCMS confirmed the desired mass as a major peak. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL x 3), dried over sodium sulfate and concentrated to give tert-butyl (1-(2-(1-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (210 mg, crude) as a brown solid. The crude product was used directly in the next step. MS (M+H) + =689.4

[0269] Step 6. Synthesis of 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (7) To a solution of tert-butyl (1-(2-(1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (200 mg, crude) in toluene (9 mL) was added MsOH (4.05 g, 42.14 mmol, 3 mL) and the mixture was stirred at 100° C. for 3 h. The desired mass was confirmed by LCMS, and the mixture was diluted with aqueous NaHCO3 (20 mL), extracted with ethyl acetate (20 mL x 3), and the aqueous phase was concentrated by lyophilization to give a white solid, which was triturated with THF (50 mL), stirred at 20 °C for 1 h, filtered, and the filtrate was concentrated in vacuo to give 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (48 mg, crude) as a yellow oil. MS (M+H) + =469.3

[0270] 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-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (compound 37) 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 (30 mg, 67.05 μmol) in DMF (1 mL) was treated with HATU (38.24 mg, 100.57 μmol) and DIPEA (26.0 After addition of 3-(4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (38.79 mg, crude), the mixture was stirred at 20° C. for 16 h. After confirming the major peak of the desired mass by LCMS, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 48%~78%, 8 min), lyophilized, and purified as 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8H)-isopropyl ether). -pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl)-4-piperidyl)ethyl)-4-piperidyl-3-methoxybenzamide (8.5 mg, 8.99 μmol, 13.41% yield, 95% purity) was obtained as a white powder. MS (M+H) + =898.4 1H NMR (400 MHz, DMSO-d6) δ=11.10(s, 1H), 8.32-8.24(m, 2H), 8.12(d, J=7.6 Hz, 1H), 7.97(s, 1H), 7.53-7.46(m, 2H), 7.02-6.83(m, 3H), 5.36(dd, J=5.3, 12.5 Hz, 1H), 4.77(t, J=8.3 Hz, 1H), 4.05(t, J=14.2 Hz, 2H), 3.94(s, 3H), 3.84-3.71(m, 1H), 3.63(s, 3H), 3.34(s, 3H), 3.10(d, J=9.8 Hz, 2H), 2.92(d, J=9.7 Hz, 2H), 2.74-2.60(m, 4H), 2.37-2.35(m, 2H), 2.07-1.87(m, 6H), 1.90 -1.78(m, 4H), 1.76-1.75(m, 2H), 1.68-1.52(m, 6H), 1.49-1.34(m, 5H).

[0271] 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-(7-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 38) [ka] Step 1. Synthesis of 5-oxotetrahydrofuran-2-carbonyl chloride (2) To 5-oxotetrahydrofuran-2-carboxylic acid (10 g, 76.86 mmol) was slowly added SOCl (20 mL) at 0 °C, and the mixture was stirred at 85 °C for 2 h, followed by stirring at 15 °C for 4 h. TLC (dichloromethane:methanol = 10:1) confirmed complete consumption of the starting material and the formation of one major new spot of lower polarity. The mixture was concentrated in vacuo to give 5-oxotetrahydrofuran-2-carbonyl chloride (11 g, crude) as a brown oil, which was used directly in the next step. MS (M+H) + =149.5

[0272] Step 2. Synthesis of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (3) 5-Oxotetrahydrofuran-2-carbonyl chloride (11 g, 74.05 mmol) was dissolved in dry DCM (100 mL) at 0 °C under N 2 . Then, TEA (14.99 g, 148.10 mmol, 20.61 mL) and PMBNH 2 (8.13 g, 59.24 mmol, 7.67 mL) in DCM (30 mL) were added, and the mixture was stirred at 15 °C for 3 h. LCMS confirmed the desired mass peak. HO (100 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with 0.5 M HCl (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, 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: 50-100% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (10 g, 40.12 mmol, 54.18% yield) as a yellow solid. MS (M+H) + =250.0

[0273] Step 3. Synthesis of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (4)

[0274] A solution of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (1.5 g, 6.02 mmol) in anhydrous THF (15 mL) was cooled to −78°C. Then, t-BuOK (1 M, 6.62 mL) (1 N in THF) in anhydrous THF (10 mL) was added dropwise at −78°C under nitrogen atmosphere. The resulting mixture was stirred at −40°C for 1 h. TLC (ethyl acetate) confirmed complete consumption of the starting material and the formation of two new spots. The reaction mixture was quenched by the addition of NH4Cl (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, 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: 0-60% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (900 mg, crude) as a white solid. MS (M+H) + =250.3

[0275] Step 4. Synthesis of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (5)

[0276] To a solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (500 mg, 2.01 mmol) and Py (317.44 mg, 4.01 mmol, 323.92 μL) in DCM (5 mL) was added TfO (848.84 mg, 3.01 mmol, 496.40 μL) dropwise at 0 °C. The mixture was stirred at −10 °C under N for 1.5 h. TLC (petroleum ether:ethyl acetate = 3:1) confirmed complete consumption of the starting material and the formation of one major new spot with lower polarity. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to afford 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (740 mg, 1.94 mmol, 96.74% yield) as a yellow oil. MS (M+H) + =381.3

[0277] Step 5. Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (7) To a solution of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (396.57 mg, 1.75 mmol) in THF (10 mL) was added t-BuOK (1 M, 2.33 mL). The mixture was stirred at 0 °C for 30 minutes. Then, 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (740 mg, 1.94 mmol) in THF (4 mL) was added dropwise. The resulting reaction mixture was stirred at 20 °C under N for 30 minutes. LCMS confirmed the desired mass as a major peak. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over sodium sulfate, 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: 20–100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) and repurified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (600 mg, 1.17 mmol, 60.04% yield, 89% purity) as a yellow solid. MS (M+H) + =458.0

[0278] Step 6. Synthesis of benzyl (7-((1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (9) To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (300 mg, 654.59 μmol) and benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (291.09 mg, 654.97 μmol, 2HCl) in dioxane (3 mL), Pd-PEPPSI-IHeptCl (63.68 mg, 65.46 μmol) and CsCO (1.07 g, 3.27 mmol) were added, and the mixture was stirred at 100 °C for 16 h. LCMS confirmed the desired mass peak (20%). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent: 50–100% ethyl acetate / petroleum ether to 10% methanol / ethyl acetate gradient @ 40 mL / min) and repurified by preparative TLC (SiO2, DCM:methanol = 10:1) to afford benzyl (7-((1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (70 mg, 93.47 μmol, 14.28% yield, N / A purity) as a yellow solid. MS (M+H) + =749.4

[0279] Step 7. Synthesis of 3-(4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (10) To a solution of benzyl (7-((1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (70 mg, 93.47 μmol) in TFA (0.5 mL) was added TfOH (1.19 g, 7.93 mmol, 700.01 μL) and the mixture was stirred at 100° C. for 2 h. LCMS confirmed the desired mass peak (33%). 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-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (50 mg, crude, TFA) as a brown oil, which was used directly in the next step. MS (M+H) + =495.3

[0280] 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-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-...

Claims

1. A compound represented by the following formula I, its stereoisomers, or pharmaceutically acceptable salts thereof: 【Chemistry 58】 In the formula I, ULM is a moiety represented by formula 1 below: 【Chemical Formula 59】 PTM is a moiety represented by formula 2: 【Chemistry 60】 Linker is a group that chemically links the ULM and PTM; Rx is —H or —C １－４ is alkyl; V is -NH-C(=O)-, -(CH ２ ) v-NH-, -(CH ２ ) v-N-C １－４ alkyl-, —O—, —C(═O)—, or —C(═NH)— {wherein, in V, —(CH ２ ) the N atom of v-NH- can be linked to said Rx to form a 5- or 6-membered ring, and said v is 0, 1, 2, 3, or 4; Ring U is phenyl, pyridinyl, or pyrimidinyl, wherein one or more H in the phenyl, pyridinyl, or pyrimidinyl ring is R Ｕ may be replaced by}; R Ｕ is -C １－４ Alkyl, -C １－４ Hydroxyalkyl, —C １－４ Aminoalkyl, -C １－４ Haloalkyl, —C １－４ Alkoxy, —NH ２ , —OH, or -halo {wherein Ｕ In the above V, -(CH ２ ) v-NH- to form a 5- or 6-membered ring, wherein one or more H in the 5- or 6-membered ring may be -C １－４ may be substituted with alkyl or ═O, Ｕ can be bonded to the N atom of —C(═NH)— in V to form a 5- or 6-membered ring, wherein one or more H in the 5- or 6-membered ring is —C １－４ optionally substituted with alkyl]}; Y is CR ７ and R １ is -C １－４ alkyl or 3- to 7-membered cycloalkyl; R ２ is —H; R ３ and R ４ are each independently —H, —C １－４ alkyl, or -halo; R ５ is -C １－４ is alkyl; R ６ is -C １－４ Alkyl or -C １－４ is alkoxy; R ７ is —H or -halo.

2. The ULM is a moiety represented by the following formula 1-1 or 1-2: 【Hua 61】 【Hua 62】 Rx is —H or —C １－４ is alkyl; V is -NH-C(=O)-, -(CH ２ ) v-NH-, -(CH ２ ) v-N-C １－４ alkyl-, —O—, or —C(═NH)— {wherein, in the above V, —(CH ２ ) the N atom of v-NH- can be linked to Rx to form a 5- or 6-membered ring, and v is 0, 1, or 2; U １ ~U ５ are each independently CR Ｕ or N {wherein the U １ R Ｕ In the above V, -(CH ２ ) v-NH- to form a 5- or 6-membered ring, wherein one or more H in the 5- or 6-membered ring may be -C １－４ may be substituted with alkyl or ═O, １ R Ｕ can be bonded to the N atom of —C(═NH)— in V to form a 5- or 6-membered ring, wherein one or more H in the 5- or 6-membered ring is —C １－４ optionally substituted with alkyl]}; R Ｕ is -C １－４ Alkyl, -C １－４ Haloalkyl, —NH ２ , or -halo; 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof. 【Request 3】 【Chemical 63】 【Hua 64】 R Ｕ１ and R Ｕ２ are each independently -C １－４ Alkyl, -C １－４ haloalkyl, or -halo; 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof. 【Request 4】 【Chemical 65】 R Ｕ１ and R Ｕ２ are each independently -C １－４ haloalkyl or -halo; 4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof. 【Request 5】 【Chemical 66】 R ６ is -C １－４ is alkoxy; R ７ is —H or -halo; 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

6. Linker is -L Ｕ -L １ -L ２ -L ３ -L Ｐ - and; L Ｕ is -(CH ２ ) x-, -(CH ２ )x-NH-, -(CH ２ ) x is —O—, —C(═O)—, phenyl, or null {wherein L Ｕ is connected to ULM [at this time, the L Ｕ If is null, then L １ is directly linked to the ULM, wherein x is 0, 1, 2, 3, or 4; L １ is heterocycloalkyl or null {wherein １ If is null, then L Ｕ and L ２ is directly linked, 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 Haloalkyl, —C １－４ optionally substituted with alkoxy, -OH, -halo, or ═O); L ２ is -(CH ２ ) y １ -, - (CD ２ ) y １ -, -(CH ２ ) y ２ -C(=O)-(CH ２ ) y ３ -, -(CH ２ ) y ２ -NH-(CH ２ ) y ３ - or -(CH ２ ) y ２ -N(C １－４ alkyl)-(CH ２ ) y ３ - where the y １ ~y ３ are each independently 0, 1, 2, 3, 4, 5, or 6; L ３ is cycloalkyl, heterocycloalkyl, or null {wherein ３ If is null, then L ２ and L ｐ is directly linked, and 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 optionally substituted with haloalkyl, or -halo; L Ｐ is -(CH ２ ) p-NH-C(=O)- or -(CH ２ ) p-O- {wherein Ｐ -(C=O)- or -O- is linked to PTM, and p is 0, 1, or 2; 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

7. L Ｕ is -(CH ２ )x- or -(CH ２ ) x-NH- {wherein L Ｕ is linked to a ULM, and said x is 0 or 1; L １ is a 4- to 12-membered heterocycloalkyl or null {wherein the L １ If is null, then L Ｕ and L ２ is directly linked, and the 4- to 12-membered heterocycloalkyl is a monocyclic, bridged bicyclic, or spirocyclic ring, and the 4- to 12-membered heterocycloalkyl contains one or more N atoms in the ring, and the N atoms are not bonded to L Ｕ or directly linked to ULM, wherein one or more H in said 4- to 12-membered heterocycloalkyl ring is -C １－４ optionally substituted with alkyl, -OH, or -halo); L ２ is -(CH ２ ) y １ -, -(CH ２ ) y ２ -C(=O)-(CH ２ ) y ３ -, -(CH ２ ) y ２ -NH-(CH ２ ) y ３ - or -(CH ２ ) y ２ -N(C １－４ alkyl)-(CH ２ ) y ３ - where the y １ ~y ３ are each independently 0, 1, 2, or 3; L ３ 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 Alkyl, -C １－４ optionally substituted with haloalkyl, or -halo; L Ｐ is -(CH ２ ) p-NH-C(=O)- {wherein Ｐ -(C=O)- is linked to PTM, and p is 0 or 1; 7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from the group consisting of the following compounds: 【Table 6】 。

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

10. A pharmaceutical composition for preventing or treating a PLK1-associated disease, comprising the compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10, wherein the PLK1-associated disease is one or more selected from the group consisting of cancer, benign tumor, and neurological disease.

12. The cancer or benign tumor may be squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, skin cancer, cutaneous or intraocular melanoma, rectal cancer, perianal adenocarcinoma, esophageal cancer, small intestine cancer, endocrine gland cancer, parathyroid cancer, adrenal gland 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, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer. , thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, Barrett's esophagus, colon adenoma and polyp, breast fibroadenoma and cyst, monoclonal gammopathy of undetermined significance (MGUS), monoclonal lymphocytosis, solid cancer, blood cancer, bone cancer, large cell lymphoma, adrenocortical tumor, T-cell lymphoma / leukemia, neuroendocrine cancer, neuroendocrine tumor, cholangiocarcinoma, neuroblastoma, glioblastoma, and glioma.

13. 12. The pharmaceutical composition according to claim 11, wherein the neurological disease is one or more selected from the group consisting of 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 axon degeneration due to brain or spinal cord injury.

14. A method for treating or preventing a PLK1-associated disease, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 8, its stereoisomer, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

15. The method for treating or preventing a PLK1-associated disease according to claim 14, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof induces degradation of PLK1 protein.

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

17. 10. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment or prevention of a PLK1-related disease.

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