Novel PLK1 degradation-inducing compounds

Abstract

The invention relates to a novel PLK1 degradation inducing compound, and a preparation method and application thereof. The compound disclosed by the invention has an effect of inducing PLK1 degradation. Therefore, the compound disclosed by the invention can be used for effectively preventing or treating PLK1 related diseases.

Description

Technical Field

[0001] The present disclosure relates to a novel PLK1 degradation-inducing compound, as well as its preparation method and use. The compound can specifically act on abnormal cells and the like, and can treat various diseases by effectively degrading PLK1. Background Art

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

[0003] PLK1 is overexpressed in various cancers, such as colon cancer, lung cancer, bladder cancer, and melanoma, and cancer cells that overexpress PLK1 often show resistance to various types of anticancer drugs. Due to the PLK1 dependency revealed in various cancers as described above, efforts have been made to develop PLK1 inhibitor compounds, such as volasertib (also known as BI6727).

[0004] However, conventional PLK1 inhibitors do not sufficiently inhibit PLK1 activity at clinically safe concentrations. Consequently, there is a problem: even if the cell cycle of cancer cells is temporarily delayed, some cancer cells eventually restart their cell cycle, which may prevent the expected clinical effect (see Gheghiani et al., Cell Reports, 2017, 19: 2060, etc.). In fact, many pharmaceutical companies, such as Boehringer Ingelheim and GlaxoSmithKline, have attempted to develop PLK1 inhibitors based on small molecule compounds, but most of these have failed or been discontinued during clinical trials. As a result, there are no commercially available PLK1 inhibitors to date. This suggests that pharmacological mechanisms that inhibit enzyme activity by binding to the active site of PLK1 (such as small molecule compound inhibitors) are not effective enough in the development of new drugs designed to produce anticancer effects by inhibiting PLK1 activity in cancer cells.

[0005] Recently, it has been proposed to use proteolysis targeting chimeras (PROTACs) as a small molecule-based platform technology that can induce proteolysis of target proteins in vivo. PROTAC is a bifunctional compound in which the ligand molecule and the E3 ubiquitin ligase binding portion of the disease-related target protein are connected by a chemical linker. In theory, PROTAC compounds can induce the degradation of the target protein by placing the target protein related to the disease near the E3 ubiquitin ligase. Based on this new mechanism different from existing inhibitors, many PROTAC compounds have been developed as therapeutic agents for cancer and inflammatory diseases, and various scalability studies are underway (for example, as an effective load for ADC (antibody-drug conjugates)). However, the compound does not show activity in all binding moieties or linkers, and in order to make PROTAC show the desired level of efficacy, it is known that each binding moiety and linker must have a properly connected structure (see US2020-0325130A) through several studies. In particular, in the case of CRBN (Cereblon) E3 ligase targeting moieties, depending on the type of binding moiety or the structure of the compound attached thereto, there is a risk of degrading CRBN neosubstrates (GSPT1, IKZF1 / 3, etc.) or correspondingly exhibiting off-target toxicity. Therefore, it is important to select an appropriate binding moiety and optimize the structure of the entire compound so that unexpected toxicities are not exhibited during PROTAC drug development.

[0006] In the case of PROTAC compounds using PLK1 as a target protein, Chinese Patent Publication No. 106543185A discloses some bifunctional compounds in which a volasertib derivative compound and a binding moiety for the E3 ubiquitin ligase CRBN are connected by a chemical linker. However, the relevant technical literature only describes some limited forms of synthetic examples of PROTAC compounds. In general, the target degradation activity and selectivity of PROTACs can vary significantly depending on the choice of target protein moiety, E3 ubiquitin ligase binding moiety, etc. (see Burslem and Crews, Chemical Reviews, 2017, 117(17): 11269, etc.).

[0007] In addition, the PROTAC compounds described in the above-mentioned documents are characterized by being compounds that degrade PLK1 and BRD4 simultaneously, and degrade various proteins (e.g., other PLK family proteins and BRD4, etc.). This compound may cause side effects due to off-target toxicity during drug development. In particular, it is known that strong inhibition of BRD4 activity is inevitably accompanied by target toxicity such as hematotoxicity and gastrointestinal toxicity as well as pharmacological effects. Therefore, when more BRD4 protein is degraded, the PROTAC compounds described in the above-mentioned documents will be expected to face greater clinical side effects (see Bolden et al., Cell Reports, 2014, 8(6): 1919).

[0008] In addition, according to the literature published by the inventors of the above-mentioned literature (see Mu et al., BBRC, 2020, 521(4): 833), it can be confirmed that the PROTAC compound that degrades PLK1 and BRD4 simultaneously has a BRD4 degradation ability that is much stronger than PLK1 degradation ability at the cellular level, and its cell cycle is almost arrested in the G1 phase, etc. That is, regardless of how conventional PLK1 inhibitors exert their pharmacological effects, PROTAC compounds actually only act as BRD4 inhibitors.

[0009] Therefore, there is a need for an effective PLK1 degradation-inducing compound with no or minimal side effects (e.g., off-target toxicity). Summary of the Invention

[0010] Technical Problems to be Solved by the Invention

[0011] An object of the present disclosure is to provide novel PLK1 degradation-inducing compounds.

[0012] Another object of the present disclosure is to provide a method for preparing the compound.

[0013] Yet another object of the present disclosure is to provide uses of the compounds.

[0014] Technical Solution

[0015] To achieve the above objectives, the present inventors have conducted diligent research and found that the novel PROTAC compound of the present invention specifically acts on abnormal cells overexpressing PLK1 through appropriate structural combination and optimization of the E3 ligase binder, target binding portion and linker to induce efficient PLK1 degradation and minimize side effects, thereby completing the present invention.

[0016] Selective PLK1 degradation-inducing compounds

[0017] The present disclosure provides novel compounds that induce efficient degradation of polo-like kinase 1 (PLK1). Specifically, the present disclosure provides a bifunctional compound in which a PLK1 binding moiety and an E3 ubiquitin ligase binding moiety are linked by a chemical linker.

[0018] One embodiment of the present invention relates to a compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0019] [Chemical Formula I]

[0020] ULM-Connector-PTM

[0021] In the chemical formula I,

[0022] ULM is a moiety represented by the following Chemical Formula 1:

[0023] [Chemical Formula 1]

[0024]

[0025] The PTM is a moiety represented by the following chemical formula 2:

[0026] [Chemical Formula 2]

[0027]

[0028] Linker is a group that chemically connects ULM and PTM;

[0029] X is CH or N;

[0030] V is -NR V - or single key;

[0031] R V is -H or -CH3;

[0032] Ring U is phenyl or 5-membered to 6-membered heteroaryl {wherein one or more H on the phenyl or 5-membered to 6-membered heteroaryl ring can be replaced by R U replace};

[0033] R U -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -C 1-3 aminoalkyl, -C 1-3 Haloalkyl, -C 1-3 Alkoxy, -CN or -halo;

[0034] Y1 is CR Y or N;

[0035] Y2 to Y4 are each independently CRY ;

[0036] R Y -H, -C 1-3 Alkyl, -C 1-3 Alkoxy or -halo;

[0037] R1 is -C 1-4 Alkyl or 5-membered to 6-membered cycloalkyl;

[0038] R2 and R3 are each independently -H, -C 1-3 Alkyl or -halo;

[0039] R4 is -C 1-3 alkyl.

[0040] In one embodiment of the present invention,

[0041] ULM is a moiety represented by the following Chemical Formula 1-1, Chemical Formula 1-2, or Chemical Formula 1-3;

[0042] [Chemical Formula 1-1]

[0043]

[0044] [Chemical formula 1-2]

[0045]

[0046] [Chemical formula 1-3]

[0047]

[0048] R V is -H or -CH3;

[0049] Ring U is phenyl or pyridyl {wherein one or more H on the phenyl or pyridyl ring can be replaced by R U replace};

[0050] R U -C 1-3 Alkyl, -C 1-3 Alkoxy, -CN or -halo.

[0051] In one embodiment of the present invention,

[0052] ULM is:

[0053]

[0054]

[0055] R U1 and R U2Each independently is -C 1-3 Alkyl, -C 1-3 In one embodiment of the present invention,

[0056] ULM is:

[0057]

[0058]

[0059] R U1 and R U2 Each independently is -C 1-3 Alkyl, -C 1-3 Alkoxy, -CN or -halo.

[0060] In one embodiment,

[0061] PTM is

[0062] Y1 is CR Y or N;

[0063] Y2 to Y4 are each independently CR Y ;

[0064] R Y -H, -C 1-3 Alkoxy or -halo;

[0065] R1 is -C 1-4 Preferably, R1 can be methyl, ethyl, isopropyl or cyclopentyl, but is not limited thereto.

[0066] In one embodiment of the present invention,

[0067] Linker is -L U -L1-L2-L P -;

[0068] L U is a heterocycloalkyl group {wherein the heterocycloalkyl group contains one or more N atoms on the ring, and one or more H atoms on the heterocycloalkyl group can be replaced by -C 1-4 Alkyl, -C 1-4 alkoxy or -halo substituted};

[0069] L1 is -(CH2) X1 -、-(CH2) X2 -NH-(CH2) X3 -、-(CH2) X2 -N(C 1-4 alkyl)-(CH2)X3 - or a single bond {wherein, each of X1 to X3 is independently 0, 1, 2, 3 or 4};

[0070] L2 is a cycloalkyl or heterocycloalkyl group {wherein the heterocycloalkyl group contains one or more nitrogen atoms on the ring, and one or more hydrogen atoms on the cycloalkyl or heterocycloalkyl ring can be replaced by -C 1-4 Alkyl, -C 1-4 alkoxy or -halo substituted};

[0071] L P It is -NH-C(=O)- or -(CH2)p-heteroaryl {wherein, the -C(=O)- of the -NH-C(=O)- or the -(CH2)p-heteroaryl is connected to PTM, the heteroaryl contains N and O atoms in the ring, and p is 0, 1, 2 or 3}.

[0072] In one embodiment of the present invention,

[0073] L U is a 4- to 12-membered heterocycloalkyl group {wherein the 4- to 12-membered heterocycloalkyl group is a monocyclic, bridged bicyclic or spirocyclic ring, the 4- to 12-membered heterocycloalkyl group contains one or more N atoms on the ring, the N atoms are directly connected to the ULM, and one or more H atoms on the 4- to 12-membered heterocycloalkyl ring can be replaced by -C 1-4 alkyl or -halo substituted};

[0074] L1 is -(CH2) X1 -、-(CH2) X2 -N(C 1-4 alkyl)-(CH2) X3 - or a single bond {wherein, each of X1 to X3 is independently 0, 1, 2 or 3};

[0075] L2 is a 4-membered to 6-membered cycloalkyl group or a 4-membered to 12-membered heterocycloalkyl group {wherein the 4-membered to 12-membered heterocycloalkyl group is a monocyclic, bridged bicyclic or spirocyclic ring, the 4-membered to 12-membered heterocycloalkyl group contains one or more nitrogen atoms on the ring, and one or more hydrogen atoms on the 4-membered to 6-membered cycloalkyl group or the 4-membered to 12-membered heterocycloalkyl ring can be replaced by -C 1-4 alkyl or -halo substituted};

[0076] L P It is -NH-C(=O)- or -(CH2)p-1,3,4-oxadiazole {wherein, the -C(=O)- of the -NH-C(=O)- or the 1,3,4-oxadiazole of the -(CH2)p-1,3,4-oxadiazole is connected to PTM, and the p is 0 or 1}.

[0077] Preferably, L U Can be L2 can be But it’s not limited to this.

[0078] In an embodiment of the present disclosure, the compound represented by Chemical Formula I is selected from the group consisting of compounds 1 to 77.

[0079] In the present disclosure, a pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt having a relatively non-toxic, harmless and effective concentration for a patient, wherein the side effects caused by the salt do not impair the beneficial effects of the compound represented by Chemical Formula I. For example, a pharmaceutically acceptable salt may be an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, or the like, or an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, but is not limited thereto.

[0080] Use of selective PLK1 degradation-inducing compounds

[0081] One embodiment of the present disclosure is a composition for inducing PLK1 degradation, comprising a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof. Chemical Formula I is the same as defined above.

[0082] In the experimental examples of the present disclosure, it was confirmed that the compounds of the present disclosure can effectively induce protein degradation of PLK1.

[0083] In view of the mechanism of action, the PLK1 degradation-inducing PROTAC compounds disclosed herein are able to fundamentally degrade the target protein PLK1, thereby achieving excellent PLK1 inhibition compared to conventional PLK1 small molecule inhibitors that simply inhibit the activity of PLK1.

[0084] Therefore, the composition comprising the compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof of the present disclosure can be effectively used to selectively degrade PLK1.

[0085] One embodiment of the present disclosure is a composition for preventing or treating a PLK1-related disease, comprising a compound represented by Formula I or a pharmaceutically acceptable salt thereof. Another embodiment of the present disclosure is a method for preventing or treating a PLK1-related disease, comprising administering the composition to a subject in need thereof. Formula I is as defined above.

[0086] In the present disclosure, a PLK1-related disease refers to any disease or condition that can be treated, alleviated, delayed, inhibited, or prevented by inducing PLK1 degradation or inhibiting PLK1 activity. In one embodiment, the PLK1-related disease can be cancer (malignant tumor), benign tumor, neurological disease, or other genetic or non-genetic disease caused by excessive cell division.

[0087] Cancer includes all cancers that can exhibit preventive or therapeutic efficacy due to inhibition of PLK1 activity, and can be solid cancers or blood cancers. For example, the cancer can be one or more selected from the following groups: squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, anal muscle cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian ... The term "cancer" includes, but is not limited to, ovarian cancer, liver cancer, bladder cancer, liver tumors, breast cancer, colon cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, solid tumors, blood cancer, bone cancer, large cell lymphoma, adrenocorticoid tumors, T-cell lymphoma / leukemia, neuroendocrine cancer, neuroendocrine tumors, bile duct cancer, neuroblastoma, glioblastoma, glioma, etc. Cancer includes not only primary cancers but also metastatic cancers.

[0088] Benign tumors include all benign tumors for which inhibition of PLK1 activity can exhibit preventive or therapeutic efficacy, for example, benign tumors in the precancerous stage, and may be solid tumors or hematological tumors. For example, the tumor may be one or more selected from Barrett's esophagus, colon adenomas and polyps, breast fibroadenomas and cysts, monoclonal gammopathy of undetermined significance (MGUS), monoclonal lymphocytosis, etc., but is not limited thereto.

[0089] Neurological diseases include all neurological diseases that can exhibit preventive or therapeutic efficacy due to the inhibition of PLK1 activity, and specifically, can be one or more selected from the following group, which consists of the following items: central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, leukemia, stroke, and neural damage and axonal degeneration-related disorders after brain or spinal cord injury, but is not limited thereto.

[0090] In addition to the compound represented by the above Chemical Formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present disclosure may further comprise one or more active ingredients that exhibit the same or similar medical effects.

[0091] One embodiment of the present disclosure describes a method for degrading PLK1 by administering a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof to mammals including humans.

[0092] Another embodiment of the present disclosure describes a method for degrading PLK1 by administering a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof to an in vitro sample. The sample can be a cell, cell culture, body fluid or tissue of a mammal including a human, but is not limited thereto.

[0093] Effects of the Invention

[0094] The compounds disclosed herein have the effect of inducing PLK1 degradation. Therefore, the compounds disclosed herein can effectively prevent or treat PLK1-related diseases. DETAILED DESCRIPTION

[0095] Unless defined otherwise, 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 terminology used herein is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0096] The present disclosure provides methods for synthesizing compounds 1 to 77 shown in the following table.

[0097] Table 1

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] The compounds of the present disclosure were purified and their structures analyzed according to the following methods.

[0113] instrument

[0114] LCMS: Shimadzu LCMS-2020, Agilent 1200 / G6110A, Agilent1200 / G1956A

[0115] HPLC: Agilent 1260II LC, Agilent1200 / G6410B

[0116] NMR:BRUKER AVANCE III / 400MHz

[0117] LCMS analysis

[0118] LCMS data were recorded using a Shimadzu LCMS-2020 or Agilent 1200 / G6110A or Agilent 1200 / G1956A equipped with an ESI (electrospray ionization) device. 0.0375% TFA / water (solvent A) and 0.01875% TFA / ACN (solvent B) or 0.025% NH3·H2O / water (solvent A) and ACN (solvent B) were used as mobile phases. Kinetex EVO C18 (2.1×30 mm, 5 μm) or HALO C18 were used.

[0119] (3.0×30 mm, 2.7 μm) as columns.

[0120] HPLC analysis

[0121] In HPLC analysis, Agilent 1260II LC or Agilent

[0122] 1200 / G6410B. 0.0375% TFA in water (solvent A) and 0.01875% TFA in ACN (solvent B) were used as mobile phases. Zobrax Eclipse Plus C18 (4.6×150 mm, 3.5 μm) or YMC ODS A (4.6×150 mm, 3 μm) columns were used.

[0123] NMR analysis

[0124] Recorded using a Bruker AVANCE III 400MHz / 5mm probe (BBO) 1 H NMR spectrum.

[0125] Example 1. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 1)

[0126]

[0127] Step 1. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (3)

[0128] To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (1.9 g, 5.13 mmol) and 3-hydroxyphenylboronic acid (920.17 mg, 6.67 mmol) in dioxane (20 mL) and H2O (5 mL) was added Pd(PPh3)4 (296.51 mg, 256.59 μmol) and K2CO3 (2.13 g, 15.40 mmol). The resulting mixture was stirred for 2 hours under N2 and 100°C. By LCMS, it was confirmed that the starting material was completely consumed and the peak of the desired mass (59%) was confirmed. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed using a silica gel flash column with a 0-12% EtOAc / petroleum ether gradient at 100 mL / min to obtain 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (2 g, 5.11 mmol, 99.61% yield, 98% purity) as a yellow oil. MS (M+H) + =384.3.

[0129] Step 2. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (4)

[0130] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (1 g, 2.61 mmol) in DCM (20 mL) was added TEA (1.06 g, 10.43 mmol, 1.45 mL) and Tf2O (1.38 g, 4.88 mmol, 804.66 μL) at 0°C. The resulting mixture was stirred for 12 hours at 20°C. By LCMS, complete consumption of the starting material was confirmed, and the peak of the desired mass (87%) was confirmed. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed using a silica gel flash column with a 0-1% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (448 mg, 842.99 μmol, 32.32% yield, 97% purity) as a colorless oil. MS (M+H) + =516.1.

[0131] Step 3. Synthesis of tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (6)

[0132] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl trifluoromethanesulfonate (395 mg, 766.25 μmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (208.10 mg, 919.50 μmol) in dioxane (6 mL) were added BINAP (47.71 mg, 76.62 μmol), Pd(OAc)2 (17.20 mg, 76.62 μmol) and Cs2CO3 (748.97 mg, 2.30 mmol). The resulting mixture was stirred under N2 and 100°C for 12 hours. By LCMS, it was confirmed that the starting material was completely consumed and the peak of the desired mass (54%) was confirmed. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (10 g of Purification was performed using a silica gel flash column with a 0-15% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (396 mg, 669.22 μmol, 87.34% yield) as a yellow oil. MS (M+H) + =592.3.

[0133] Step 4. Synthesis of tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (7)

[0134] To a solution of tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (396 mg, 669.22 μmol) in CF3CH2OH (10 mL) was added Pd / C (0.1 g, 10% purity) and TFA (76.31 mg, 669.22 μmol, 49.71 μL). The suspension was degassed and purged with H2 three times. The resulting mixture was stirred for 12 hours under H2 (15 Psi) and 20°C. By LCMS, complete consumption of the starting material was confirmed, and a peak of the desired mass was confirmed. The reaction mixture was diluted with CF3CH2OH (30 mL) and filtered, and the filtrate was adjusted to pH = 7 using DIPEA. The resulting mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (12 g of Purification was performed using a silica gel flash column with a 0-80% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (76 mg, 167.25 μmol, 24.99% yield, 91% purity) as a yellow oil. MS (M+H) + =414.4.

[0135] Step 5. Synthesis of 3-(3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (8)

[0136] To a solution of tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate in dioxane (1 mL) was added HCl / dioxane (4 M, 2 mL). The resulting mixture was stirred at 20°C for 1 hour. LCMS confirmed complete consumption of the starting material and confirmed the presence of a major peak of the desired mass. The reaction mixture was concentrated in vacuo to afford 3-(3-(2,7-diazaspiro[3.5]nonane-7-yl)phenyl)piperidine-2,6-dione (65 mg, crude product, HCl salt) as a white solid. MS (M+H) + =314.3.

[0137] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 1)

[0138] To a solution of 3-(3-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (61.79 mg, 176.61 μmol, HCl salt) in DCM (4 mL) were added TEA (44.68 mg, 441.53 μmol, 61.46 μL), 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(4-oxopiperidin-1-yl)benzamide (80 mg, 147.18 μmol), and 4A MS (50 mg). The mixture was stirred at 20° C. for 0.5 h. NaBH(OAc)3 (93.58 mg, 441.53 μmol) was slowly added to the reaction mixture. The resulting mixture was stirred at 20°C for 12 hours. By LCMS, it was confirmed that the starting material was completely consumed and the peak of the required mass (63%) was confirmed. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (SiO2, DCM:MeOH=10:1) to obtain a crude product. The crude product was dissolved in a mixed solution (20 mL, ACN:H2O=1:3). The eluate was lyophilized to obtain a residue (51 mg, 93% purity). The residue was purified again by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 8 minutes). The eluate was lyophilized to obtain 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(7-(3-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-3-methoxybenzamide (15.3 mg, 17.28 μmol, yield 11.74%, purity 95%) as a white solid. MS (M+H) + =841.4.

[0139] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.32 (s, 1H), 8.31-8.20 (m, 2H), 7.95 (s,1H),7.49-7.37(m,2H),7.13(t,J=7.8Hz,1H),6.86-6.76(m,2H),6.58(d, J=7.6Hz,1H),4.83-4.70(m,1H),4.11-3.98(m,2H),3.92(s,3H),3.75(dd,J= 4.8,11.2Hz,1H),3.33(s,3H),3.12-3.03(m,4H),3.02-2.88(m,6H),2.79(br t,J=8.9Hz,2H),2.72-2.59(m,1H),2.48-2.42(m,1H),2.25-2.15(m,1H),2.15-2.06(m,1H),2.04-2.01 (m,1H),1.98-1.88(m,2H),1.85-1.74(m,4H),1.73-1.64(m,4H),1.60-1.56(m,4H),1.37-1.22(m,2H).

[0140] Example 2. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 2)

[0141]

[0142] Step 1. Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (2)

[0143] In a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (15 g, 80.98 mmol) in THF (50 mL), LiHMDS (1 M, 97.18 mL) was added at -70 ° C. After 0.5 hours, PhNTf2 (31.83 g, 89.08 mmol) in THF (50 mL) was added dropwise at -70 ° C. The resulting mixture was stirred for 2 hours at -70 ° C. By TLC (petroleum ether: EtOAc = 5: 1), the formation of multiple new spots was confirmed. The reaction mixture was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with saturated brine (150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (30 g, crude product) as a yellow oil. MS (Mt-Bu+H) + =261.7.

[0144] Step 2. Synthesis of tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4)

[0145] The product was synthesized by a method similar to that described in Step 1 of Example 1, and tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4 g, 4.38 mmol, 9.27% ​​yield, 27% purity) was obtained as a yellow oil. MS (M+H) + =247.1.

[0146] Step 3. Synthesis of tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (5)

[0147] To a solution of tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate in MeOH (30 mL) was added PtO2 (300 mg, 1.32 mmol) under N2 conditions. The mixture was stirred for 12 hours under H2 (50 psi) and 50°C. By LCMS, it was confirmed that tert-butyl 3-(pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was completely consumed, and ~30% of the intermediate state (m / z=249.2) was detected. AcOH (3.15 g, 52.45 mmol, 3 mL) was added to the mixture. Under H2 (50 psi) and 50°C conditions, the mixture was stirred for 12 hours. By LCMS, the main peak of the desired mass was confirmed. The catalyst was removed by filtering the mixture. The filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in water (50 mL). The mixture was adjusted to pH = 8 with saturated NaHCO3 solution and extracted with EtOAc (50 mL x 8). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (4 g, crude product) as a yellow oil. MS (M+H) + =255.1.

[0148] Step 4. Synthesis of benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)piperidine-1-carboxylate (6)

[0149] To a solution of tert-butyl 3-(piperidin-4-yl)pyrrolidine-1-carboxylate (3.5 g, 13.76 mmol) in THF (10 mL) and H2O (10 mL) was added K2CO3 (3.80 g, 27.52 mmol) and CbzCl (2.35 g, 13.76 mmol, 1.96 mL). The mixture was stirred for 2 hours at 25 ° C. The main peak of the desired mass was confirmed by LCMS. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g Purification was performed using a silica gel flash column with a 0-20% petroleum ether:EtOAc gradient at 80 mL / min as the eluent to afford benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)piperidine-1-carboxylate (2.8 g, 7.21 mmol, 52.38% yield) as a yellow oil. MS (M-Boc+H) + =289.2.

[0150] Step 5. Synthesis of benzyl 4-(pyrrolidin-3-yl)piperidine-1-carboxylate (7)

[0151] Synthesized by a method similar to that described in Step 5 of Example 1, benzyl 4-(pyrrolidin-3-yl)piperidine-1-carboxylate (1.3 g, 3.64 mmol, 50.53% yield, 91% purity, HCl salt) was obtained as a gray solid. MS (M+H) + =288.9.

[0152] Step 6. Synthesis of benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidine-1-carboxylate (9)

[0153] By a method similar to that described in Step 3 of Example 1, Pd(OAc)2 and BINAP were replaced with Pd2(dba)3 (56.38 mg, 61.57 μmol) and RuPhos (28.73 mg, 61.57 μmol) to obtain benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidine-1-carboxylate (0.6 g, 844.00 μmol, 27.42% yield, 94.5% purity) as a yellow oil. MS (M+H) + =672.5.

[0154] Step 7. Synthesis of 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (10)

[0155] 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (420 mg, crude product) was synthesized by a method similar to that described in Step 4 of Example 1 as a yellow oil. MS (M+H) + =360.2.

[0156] Step 8. Synthesis of 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (11)

[0157] To a solution of 3-(3-fluoro-4-(3-(piperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (320 mg, 890.28 μmol) in THF (15 mL) were added t-BuONO (183.61 mg, 1.78 mmol, 211.78 μL) and TEA (315.30 mg, 3.12 mmol, 433.71 μL). The mixture was stirred at 60° C. for 12 hours. LCMS confirmed the desired mass of ~54%. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 20g Purification was performed on a silica gel flash column with a 0-70% petroleum ether:EtOAc gradient @ 80 mL / well to afford 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (130 mg, 314.93 μmol, 35.37% yield, 94.1% purity) as a yellow solid. MS (M+H) + =388.9.

[0158] Step 9. Synthesis of 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (12)

[0159] To a solution of 3-(3-fluoro-4-(3-(1-nitrosopiperidin-4-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (130 mg, 334.68 μmol) in THF (8 mL) were added Zn (109.42 mg, 1.67 mmol) and a solution of NHCl (53.71 mg, 1.00 mmol) in H₂O (2 mL) at 0°C. The mixture was stirred at 25°C for 12 hours. LCMS confirmed a desired mass of ~85%. The mixture was filtered to remove solids. The filter cake was washed with THF (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 0% to 25%, 10 min). The eluate was lyophilized to obtain 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (70 mg, 186.94 μmol, 55.86% yield, 100% purity) as a white solid. MS (M+H) + =375.0.

[0160] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (Compound 2)

[0161] To a solution of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (78.78 mg, 186.94 μmol) in DMF (5 mL) was added DIPEA (72.48 mg, 560.82 μmol, 97.68 μL) and HATU (85.30 mg, 224.33 μmol). After 0.5 hours, 3-(4-(3-(1-aminopiperidin-4-yl)pyrrolidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (70 mg, 186.94 μmol) was added. The resulting mixture was stirred at 25°C for 1 hour. LCMS confirmed the desired mass to be approximately 32%. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g The crude product was purified by silica gel flash column (eluent: 0-100% petroleum ether:EtOAc gradient @ 80 mL / min) to obtain the crude product. The crude product was purified by prep-HPLC (column: Waters xbridge 150×25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%-62%, 11 minutes) and further purified by prep-TLC (DCM:MeOH = 10:1). The eluate was lyophilized to obtain 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)pyrrolidin-3-yl)piperidin-1-yl)-3-methoxybenzamide (15.7 mg, 19.35 μmol, yield: 10.35%, purity: 99.0%) as a white solid. MS (M+H) + =778.3.

[0162] 1H NMR (400MHz, DMSO-d6) δ=10.83-10.69(m,1H),9.27(s,1H),8.30(d,J=8.1Hz,1H),8.22(s,1H),7.87(s,1H),7.49-7.38(m,2H) ,6.93(d,J=15.4Hz,1H),6.85(d,J=8.4Hz,1H),6.68(t,J=8.9Hz,1H),4.90-4.87(m,1H),4.03(t,J=13.6Hz,2H),3.93(s,3H), 3.73(dd,J=4.9,11.6Hz,1H),3.51-3.35(m,6H),3.11-2.99(m,3H),2.75(t,J=11.1Hz,2H),2.68-2.59(m,1H),2.48-2.41(m,1 H),2.22-2.11(m,1H),2.10-1.92(m,3H),1.84-1.67(m,2H),1.65-1.51(m,1H),1.50-1.27(m,3H),1.25-1.23(m,J=6.6Hz,6H).

[0163] Example 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (Compound 3)

[0164]

[0165] Step 1. Synthesis of benzyl 3-(4-((tert-Butyloxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (3)

[0166] To a solution of benzyl 3-oxoazetidine-1-carboxylate (10 g, 48.73 mmol) and tert-butyl piperidin-4-ylcarbamate (9.76 g, 48.73 mmol) in MeOH (100 mL) was added AcOH (292.64 mg, 4.87 mmol, 278.97 μL). After the mixture was stirred at 20 ° C for 0.5 hours, NaBH3CN (4.59 g, 73.10 mmol) was added and the resulting mixture was stirred at 20 ° C for 16 hours. The required mass was detected by LCMS. The mixture was concentrated under reduced pressure, and the crude product was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with NaHCO3 (20 mL×2), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash silica gel chromatography ( 120g Purification was performed using a silica gel flash column with a gradient of 0-60% EtOAc / petroleum ether at 100 mL / min to obtain two batches. Batch 1: benzyl 3-(4-((tert-butyloxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (3.64 g, 9.35 mmol, 19.18% yield) as a white solid. Batch 2: product containing impurities, which was purified by MPLC (0.1% FA conditions; 330 g flash column; TELEDYNE ISCO CombiFlash RF 150 Welch Ultimate XB_C 18 20-40 μm; 120A; 4 g of the sample was dissolved in 10 mL of DMF (solvent; eluent: 5-50% ACN / H2O gradient @ 100 mL / min over 35 minutes, 50% ACN / H2O gradient @ 100 mL / min over 10 minutes). The eluate was lyophilized to obtain benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (2.4 g, 6.16 mmol, 12.64% yield) as a white solid. MS (M+H) + =390.3.

[0167] Step 2. Synthesis of tert-butyl (1-(azetidin-3-yl)piperidin-4-yl)carbamate (4)

[0168] To a solution of benzyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)azetidine-1-carboxylate (6.44 g, 16.53 mmol) and AcOH (496.47 mg, 8.27 mmol, 473.28 μL) in EtOH (70 mL), Pd / C (600 mg, 10% purity) and Pd(OH)2 / C (600 mg, 20% purity) were added under N2 atmosphere. The suspension was degassed and purged with H2 three times and stirred for 16 hours under H2 (15 Psi) and 20°C. LCMS confirmed complete consumption of the starting material. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (1-(azetidine-3-yl)piperidin-4-yl)carbamate (5.6 g, crude product) as a white solid, which was used directly. MS (M+H) + =256.2.

[0169] Step 3. Synthesis of tert-butyl (1-(1-(4-bromo-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (6)

[0170] By a method similar to that described in Step 6 of Example 2, RuPhos was replaced with Xantphos (91.73 mg, 158.53 μmol) to obtain tert-butyl (1-(1-(4-bromo-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (540 mg, 1.26 mmol, 79.53% yield) as a yellow solid. MS (M+H) + =428.1.

[0171] Step 4. Synthesis of tert-butyl (1-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (8)

[0172] By a method similar to that described in Step 1 of Example 1, replacing Pd(PPh3)4 with Pd(dppf)Cl2 (68.33 mg, 93.38 μmol), synthesis was performed to obtain tert-butyl (1-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (586 mg, 917.39 μmol, 98.24% yield) as a yellow solid. MS (M+H) + =639.4.

[0173] Step 5. Synthesis of tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (9)

[0174] A similar method to that described in Step 4 of Example 1 was used to synthesize the product by adding THF to obtain tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (680 mg, crude product) as a brown oil, which was used directly. MS (M+H) + =461.2.

[0175] Step 6. Synthesis of 3-(4-(3-(4-aminopiperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (10)

[0176] A mixture of tert-butyl (1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)carbamate (340 mg, 738.26 μmol) and TFA (1 mL) in DCM (3 mL) was stirred at 20°C for 1 hour. Complete consumption of the starting material was confirmed by LCMS, with 95% of the desired mass detected. The mixture was concentrated in vacuo to give 3-(4-(3-(4-aminopiperidin-1-yl)azetidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (360 mg, TFA salt) as a brown gum, which was used directly. MS (M+H) + =361.2.

[0177] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (Compound 3)

[0178] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)azetidin-3-yl)piperidin-4-yl)-3-methoxybenzamide (211.5 mg, 204.71 μmol, 47.92% yield, 96% purity, 2TFA salt) was synthesized as a white solid. MS (M+H) + =764.3.

[0179] 1H NMR (400MHz, CD3OD) δ = 8.16 (d, J = 8.3Hz, 1H), 8.13 (s, 1H), 7.65-7.49 (m, 2H), 6.98 (s, 1H), 6.9 7-6.93(m,1H),6.63(t,J=8.7Hz,1H),5.11(td,J=6.8,13.5Hz,1H),4.39-4.29(m,2H),4.21(br d,J=15.4Hz,2H),4.17-4.07(m,4H),4.01(s,3H),3.80(dd,J=5.5,10.6Hz,1H),3.76-3.58(m,2H),3.39(s,3H),3. 27-3.03(m,2H),2.81-2.57(m,2H),2.42-2.25(m,2H),2.25-2.13(m,2H),2.11-1.83(m,2H),1.32(d,J=6.7Hz,6H).

[0180] Example 4. Synthesis of N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 4)

[0181]

[0182] Step 1. Synthesis of benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (16)

[0183] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-4-carbaldehyde (850 mg, 2.67 mmol) and benzyl (7-azaspiro[3.5]nonan-2-yl)carbamate (829.91 mg, 2.67 mmol, HCl salt) in DCM (10 mL) was added NaOAc (438.05 mg, 5.34 mmol), and the resulting mixture was stirred at 20°C for 0.5 hours. NaBH(OAc)3 (1.70 g, 8.01 mmol) was then added, and the resulting mixture was stirred at 20°C for 16 hours. LCMS confirmed the presence of a major peak of the desired mass. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (90 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g of The product was purified by silica gel flash column with an eluent of 50-100% EtOAc / petroleum ether to 10% MeOH / EtOAc gradient at 100 mL / min. The product was further purified by reverse phase HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B over 10 minutes) to obtain benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate as a yellow solid (500 mg, 723.88 μmol, yield 27.11%, TFA salt). MS (M+H) + =577.3.

[0184] Step 2. Synthesis of 3-(4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (13)

[0185] A mixture of benzyl (7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (200 mg, 346.80 μmol) in TFA (2 mL) was stirred at 60°C for 16 hours. The desired mass of the main peak was confirmed by LCMS. The mixture was concentrated in vacuo to give 3-(4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (200 mg, crude, TFA salt) as a white solid. MS (M+H) + =443.2.

[0186] Step 3. Synthesis of N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethylamine (3)

[0187] A mixture of (1H-benzo[d][1,2,3]triazol-1-yl)methanol (2 g, 13.41 mmol) and N-benzylethylamine (1.81 g, 13.41 mmol, 1.99 mL) in EtOH (20 mL) was stirred at 15 ° C for 12 hours. By TLC (petroleum ether: EtOAc = 3: 1), it was confirmed that the starting material was completely consumed and a new main spot was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10 g of Purification was performed on a silica gel flash column with a 0-50% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethylamine (3.5 g, crude product) as a yellow oil. MS (M+H) + =267.4.

[0188] Step 4. Synthesis of ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropionate (5)

[0189] To a suspension of Zn (1.33 g, 20.27 mmol) in THF (60 mL), TMSCl (2.08 g, 19.15 mmol, 2.43 mL) was added dropwise under N2 at 0°C, maintaining the temperature below 5°C. After stirring for 20 minutes, ethyl 2-bromo-2,2-difluoroacetate (3.66 g, 18.02 mmol, 2.32 mL) was slowly added under N2 at 0°C, maintaining the temperature below 30°C. The mixture was stirred for 20 minutes and cooled to 0°C. A suspension of N-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-N-benzylethylamine (3 g, 11.26 mmol) in THF (48 mL) was added at 0°C, maintaining the temperature below 10°C. After 20 minutes, the suspension was warmed to 15°C and stirred for 3 hours. LCMS confirmed the presence of a major peak of the desired mass. The reaction mixture was filtered, and the filter cake was washed with EtOAc (100 mL) and THF (100 mL). The combined filtrates were concentrated in vacuo. The suspension was filtered, and the filter cake was washed with a solution (200 mL, petroleum ether:EtOAc=8:1). The filtrate was concentrated in vacuo to obtain ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropanoate (6 g, crude product) as a yellow viscous substance. MS (M+H) + =272.3.

[0190] Step 5. Synthesis of ethyl 3-(ethylamino)-2,2-difluoropropionate (6)

[0191] Under N2 gas conditions, Pd(OH)2 (500.00 mg, 712.08 μmol, purity 20%) was added to a solution of ethyl 3-(benzyl(ethyl)amino)-2,2-difluoropropionate (5 g, 18.43 mmol) and HCl (12 M, 2.00 mL) in EtOH (100 mL), and the suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred for 64 hours under H2 (15 psi) and 25 ° C. The main peak of the desired mass was confirmed by LCMS. The mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give ethyl 3-(ethylamino)-2,2-difluoropropionate (5 g, crude product, HCl salt) as a yellow oil. MS (M+H) + =182.1.

[0192] Step 6. Synthesis of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropionate (8)

[0193] To a solution of ethyl 3-(ethylamino)-2,2-difluoropropionate (5 g, 22.97 mmol, HCl salt) and 2,4-dichloro-5-nitropyrimidine (2.97 g, 15.32 mmol) in acetone (100 mL) was added K2CO3 (12.70 g, 91.89 mmol), and the temperature was maintained at 0°C to 5°C. The suspension was stirred for 16 hours at 15°C. By TLC (petroleum ether: EtOAc = 5: 1), it was confirmed that the starting material was completely consumed. The reaction mixture was diluted with H2O (100 mL), and the resulting mixture was extracted with EtOAc (100 mL × 5), and the combined organic layers were concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g of Purification was performed using a silica gel flash column with a 0-12% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (3 g, 8.86 mmol, 57.83% yield) as a yellow oil. MS (M+H) + =339.7.

[0194] Step 7. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (9)

[0195] To a solution of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (3 g, 8.86 mmol) in AcOH (30 mL) was added Fe (989.30 mg, 17.72 mmol), and the mixture was stirred at 20°C for 1 hour. The suspension was further heated at 80°C for 16 hours. The main peak of the desired mass was confirmed by LCMS. The reaction mixture was concentrated in vacuo to remove most of the solvent, and the residue was diluted with H2O (100 mL) and EtOAc (100 mL). The suspension was filtered, and the filter cake was washed with EtOAc (200 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated NaHCO3 solution (300 mL×2), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 20 g of Purification was performed on a silica gel flash column with an eluent of 0-50% EtOAc / petroleum ether gradient @ 100 mL / min. The eluate was concentrated in vacuo to obtain a residue. The residue was crushed with a mixture (petroleum ether / EtOAc = 1 / 1, 20 mL) at 15°C for 10 minutes, and the suspension was filtered. The filter cake was washed with a mixture (petroleum ether / EtOAc = 1 / 1, 100 mL). The filtrate was concentrated in vacuo to obtain 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1 g, 3.81 mmol, yield 42.99%) as a yellow solid. MS (M+H) + =263.0.

[0196] Step 8. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (10)

[0197] To a solution of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (900 mg, 3.43 mmol) in acetone (10 mL) were added K2CO3 (710.41 mg, 5.14 mmol) and MeI (486.39 mg, 3.43 mmol, 213.33 μL), and the mixture was stirred at 15 ° C for 16 hours. The main peak of the desired mass was confirmed by LCMS. The mixture was filtered through a celite pad. The filter cake was washed with EtOAc (10 mL). Most of the solvent was removed by concentrating the filtrate under vacuum. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1 g, crude product) as a gray solid. MS (M+H) + =277.0.

[0198] Step 9. Synthesis of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (12)

[0199] To a solution of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (300 mg, 1.08 mmol) and 4-amino-3-methoxybenzoic acid (181.26 mg, 1.08 mmol) in EtOH (2 mL) and H₂O (8 mL) was added HCl (12 M, 135.54 μL), and the resulting mixture was stirred at 100°C for 16 hours. LCMS confirmed the presence of a major peak of the desired mass. The mixture was concentrated under vacuum to remove half of the solvent, and the residue was filtered. The filter cake was washed with H₂O (10 mL), collected, and concentrated under vacuum. The residue was triturated with EtOAc (10 mL) for 30 minutes. The suspension was filtered, and the filter cake was washed with EtOAc (10 mL). The filter cake was collected and dried to give 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (300 mg, 736.43 μmol, yield 67.92%) as a gray solid. MS (M+H) + =408.1.

[0200] Step 10. Synthesis of N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 4)

[0201] N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (47.3 mg, 54.58 μmol, 31.76% yield, 96% purity) was obtained as a white solid. MS (M+H) + =832.4.

[0202] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.48-8.39 (m, 1H), 8.31 (d, J = 8.4Hz, 1H), 8.23 ​​(s, 1H), 7.9 0(s,1H),7.53-7.44(m,2H),7.05-6.92(m,3H),4.49-4.34(m,1H),4.17(t,J=13.7Hz,2H),3.94(s ,3H),3.84-3.75(m,1H),3.70-3.59(m,2H),3.50-3.33(m,5H),2.72-2.56(m,6H),2.49-2.42(m,2 H),2.26-2.10(m,5H),2.04-1.94(m,2H),1.88-1.74(m,5H),1.66-1.56(m,2H),1.35-1.15(m,6H).

[0203] Example 5. Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 5)

[0204]

[0205] 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (52.5 mg, 60.34 μmol, 33.90% yield, 94% purity) was obtained as a white solid. MS (M+H) + =818.4.

[0206] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.44 (d, J = 7.2Hz, 1H), 8.36 (d, J = 8.4Hz, 1H), 8.29 (s, 1H) ,7.96(s,1H),7.56-7.46(m,2H),7.05-6.90(m,3H),4.45-4.36(m,1H),4.17(t,J=14.4Hz,2H),3. 94(s,3H),3.83-3.76(m,1H),3.36-3.32(m,5H),3.06(s,3H),2.72-2.57(m,4H),2.49-2.41(m,3H ),2.29-2.12(m,5H),2.02-1.96(m,1H),1.89-1.73(m,5H),1.71-1.59(m,4H),1.33-1.21(m,3H).

[0207] Example 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 6)

[0208]

[0209] Step 1. Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carboxaldehyde (2)

[0210] DMP (1.01 g, 2.37 mmol) was added to a solution of 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (0.5 g, 1.58 mmol) in DCM (30 mL), and the mixture was stirred at 25° C. for 2 hours. By TLC (petroleum ether: EtOAc = 1: 1), it was confirmed that 3-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione was completely consumed, and the formation of a new spot was confirmed. The mixture was filtered, and the filtrate was concentrated to give 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carboxaldehyde (0.5 g, crude product) as a yellow oil. MS (M+H) + =315.1.

[0211] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3)

[0212] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidine-4-carboxaldehyde (0.5 g, 1.59 mmol) and tert-butyl ((1r, 4r)-4-(methylamino)cyclohexyl)carbamate (363.15 mg, 1.59 mmol) in DCM (10 mL) were added NaBH(OAc)3 (505.62 mg, 2.39 mmol) and AcOH (105.06 mg, 1.75 mmol, 100.06 μL), and the resulting mixture was stirred at 25°C for 12 hours. The main peak of the desired mass (77%) was confirmed by LCMS. Water (20 mL) was poured into the mixture and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g of Purification was performed on a silica gel flash column with a 0-30% MeOH / EtOAc gradient at 80 mL / min as the eluent to afford tert-butyl ((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (0.27 g, 512.62 μmol, 32.23% yield) as a yellow solid. MS (M+H) + =527.5.

[0213] Step 3. Synthesis of 3-(4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (4)

[0214] 3-(4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-methylphenyl)piperidine-2,6-dione (0.2 g, crude, HCl salt) was obtained as a yellow oil by a method similar to that described in Step 5 of Example 1. MS (M+H) + =427.3.

[0215] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 6)

[0216] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-(2,6-dioxopiperidin-3-yl)-2-methylphenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (33 mg, 37.39 μmol, 17.32% yield, 97% purity) was obtained as a white solid. MS (M+H) + =856.4.

[0217] 1 H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30-8.24 (m, 2H), 8.09 (br d,J=8.1Hz,1H),7.96(s,1H),7.54-7.44(m,2H),7.04-6.92(m,3H),4.87-4.69(m,1H),4.17-4.00(m,2H),3.94(s,3H),3.74(br dd,J=5.1,11.1Hz,2H),3.55-3.37(m,1H),3.33(s,3H),3.10-3.02(m,2H),2.70-2.53(m,4H),2.47-2.42(m,1H),2.38-2.26(m,3H), 2.28-2.19(m,4H),2.15-2.01(m,2H),2.01-1.89(m,5H),1.87-1.66(m,6H),1.65-1.57(m,4H),1.48-1.39(m,4H),1.34-1.26(m,2H).

[0218] Example 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 7)

[0219]

[0220] Step 1. Synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene (2)

[0221] By a method similar to that described in Step 8 of Example 4, acetone was replaced with DMF (30 mL) and the reaction was performed to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene (3.9 g, crude product) as a yellow oil. MS (M+H) + =190.2.

[0222] Step 2. Synthesis of tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3)

[0223] By a method similar to that described in Step 6 of Example 4, tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4.3 g, 12.10 mmol, 58.68% yield) was obtained as a yellow solid by replacing acetone with ACN. MS (M-56+H) + =300.1.

[0224] Step 3. Synthesis of tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (4)

[0225] By a method similar to that described in Step 9 of Example 2, Zn and THF were replaced with Fe (3.38 g, 60.50 mmol) and EtOH (60 mL) to obtain tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (4 g, 11.80 mmol, 97.53% yield, 96% purity) as a brown solid. MS (M+H) + =326.1.

[0226] Step 4. Synthesis of tert-butyl 4-(2-fluoro-4-iodo-5-methoxyphenyl)piperazine-1-carboxylate (5)

[0227] To a solution of tert-butyl nitrite (1.27 g, 12.29 mmol, 1.46 mL) in ACN (40 mL), tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (2 g, 6.15 mmol), I2 (3.12 g, 12.29 mmol) and CuI (2.34 g, 12.29 mmol) were added at 0 ° C, and the resulting mixture was stirred for 16 hours at 20 ° C. The peak of the required mass (23%) was confirmed by LCMS. After filtering the reactant, the filtrate was concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 10g Purification was performed using a silica gel flash column with a 0-30% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl 4-(2-fluoro-4-iodo-5-methoxyphenyl)piperazine-1-carboxylate (560 mg, 1.17 mmol, 19.00% yield, 91% purity) as a yellow oil. MS (M+H) + =437.0.

[0228] Step 5. Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (7)

[0229] A similar method to that described in Step 4 of Example 3 was used to synthesize tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (570 mg, 845.94 μmol, 65.90% yield, 89% purity) as a yellow oil. MS (M+H) + =600.3.

[0230] Step 6. Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (8)

[0231] By a method similar to that described in Step 2 of Example 3, replacing EtOH and AcOH with CF3CH2OH (20 mL) and TFA (47.53 mg, 416.88 μmol, 30.97 μL), tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (0.2 g, 373.49 μmol, 89.59% yield, TFA salt) was obtained as a brown solid. MS (M+H+Na) + =444.3.

[0232] Step 7. Synthesis of 3-(5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (9)

[0233] By a method similar to that described in Step 5 of Example 1, replacing dioxane with DCM (2 mL), 3-(5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (0.17 g, crude product, HCl) was obtained as a white solid. MS (M+H) + =322.2.

[0234] Step 8. Synthesis of tert-butyl (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (11)

[0235] By a method similar to that described in step 6 of Example 1, tert-butyl (4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (60 mg, 93.12 μmol, 19.95% yield, 85% purity) was obtained as a yellow solid. MS (M+H) + =548.3.

[0236] Step 9. Synthesis of 3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)piperidine-2,6-dione (12)

[0237] 3-(4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)piperidine-2,6-dione (50 mg, 89.04 μmol, 97.52% yield, TFA) was obtained as a brown oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =448.3.

[0238] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 7)

[0239] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (36.6 mg, 36.03 μmol, 40.47% yield, 95% purity, TFA) was obtained as a white solid. MS (M+H) + =851.6.

[0240] 1 H NMR (400MHz, DMSO-d6) δ = 10.74 (s, 1H), 9.53 (br s,1H),8.28(d,J=8.4Hz,1H),8.23(s,1H),8.16-8.03(m,1H),7.50-7.37(m,2H),7.04(d,J=13.1Hz,1H) ,6.67(d,J=7.5Hz,1H),4.99-4.81(m,1H),4.08(s,2H),3.94(s,3H),3.95-3.86(m,4H),3.63-3.57(m,4H ),3.33(s,3H),3.28-3.18(m,4H),3.14-3.04(m,4H),2.87-2.78(m,2H),2.62-2.57(m,2H),2.28-2.12(m ,1H),1.92-1.83(m,1H),1.81-1.73(m,2H),1.71-1.62(m,2H),1.45-1.36(m,3H),1.25(d,J=6.6Hz,6H).

[0241] Example 8. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 8)

[0242]

[0243] Step 1. Synthesis of 3-((3-bromophenyl)amino)propionic acid (2)

[0244] To a solution of 3-bromoaniline (1 g, 5.81 mmol, 632.91 μL) in toluene (10 mL) was added acrylic acid (630.00 mg, 8.74 mmol, 0.6 mL). The mixture was stirred at 80° C. for 14 hours. LCMS confirmed 96% of the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g of Purification was performed using a silica gel flash column with a 20-40% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford 3-((3-bromophenyl)amino)propanoic acid (890 mg, 3.50 mmol, 60.22% yield, 96% purity) as a yellow oil. MS (M+H) + =244.2.

[0245] Step 2. Synthesis of methyl 3-((3-bromophenyl)amino)propionate (3)

[0246] To a solution of 3-((3-bromophenyl)amino)propionic acid (890 mg, 3.65 mmol) in toluene (8 mL) and MeOH (8 mL) was slowly added TMSCHN2 (2 M, 5.5 mL) and stirred at 25°C for 14 hours. By LCMS, 41% of the remaining starting material and 34% of the desired mass were confirmed. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g of Purification was performed using a silica gel flash column with a 10-50% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford methyl 3-((3-bromophenyl)amino)propanoate (340 mg, 1.28 mmol, 35.04% yield, 97% purity) as a yellow oil. MS (M+H) + =258.1.

[0247] Step 3. Synthesis of methyl 3-((3-(4-((((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (5)

[0248] To a solution of tert-butyl ((1r, 4r)-4-(methyl(piperidin-4-ylmethyl)amino)cyclohexyl)carbamate (396 mg, 1.22 mmol) and methyl 3-((3-bromophenyl)amino)propanoate (0.24 g, 929.83 μmol) in dioxane (5 mL) was added Cs2CO3 (607 mg, 1.86 mmol) and Pd-PEPPSI-IHeptCl (63.32 mg, 65.09 μmol) and stirred at 100 ° C for 14 hours. The required mass was confirmed by LCMS. The mixture was filtered and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g of The residue was purified by silica gel flash column with an eluent of 80-100% EtOAc / petroleum ether to 10% MeOH / EtOAc gradient at 100 mL / min, and then further purified by prep-TLC (DCM:MeOH = 10:1) to give methyl 3-((3-(4-((((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (150 mg, 298.40 μmol, 32.09% yield) as a yellow oil. MS (M+H) + =503.5.

[0249] Step 4. Synthesis of methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (6)

[0250] To a solution of methyl 3-((3-(4-((((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)amino)propanoate (120 mg, 238.72 μmol) in AcOH (1 mL) was added KOCN (30.5 mg, 358.19 μmol), and the mixture was stirred at 25°C for 14 hours. LCMS confirmed 80% of the desired mass. The mixture was concentrated under reduced pressure. The crude product was diluted with MeCN (3 mL) and water (30 mL), and the suspension was lyophilized to give methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (150 mg, crude, AcOH salt) as a yellow solid. MS (M+H) + =546.6.

[0251] Step 5. Synthesis of tert-butyl ((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (7)

[0252] To a solution of methyl 3-(1-(3-(4-((((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)ureido)propanoate (120 mg, 198.10 μmol, AcOH salt) in ACN (2.5 mL) was slowly added benzylmethylamine hydroxide (Triton B) (552.00 mg, 1.32 mmol, 600 μL, 40% purity) and the mixture was stirred at 25 ° C for 1 hour. LCMS confirmed 61% of the desired mass. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3), and the combined organic layers were washed with water (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl ((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (90 mg, crude product) as a yellow solid. MS (M+H) + =514.5.

[0253] Step 6. Synthesis of 1-(3-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (8)

[0254] 1-(3-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (90 mg, crude, TFA) was obtained as a yellow oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =414.4.

[0255] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 8)

[0256] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (48.8 mg, 56.73 μmol, 36.26% yield, 98% purity) was obtained as a white solid. MS (M+H) + =843.4.

[0257] 1H NMR (400MHz, CD3CN) δ=8.47(d,J=8.3Hz,1H),8.30-8.19(m,1H),8.10(s,1H),7.70(s,1H),7.44-7.37(m,2H),7.24(t,J=8.1Hz,1 H),6.91-6.82(m,3H),6.75-6.69(m,1H),4.92-4.80(m,1H),4.01-3.92(m,5H),3.89-3.82(m,1H),3.77(t,J=6.7Hz,2H),3.72(br d,J=12.5Hz,2H),3.33(s,3H),3.11-3.02(m,1H),2.86-2.81(m,2H),2.78-2.73(m,2H),2.72-2.69(m,2H),2.64(s,3H),2.15- 2.08(m,2H),2.06-1.99(m,3H),1.89-1.82(m,2H),1.79-1.73(m,2H),1.69-1.57(m,7H),1.52-1.40(m,2H),1.40-1.26(m,3H).

[0258] Example 9. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 9)

[0259]

[0260] Step 1. Synthesis of benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (2)

[0261] Benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (410 mg, crude product, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a bright yellow solid. MS (M+H) + =263.2.

[0262] Step 2. Synthesis of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (3)

[0263] A similar method to that described in Step 6 of Example 1 was used to synthesize tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (670 mg, crude product) as a yellow solid. MS (M+H) + =446.3.

[0264] Step 3. Synthesis of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)(methyl)amino)piperidine-1-carboxylate (4)

[0265] To a solution of tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)amino)piperidine-1-carboxylate (670 mg, 1.50 mmol, crude product) in MeOH (30 mL) were added AcOH (90.29 mg, 1.50 mmol, 86.00 μL) and HCHO (1.22 g, 15.04 mmol, 1.12 mL, 37% purity). The mixture was stirred at 20°C for 2 hours. Then, NaBH3CN (800 mg, 12.73 mmol) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 14 hours. LCMS confirmed the desired mass peak (87%). After adding H2O (30 mL) to the reaction mixture, MeOH was removed by concentration and diluted with EtOAc (40 mL). Then, saturated NaHCO3 solution was added to the mixture at 0°C until pH = 8-9. The mixture was extracted with EtOAc (50 mL×2), and the combined organic layers were washed with brine (40 mL×2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC (column: Waters Xbridge C18 150×50mm×10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 54%-84%, 10 min, column temperature: 30°C), and the eluate was lyophilized to obtain tert-butyl 4-((((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)methyl)(methyl)amino)piperidine-1-carboxylate (300 mg, 652.71 μmol, yield 43.41%) as a bright yellow solid. MS (M+Na) + =482.3.

[0266] Step 4. Synthesis of benzyl ((1r,4r)-4-((methyl(piperidin-4-yl)amino)methyl)cyclohexyl)carbamate (5)

[0267] Benzyl ((1r,4r)-4-((methyl(piperidin-4-yl)amino)methyl)cyclohexyl)carbamate (170 mg, crude, HCl salt) was synthesized by a method similar to that described in Step 1 as a bright yellow solid. MS (M+H) + =360.3.

[0268] Step 5. Synthesis of benzyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)carbamate (7)

[0269] Benzyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)carbamate (90 mg, 164.33 μmol, 36.85% yield) was synthesized by a method similar to that described in Step 3 of Example 8 as a bright yellow solid. MS (M+H) + =548.3.

[0270] Step 6. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)methyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (8)

[0271] 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)methyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (77 mg, crude product, TFA salt) was synthesized by a method similar to that described in Step 2 of Example 4 as a bright yellow oil. MS (M+H) + =414.3.

[0272] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 9)

[0273] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (26.3 mg, 23.35 μmol, 13.06% yield, 94.7% purity, 2TFA salt) was obtained as a white solid. MS (M+H) + =843.5.

[0274] 1 H NMR (400MHz, CD3OD) δ=8.36(d,J=2.8Hz,1H),8.21(d,J=8.6Hz,1H),8.18-8.14(m,1H),7.86(dd,J=2.6,9.2Hz,1H) ,7.64-7.56(m,2H),7.55-7.50(m,1H),5.11-4.99(m,2H),4.17-4.07(m,4H),4.02(s,3H),3.96-3.87(m,1H),3.63- 3.53(m,1H),3.41(s,3H),3.28-3.21(m,1H),3.10-3.00(m,3H),2.93(s,3H),2.81-2.74(m,2H),2.45-2.35(m,1H) ,2.33-2.16(m,3H),2.13-2.02(m,5H),2.00-1.82(m,6H),1.75-1.66(m,4H),1.59-1.47(m,2H),1.38-1.26(m,2H).

[0275] Example 10. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 10)

[0276]

[0277] Step 1. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3)

[0278] A method similar to that described in Step 3 of Example 8 was used to synthesize tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (550 mg, 1.26 mmol, 60.27% yield) as a bright yellow solid. MS (M+H) + =437.2.

[0279] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-[2,3'-bipyridyl]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (5)

[0280] A mixture of tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (400 mg, 915.30 μmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (666.67 mg, 1.60 mmol), K3PO4 (666.67 mg, 3.14 mmol), and CataCXium A Pd G2 (80 mg, 119.65 μmol) in dioxane (20 mL) and water (5 mL) was degassed and purged with N2 gas three times. The resulting mixture was stirred at 80°C under N2 gas for 16 hours. By LCMS, it was confirmed that tert-butyl ((1r,4r)-4-(((1-(6-chloropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate was completely consumed, and the peak of the desired mass (41%) was confirmed. The reaction mixture was diluted with H2O (15mL) and extracted with EtOAc (30mL×2). The combined organic layer was washed with 90mL of brine (30mL×3), dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 10g Purification was performed on a silica gel flash column with a 2-10% DCM:MeOH gradient (60 mL / min) as the eluent to afford tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-[2,3'-bipyridyl]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (520 mg, 751.55 μmol, 82.11% yield) as a yellow solid. MS (M+H) + =692.5.

[0281] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6)

[0282] A similar method to that described in Step 4 of Example 1 was used to synthesize tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (230 mg, 447.76 μmol, 96.81% yield) as a yellow oil. MS (M+H) + =514.3.

[0283] Step 4. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (7)

[0284] 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (156 mg, crude, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a bright yellow solid. MS (M+H) + =414.3.

[0285] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 10)

[0286] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (42.0 mg, 44.82 μmol, 13.37% yield, 89.95% purity) was obtained as a white solid. MS (M+H) + =843.5.

[0287] 1 H NMR (400MHz, DMSO-d6) δ = 10.77 (s, 1H), 8.31-8.23 (m, 2H), 8.22-8.16 (m, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.95 (s, 1H), 7.53-7. 44(m,2H),7.35-7.27(m,1H),7.15(d,J=8.7Hz,1H),4.82-4.70(m,1H),4.09-3.99(m,2H),3.93(s,3H),3.91-3.84(m,1H) ,3.79-3.63(m,3H),2.74-2.63(m,2H),2.60-2.51(m,2H),2.50-2.48(m,3H),2.36-2.29(m,1H),2.28-2.23(m,2H),2.20( s,3H),2.18-2.04(m,2H),1.98-1.86(m,4H),1.82-1.67(m,6H),1.64-1.52(m,5H),1.43-1.29(m,4H),1.23-1.11(m,2H).

[0288] Example 11. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 11)

[0289]

[0290] Step 1. Synthesis of 3-(5-bromopyridin-2-yl)piperidine-2,6-dione (2)

[0291] To a solution of methyl 2-(5-bromopyridin-2-yl)acetate (2.0 g, 8.69 mmol) in DMF (15 mL), acrylamide (617.91 mg, 8.69 mmol, 599.91 μL) and t-BuOK (1 M, 8.69 mL) were added at 0°C. The mixture was stirred for 2 hours at 0°C. By TLC (petroleum ether: EtOAc = 1: 1), it was confirmed that the starting material was completely consumed and the formation of new spots was confirmed. The reaction mixture was filtered and the filter cake was dried to obtain a crude product, which was then crushed with EtOAc: water = 1: 1 at 20°C for 30 minutes to give 3-(5-bromopyridin-2-yl)piperidine-2,6-dione (1.5 g, 5.57 mmol, yield 64.12%) as a white solid. MS (M+H) + =270.1.

[0292] 1 H NMR (400MHz, DMSO-d6) δ=11.01-10.73(m,1H),8.64(d,J=2.0Hz,1H),8.04(dd,J=2.4,8.3Hz,1H),7.38(d,J =8.3Hz,1H),4.12-3.97(m,1H),2.68-2.58(m,1H),2.56-2.52(m,1H),2.31-2.19(m,1H),2.16-2.06(m,1H).

[0293] Step 2. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (3)

[0294] 3-(5-(4-(1,3-dioxolan-2-yl)-1-piperidinyl)-2-pyridinyl)piperidine-2,6-dione (1.1 g, 3.06 mmol, 54.85% yield, 96% purity) was synthesized by a method similar to that described in Step 3 of Example 8 as a yellow solid. MS (M+H) + =346.2.

[0295] 1H NMR (400MHz, DMSO-d6) δ=10.77(s,1H),8.19(d,J=2.8Hz,1H),7.31(dd,J=2.9,8.7Hz,1H),7.16(d,J=8.7Hz,1H),4.62(d,J=4.9Hz,1H),3.91-3.84 (m,3H),3.81-3.73(m,4H),2.74-2.63(m,2H),2.59-2.53(m,2H),2.25-2 .05(m,2H),1.74(d,J=13.8Hz,2H),1.69-1.60(m,1H),1.46-1.33(m,2H).

[0296] Step 3. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde (4)

[0297] FA (83.46 mg, 1.74 mmol, 6 mL) was added to a solution of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (600 mg, 1.74 mmol) in dioxane (2 mL) and H₂O (2 mL). The mixture was stirred at 20°C for 48 hours. LCMS confirmed that 6% of the starting material remained, and the appearance of multiple new peaks and a peak of the desired mass (93%) was confirmed by LCMS. The reaction mixture was diluted with aqueous saturated Na₂CO₃ (50 mL) at 0°C and adjusted to pH = 7, then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidine-4-carbaldehyde (520 mg, 1.55 mmol, 89.40% yield, 90% purity) as a yellow solid. MS (M+H+H2O) + =320.2.

[0298] Step 4. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6)

[0299] By a method similar to that described in step 2 of Example 6, tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (200 mg, 346.62 μmol, 20.09% yield, 97% purity, FA) was obtained as a yellow solid. MS (M+H) + =514.4.

[0300] Step 5. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (7)

[0301] 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (110 mg, crude, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a white solid. MS (M+H) + =414.2.

[0302] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 11)

[0303] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (82.1 mg, 73.77 μmol, 30.18% yield, 93.9% purity, 2TFA salt) was obtained as a white solid. MS (M+H) + =817.4.

[0304] 1H NMR (400MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.84 (dd, J = 3.9, 8.9Hz, 1H), 8.31 (d, J = 2.3Hz, 1H), 8.27-8.13 (m, 4H), 7.74-7.61 (m,1H),7.56-7.38(m,3H),4.95-4.82(m,1H),4.14-4.02(m,3H),3.93(s,3H),3.90-3.84(m,2H),3.32(s,3H),3.23-3.1 9(m,1H),2.99-2.88(m,2H),2.87-2.77(m,5H),2.65-2.57(m,2H),2.45-2.39(m,1H),2.31-2.20(m,1H),2.15-2.06(m,2 H), 2.04-1.93 (m, 5H), 1.85-1.75 (m, 1H), 1.74-1.59 (m, 2H), 1.52-1.40 (m, 2H), 1.39-1.28 (m, 2H), 1.24 (d, J = 6.7Hz, 6H).

[0305] Example 12. Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 12)

[0306]

[0307] Step 1. Synthesis of 5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)-2-chloro-4-methylpyridine (3)

[0308] Under N2 gas and 100 ° C, a mixture of 2-chloro-5-iodo-4-methylpyridine (6.1 g, 24.07 mmol), 4-(1,3-dioxolane-2-yl)piperidine (3.78 g, 24.07 mmol), t-BuONa (6.94 g, 72.20 mmol) and RuPhos Pd G4 (409.31 mg, 481.32 μmol) in dioxane (70 mL) was stirred for 16 hours. By LCMS, it was confirmed that the starting material was completely consumed and the peak of the required mass (60%) was confirmed. The mixture was filtered, and after washing the filter cake with THF (200 mL), the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (40 g of Purification was performed using a silica gel flash column with a 5-10% EtOAc / petroleum ether gradient at 200 mL / min as the eluent to afford 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-chloro-4-methylpyridine (4.35 g, 15.38 mmol, 63.92% yield) as a yellow solid. MS (M+H) + =283.1.

[0309] Step 2. Synthesis of 5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (5)

[0310] 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (6 g, 11.16 mmol, 72.54% yield) was obtained as a yellow solid by a method similar to that described in Step 2 of Example 10. MS (M+H) + =538.3.

[0311] Step 3. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (6)

[0312] To a solution of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-4-methyl-2,3'-bipyridine (5 g, 9.30 mmol) in THF (200 mL) and DMF (40 mL) were added AcOH (20.98 g, 349.38 mmol, 20 mL), Pd / C (3 g, 2.82 mmol, 10% purity), and Pd(OH)2 / C (3 g, 4.27 mmol, 20% purity) at 30°C. The mixture was stirred at 30°C under H2 (50 psi) for 70 hours. LCMS confirmed the desired mass (81%). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The mixture was diluted with water (120 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4 and filtered, and the filtrate was concentrated in vacuo. The crude product was crushed by EtOAc / petroleum ether = 1 / 1 (50 mL) at 20°C for 30 minutes to give 3-(5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (2.13 g, 5.93 mmol, 63.72% yield) as a yellow solid. MS (M+H)+ =360.2.

[0313] Step 4. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidine-4-carboxaldehyde (7)

[0314] By a method similar to that described in Step 3 of Example 11, FA was replaced with HCl / dioxane (4 M, 20 mL) to obtain 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidine-4-carbaldehyde (240 mg, crude product) as a yellow solid. MS (M+H) + =316.2.

[0315] Step 5. Synthesis of tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (9)

[0316] By a method similar to that described in step 6 of Example 1, tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (170 mg, 322.15 μmol, 42.33% yield) was obtained as a yellow solid. MS (M+H) + =528.3.

[0317] Step 6. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (10)

[0318] 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione (150 mg, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a white solid. MS (M+H) + =428.3.

[0319] Step 7. Synthesis of 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 12)

[0320] 4-((7,7-difluoro-5,9-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (36.9 mg, 44.12 μmol, 27.30% yield, 96% purity) was obtained as a white solid. MS (M+H) + =803.3.

[0321] 1 H NMR (400MHz, DMSO-d6) δ = 10.83-10.76 (m, 1H), 8.34 (d, J = 8.3Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 8.07 (d, J = 7.8Hz, 1H), 7. 96(s,1H),7.53-7.47(m,2H),7.13(s,1H),4.17(t,J=14.4Hz,2H),3.94(s,3H),3.91-3.85(m,1H),3.77-3.68(m,1H),3. 31(s,3H),3.13-3.08(m,2H),3.06(s,3H),2.64-2.57(m,2H),2.45-2.40(m,2H),2.31-2.65(m,3H),2.24(s,3H),2.21(s ,3H),2.14-2.07(m,2H),1.92-1.87(m,2H),1.83-1.75(m,4H),1.55-1.49(m,1H),1.39-1.31(m,4H),1.27-1.20(m,2H).

[0322] Example 13. Synthesis of N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 13)

[0323] N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (19.3 mg, 22.44 μmol, 13.89% yield, 95% purity) was obtained as a white solid. MS (M+H) + =817.3.

[0324] 1 H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.2Hz, 1H), 7.90 (s, 1H) ,7.55-7.46(m,2H),7.13(s,1H),4.26-4.11(m,2H),3.94(s,3H),3.92-3.85(m,1H),3.78-3.70(m,1H),3.70-3.61(m,2H),3 .32(s,3H),3.15-3.09(m,2H),2.74-2.69(m,1H),2.66-2.64(m,1H),2.46-2.42(m,2H),2.32-2.27(m,3H),2.24(s,3H),2.2 1(s,3H),2.15-2.07(m,2H),1.94-1.88(m,2H),1.85-1.75(m,4H),1.59-1.49(m,1H),1.43-1.26(m,5H),1.25-1.19(m,4H).

[0325] Example 14. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 14)

[0326]

[0327] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (127.4 mg, 141.23 μmol, 22.57% yield, 95% purity) was obtained as a white solid. MS (M+H) + =857.3.

[0328] 1 H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.32-8.18 (m, 2H), 8.17-8.12 (m, 1H), 8.07 (br dd,J=1.5,6.1Hz,1H),7.95(s,1H),7.54-7.41(m,2H),7.13(s,1H),4.84-4.68(m,1H),4.04(br t,J=14.1Hz,2H),3.93(s,3H),3.88(dd,J=5.3,8.7Hz,1H),3.75-3.70(m,1H),3.36-3.55(m,3H),3.17-3.07(m,2H),2.67(br dd,J=1.7,3.5Hz,2H),2.58-2.51(m,5H),2.32-2.26(m,2H),2.24(s,3H),2.23-2.14(m,3H),2.11(br dd,J=6.4,12.3Hz,1H),1.92(br dd,J=3.1,10.2Hz,4H),1.88-1.77(m,3H),1.77-1.65(m,3H),1.65-1.49(m,5H),1.39(br d,J=5.1Hz,4H),1.27(br s,1H).

[0329] Example 15. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 15)

[0330]

[0331] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (65.7 mg, 53.21 μmol, 17.25% yield, 95% purity, 3TFA salt) was obtained as a white solid. MS (M+H) + =831.3.

[0332] 1 H NMR (400MHz, CD3OD) δ=8.42-8.31(m,1H),8.12(s,1H),8.10-7.98(m,1H),7.83-7.72( m,1H),7.58(s,1H),7.56-7.51(m,1H),5.21-5.04(m,1H),4.83-4.62(m,1H),4.16(br t,J=11.8Hz,2H),4.01(s,3H),3.99-3.92(m,1H),3.40(s,3H),3.37(br s,3H),3.34-3.27(m,1H),3.12-3.03(m,1H),2.94(s,5H),2.85-2.73(m,2H),2.63-2.51(m,3H),2.50-2.38(m,1H),2.37-2.28 (m,1H),2.28-2.13(m,4H),2.12-2.00(m,2H),1.99-1.92(m,1H),1.89-1.71(m,2H),1.69-1.49(m,4H),1.32(d,J=6.7Hz,6H).

[0333] Example 16. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (Compound 16)

[0334]

[0335] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-3-methoxybenzamide (115.3 mg, 103.43 μmol, 25.64% yield, 95% purity, 2TFA salt) was obtained as a white solid. MS (M+H) + =831.3.

[0336] 1 H NMR (400MHz, CD3OD) δ = 8.35 (br d,J=4.9Hz,1H),8.14-8.05(m,2H),7.75-7.65(m,1H),7.58(s,1H),7.54(dd,J=1.4,8.4Hz,1H),5.15-5.08(m,1H),4.84(br d,J=1.0Hz,1H),4.15(br t,J=11.9Hz,2H),4.01(s,3H),3.91-3.80(m,1H),3.57-3.43(m,3H),3.40(s,3H),3.29-3.21(m,1H),3.10-2.96 (m,3H),2.95(s,3H),2.84-2.72(m,2H),2.56(brd,J=3.3Hz,3H),2.48-2.37(m,1H),2.36-2.23(m,2H),2.20(br d,J=10.5Hz,1H),2.15-1.99(m,5H),1.98-1.83(m,2H),1.62-1.45(m,2H),1.32(d,J=6.8Hz,8H).

[0337] Example 17. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 17)

[0338]

[0339] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (70.3 mg, 78.47 μmol, 12.37% yield, 97% purity) was obtained as a white solid. MS (M+H) + =869.4.

[0340] 1 H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.44 (br d,J=7.2Hz,1H),8.34-8.23(m,2H),8.13(s,1H),7.97(s,1H),7.57-7.43(m,2H),7.13(s,1H),4.86-4.69(m,1H),4.49-4.31(m,1H),4.05(br t,J=14.1Hz,2H),3.95(s,3H),3.89(dd,J=5.4,8.7Hz,1H),3.33-3.31(m,3H),3.10(br d,J=11.0Hz,2H),2.68(br t,J=11.4Hz,2H),2.59-2.52(m,2H),2.41-2.29(m,2H),2.25-2.23(m,4H),2.21 -2.05(m,6H),2.00-1.91(m,2H),1.88-1.76(m,4H),1.74-1.68(m,2H),1.59(br dd,J=4.8,12.7Hz,9H),1.34-1.18(m,3H).

[0341] Example 18. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 18)

[0342]

[0343] Step 1. Synthesis of 3-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)-6-chloro-2-methylpyridine (3)

[0344] 3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-chloro-2-methylpyridine (1.3 g, 4.60 mmol, 58.27% yield) was obtained as a yellow oil by a method similar to that described in Step 1 of Example 12. MS (M+H) + =283.1.

[0345] Step 2. Synthesis of 5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-6-methyl-2,3'-bipyridine (5)

[0346] 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2',6'-bis(benzyloxy)-6-methyl-2,3'-bipyridine (1.9 g, 3.53 mmol, 90.84% ​​yield) was synthesized by a method similar to that described in Step 2 of Example 12 as a bright yellow solid. MS (M+H) + =538.3.

[0347] Step 3. Synthesis of 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione (6)

[0348] 3-(5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione (1.0 g, crude product) was synthesized by a method similar to that described in Step 4 of Example 1 as a yellow oil. MS (M+H) + =360.2.

[0349] Step 4. Synthesis of 1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidine-4-carbaldehyde (7)

[0350] 1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidine-4-carbaldehyde (450 mg, crude product) was obtained as a yellow solid by a method similar to that described in Step 4 of Example 12. MS (M+H) + =316.1.

[0351] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 18)

[0352] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (92.2 mg, 102.70 μmol, 16.19% yield, 96.8% purity) was obtained as a bright yellow solid. MS (M+H) + =869.5.

[0353] 1 H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.49-8.40 (m, 1H), 8.31-8.24 (m, 2H), 8.01-7.93 (m, 1H), 7.53-7.46 (m, 2H) ),7.38-7.31(m,1H),7.13-7.07(m,1H),4.83-4.73(m,1H),4.45-4.34(m,1H),4.11-4.00(m,2H),3.95(s,3H),3. 91-3.85(m,1H),3.31-3.24(m,3H),3.09-3.02(m,2H),2.64-2.54(m,6H),2.42-2.32(m,5H),2.24-2.15(m,4H),2 .15-2.04(m,2H),1.98-1.91(m,2H),1.86-1.77(m,4H),1.75-1.69(m,2H),1.68-1.54(m,9H),1.32-1.23(m,2H).

[0354] Example 19. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 19)

[0355]

[0356] Step 1. Synthesis of tert-butyl 2-(4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide)-7-azaspiro[3.5]nonane-7-carboxylate (2)

[0357] A method similar to that described in step 10 of Example 2 was used to synthesize tert-butyl 2-(4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, 706.83 μmol, 59.57% yield, 91% purity) as a brown solid. MS (M+H) + =644.3.

[0358] Step 2. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(7-azaspiro[3.5]nonan-2-yl)benzamide (3)

[0359] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-N-(7-azaspiro[3.5]nonan-2-yl)benzamide (0.35 g, HCl salt) was obtained as a yellow solid by a method similar to that described in Step 5 of Example 1 and used directly in the next step. MS (M+H) + =544.3.

[0360] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 19)

[0361] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (13.4 mg, 11.39 μmol, 56.75% yield, 91% purity, 2TFA salt) was synthesized as a white solid. MS (M+H) + =843.4.

[0362] 1 H NMR (400MHz, CD3OD) δ=8.30(s,1H),8.19(d,J=8.3Hz,1H),8.12(s,1H),7.67(s,1H),7.57(d,J=1.7Hz,1H),7.54(dd,J= 1.9,8.4Hz,1H),5.15-5.05(m,1H),4.84-4.81(m,1H),4.62-4.50(m,1H),4.12(t,J=12.3Hz,2H),4.01(s,3H),3.59(br d,J=13.3Hz,1H),3.53(br d,J=12.8Hz,1H),3.40(s,3H),3.36-3.33(m,2H),3.18-3.12(m,2H),3.11 -3.04(m,1H),3.03-2.95(m,1H),2.95-2.85(m,2H),2.85-2.73(m,2H),2. 61-2.55(m,1H),2.53(s,3H),2.48-2.39(m,1H),2.38-2.26(m,2H),2.19- 2.05(m,3H),2.05-1.89(m,6H),1.66-1.50(m,2H),1.33(d,J=6.7Hz,6H).

[0363] Example 20. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 20)

[0364]

[0365] Step 1. Synthesis of 5-bromo-4-fluoro-2-iodopyridine (2)

[0366] t-BuONO (2.70 g, 26.18 mmol, 3.11 mL), CuI (9.97 g, 52.36 mmol) and I2 (26.58 g, 104.71 mmol) were added to a solution of 5-bromo-4-fluoropyridine-2-amine (1 g, 5.24 mmol) in MeCN (10 mL) and the resulting mixture was stirred for 16 hours at 20 ° C. By TLC (petroleum ether: EtOAc = 5: 1), it was confirmed that the starting material was completely consumed and two new major spots with low polarity were confirmed. The reaction mixture was quenched by adding ice-cold Na2SO3 (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (500 mL × 2) and dried over Na2SO4, then filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 12 g of Purification was performed on a silica gel flash column with a petroleum ether gradient (100 mL / min) as the eluent to obtain 5-bromo-4-fluoro-2-iodopyridine (397 mg, crude product) as a yellow oil. MS (M+H) + =302.9.

[0367] Step 2. Synthesis of 2',6'-bis(benzyloxy)-5-bromo-4-fluoro-2,3'-bipyridine (4)

[0368] 2',6'-bis(benzyloxy)-5-bromo-4-fluoro-2,3'-bipyridine (400 mg, 747.88 μmol, 60.53% yield) was obtained as a white solid by a method similar to that described in Step 1 of Example 1. MS (M+H) + =465.1.

[0369] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridyl]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6)

[0370] A similar method to that described in step 3 of Example 8 was used to synthesize tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridyl]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (190 mg, 267.65 μmol, 41.51% yield) as a yellow solid. MS (M+H) + =710.5.

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

[0372] A mixture of tert-butyl ((1r,4r)-4-(((1-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridyl]-5-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (170 mg, 239.47 μmol) and Pd / C (50 mg, 46.98 μmol, 10% purity) in THF (20 mL) and AcOH (524.50 mg, 8.73 mmol, 0.5 mL) was degassed and purged with H2 three times. The resulting mixture was stirred at 30°C under H2 (50 Psi) gas for 36 hours. LCMS confirmed complete consumption of the starting material and the presence of a peak of the desired mass (50%). The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (SiO2, DCM:MeOH=8:1) to give tert-butyl ((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (50 mg, 94.04 μmol, 39.27% ​​yield) as a yellow solid. MS (M+H) + =532.3.

[0373] Step 5. Synthesis of 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (8)

[0374] 3-(5-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (35 mg, crude, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a white solid. MS (M+H) + =432.3.

[0375] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 20)

[0376] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (10.4 mg, 11.35 μmol, 15.18% yield, 94% purity) was obtained as a white solid. MS (M+H) + =861.4.

[0377] 1H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.30-8.17 (m, 3H), 8.06 (d, J = 7.8Hz, 1H), 7.95 (s, 1H), 7.52-7.44 (m, 2H) ,7.23(d,J=13.4Hz,1H),4.82-4.71(m,1H),4.10-3.99(m,2H),3.98-3.91(m,4H),3.80-3.67(m,1H),3.45-3.37 (m,2H),3.32(s,3H),2.80-2.69(m,2H),2.65-2.53(m,2H),2.48-2.41(m,1H),2.39-2.23(m,4H),2.20(s,3H),2 .15-2.07(m,1H),1.99-1.88(m,4H),1.83-1.70(m,5H),1.62-1.54(m,4H),1.44-1.30(m,4H),1.29-1.17(m,3H).

[0378] Example 21. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21)

[0379]

[0380] Step 1. Synthesis of tert-butyl 4-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridyl]-5-yl)piperazine-1-carboxylate (3)

[0381] A method similar to that described in step 3 of Example 8 was used to synthesize tert-butyl 4-(2',6'-bis(benzyloxy)-4-fluoro-[2,3'-bipyridyl]-5-yl)piperazine-1-carboxylate (850 mg, 1.49 mmol, 69.31% yield) as a white solid. MS (M+H) + =571.4.

[0382] Step 2. Synthesis of tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (4)

[0383] By synthesizing in a manner similar to that described in step 3 of Example 12, tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (350 mg) was obtained as a white solid. MS (M+H) + =393.4.

[0384] Step 3. Synthesis of 3-(4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione (5)

[0385] 3-(4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione (300 mg, HCl salt) was obtained as a white solid by a method similar to that described in Step 5 of Example 1 and used directly in the next step. MS (M+H) + =293.3.

[0386] Step 4. Synthesis of tert-butyl (4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (7)

[0387] By synthesizing in a manner similar to that described in Step 1 of Example 4, tert-butyl (4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (350 mg, crude product) was obtained as a yellow oil. MS (M+H) + =519.4.

[0388] Step 5. Synthesis of 3-(5-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (8)

[0389] 3-(5-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-4-fluoropyridin-2-yl)piperidine-2,6-dione (250 mg, 549.49 μmol, 94.99% yield, HCl salt) was synthesized by a method similar to that described in Step 3 as a yellow oil. MS (M+H) + =419.2.

[0390] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 21)

[0391] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-4-fluoropyridin-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (36.9 mg, 43.10 μmol, 7.84% yield, 96% purity) was obtained as a white solid. MS (M+H) + =822.5.

[0392] 1 H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.23 (s, 1H), 8.29 (d, J = 8.3Hz, 1H), 8.24-8.18 (m, 2H), 7.87 (s, 1H), 7. 48-7.39(m,2H),7.25(d,J=13.4Hz,1H),4.98-4.78(m,1H),4.10-4.00(m,2H),3.99-3.84(m,4H),3.32-3.31( m,3H),3.14-3.04(m,4H),3.03-2.94(m,2H),2.80-2.69(m,2H),2.65-2.52(m,6H),2.39-2.32(m,2H),2.29-2 .19(m,1H),2.14-2.06(m,1H),1.80-1.65(m,2H),1.48-1.38(m,2H),1.36-1.27(m,3H),1.24(d,J=6.8Hz,6H).

[0393] Example 22. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 22)

[0394]

[0395] Step 1. Synthesis of benzyl 4-(((1R,5S,6s)-6-((tert-Butyloxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate (3)

[0396] To a solution of benzyl 4-formylpiperidine-1-carboxylate (1.15 g, 4.65 mmol) in DCM (20 mL) were added TEA (1.41 g, 13.95 mmol, 1.94 mL), 4A MS (50 mg), and tert-butyl ((1R, 5S, 6s)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (919.00 mg, 4.64 mmol) at 20°C. After stirring for 10 minutes, NaBH(OAc)3 (2.96 g, 13.95 mmol) was slowly added at 20°C, and the mixture was stirred for 16 hours at 20°C. LCMS confirmed complete consumption of the starting material and confirmed a peak of 68% of the desired mass. The reaction mixture was filtered, and the filter cake was washed with MeOH (40 mL). The filtrate was concentrated in vacuo to obtain a crude product, which was triturated with EtOAc (10 mL) at 20°C for 2 hours and then filtered. The filtrate was purified by flash silica gel chromatography (40 g of Purification was performed on a silica gel flash column with a gradient of 0-100% EtOAc / petroleum ether (0-30% DCM:MeOH) at 100 mL / min to afford benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate (1.72 g, 3.80 mmol, 81.80% yield, 95% purity) as a colorless oil. MS (M+H) + =430.2.

[0397] Step 2. Synthesis of tert-butyl ((1R,5S,6s)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (4)

[0398] To a solution of benzyl 4-(((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)piperidine-1-carboxylate (1.72 g, 4.00 mmol) in EtOH (20 mL) was added Pd / C (0.8 g, 10% purity) under N2 gas conditions. The suspension was degassed and purged with H2 three times. The mixture was stirred for 12 hours under H2 (15 Psi) and 20°C. By LCMS, it was confirmed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was filtered and the filter cake was washed with EtOH (30 ml × 3). The filtrate was concentrated in vacuo to give tert-butyl ((1R,5S,6s)-3-(piperidin-4-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.15 g, crude product) as a gray solid. MS (M+H) + =296.3.

[0399] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (5)

[0400] By a method similar to that described in Step 5 of Example 4, acetone was replaced with DMF (20 mL) to obtain tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.2 g, 2.65 mmol, 68.09% yield, 92% purity) as a yellow solid. MS (M+H) + =417.3.

[0401] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6)

[0402] To a solution of tert-butyl ((1R,5S,6s)-3-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.2 g, 2.88 mmol) in EtOH (10 mL) and H2O (10 mL) were added Fe (804.47 mg, 14.41 mmol) and NH4Cl (462.34 mg, 8.64 mmol) at 20°C. The mixture was stirred at 80°C for 2 hours. LCMS confirmed complete consumption of the starting material and the desired mass (R t=0.200 min). The reaction mixture was concentrated under vacuum to obtain a residue. The residue was diluted with H2O (50 mL) and adjusted to pH = 10 with Na2CO3, and then extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)carbamate (950 mg, 2.33 mmol, yield 81.04%, purity 95%) as a yellow solid. MS (M+H) + =387.3.

[0403] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7)

[0404] To a solution of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (900 mg, 2.33 mmol) and 3-bromopiperidine-2,6-dione (625.91 mg, 3.26 mmol) in ACN (4 mL) was added NaHCO₃ (978.01 mg, 11.64 mmol, 452.99 μL) at 20°C. The mixture was stirred at 80°C for 16 hours. LCMS confirmed complete consumption of tert-butyl ((1R,5S,6s)-3-((1-(4-aminophenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate, and the expected mass was detected. The reaction mixture was filtered and the filter cake was washed with a mixed solution (40 mL, MeOH: EtOAc = 1: 1). The filtrate was concentrated under vacuum to obtain a residue. The residue was purified by flash silica gel chromatography (20 g of The product was purified by silica gel flash column with an eluent of 0-100% EtOAc / petroleum ether in a gradient of 0-50% DCM:MeOH @ 80 mL / min, and further purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 0%-30% B over 10 minutes), and then lyophilized to give tert-butyl ((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (220 mg, 397.89 μmol, yield 17.09%, purity 90%) as a brown solid. MS(M+H) + =498.2.

[0405] Step 6. Synthesis of 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (8)

[0406] 3-((4-(4-(((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, crude, HCl) was synthesized by a method similar to that described in Step 5 of Example 1 as a yellow solid. MS (M+H) + =398.2.

[0407] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 22)

[0408] By a method similar to that described in Step 10 of Example 2, 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (68.7 mg, 60.49 μmol, 21.88% yield, 90.6% purity, 2TFA) was obtained as a gray solid. MS (M+H) + =801.2.

[0409] 1 H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.57-9.27 (m, 1H), 8.55-8.45 (m, 1H), 8.29 (d, J = 8.2Hz, 1H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.50-7. 46(m,2H),7.43-7.21(m,2H),6.80-6.73(m,2H),4.91-4.84(m,1H),4.43-4.34(m,2H),4.06(t,J=13.3Hz,2H),3.93(s,3H),3.89-3.83( m,2H),3.57-3.52(m,2H),3.49-3.43(m,2H),3.32(s,3H),3.22-3.17(m,1H),3.13-3.01(m,1H),2.99-2.89(m,1H),2.81-2.69(m,1H),2 .63-2.55(m,1H),2.41-2.37(m,1H),2.16-2.15(m,1H),2.12-2.03(m,5H),1.97-1.88(m,2H),1.63-1.57(m,1H),1.24(d,J=6.6Hz,6H).

[0410] Example 23. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 23)

[0411]

[0412] Step 1. Synthesis of 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (3)

[0413] By a method similar to that described in Step 6 of Example 4, acetone was replaced with ACN to obtain 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (1 g, 3.98 mmol, 34.54% yield, 100% purity) as a yellow solid. MS (M+H) + =252.2.

[0414] Step 2. Synthesis of 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine (4)

[0415] To a solution of 2-(4-(4-nitrophenyl)piperazin-1-yl)ethane-1-ol (1 g, 3.98 mmol) in DCM (20 mL) were added PPh3 (1.36 g, 5.17 mmol) and CBr4 (1.72 g, 5.17 mmol) at 0°C, and the mixture was stirred for 16 hours under N2 gas and 25°C. The peak of the desired mass (32%) was confirmed by LCMS. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography ( 40g Purification was performed using a silica gel flash column with a 0-50% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine (0.6 g, 1.81 mmol, 45.59% yield, 95% purity) as a yellow solid. MS (M+H) + =314.2.

[0416] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6)

[0417] After adding tert-butyl ((1R, 5S, 6s) -3- azabicyclo [3.1.0] hexane -6- yl) carbamate (300 mg, 1.51 mmol), DIPEA (667.78 mg, 5.17 mmol, 899.98 μL) and NaI (45.36 mg, 302.63 μmol) to a solution of 1- (2- bromoethyl) -4- (4-nitrophenyl) piperazine (522.94 mg, 1.66 mmol) in DMF (10 mL), the mixture was stirred for 16 hours under N2 gas and 20 ° C. The peak of the desired mass (81%) was confirmed by LCMS. The reactant was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 10g Purification was performed on a silica gel flash column with a 0-100% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl ((1R,5S,6s)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.5 g, 1.16 mmol, 76.57% yield, 100% purity) as a yellow solid. MS (M+H) + =432.3.

[0418] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-aminophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7)

[0419] By a method similar to that described in Step 4 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(4-(4-aminophenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.25 g, 579.01 μmol, 49.97% yield, 93% purity) was obtained as a yellow oil. MS (M+H) + =402.3.

[0420] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (9)

[0421] By a method similar to that described in step 5 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (120 mg, 215.35 μmol, 34.59% yield, 92% purity) was obtained as a black solid. MS (M+H) + =513.4.

[0422] Step 6. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (10)

[0423] 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.1 g, 189.92 μmol, 97.36% yield, TFA) was obtained as a red solid by a method similar to that described in Step 6 of Example 3. MS (M+H) + =413.2.

[0424] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 23)

[0425] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (55.6 mg, 64.74 μmol, 34.09% yield, 95% purity) was obtained as a white solid. MS (M+H) + =816.4.

[0426] 1H NMR (400MHz, DMSO-d6) δ = 10.76 (s, 1H), 8.29 (d, J = 8.9Hz, 1H), 8.26-8.20 (m, 2H), 7.88 (s, 1H), 7.50-7.43 (m, 2H), 6.75(d,J=8.9Hz,2H),6.61(d,J=8.9Hz,2H),5.37(d,J=7.3Hz,1H),4.93-4.82(m,1H),4.25-4.14(m,1H),4.04(br t,J=13.6Hz,2H),3.93(s,3H),3.31(br s,3H),3.12(d,J=8.8Hz,2H),3.06-3.00(m,1H),2.99-2.90(m,4H),2.79-2.66(m,2H),2.64-2.56(m,4H),2.46- 2.40(m,3H),2.39-2.30(m,3H),2.17-2.05(m,1H),1.92-1.76(m,1H),1.68-1.61(m,2H),1.24(d,J=6.8Hz,6H).

[0427] Example 24. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 24)

[0428]

[0429] Step 1. Synthesis of benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (2)

[0430] Benzyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.94 g, 3.71 mmol, 97.75% yield, 50% purity) was obtained as a white solid by a method similar to that described in Step 1 of Example 6. MS (M+H) + =262.2.

[0431] Step 2. Synthesis of benzyl 4-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidine-1-carboxylate (3)

[0432] Benzyl 4-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidine-1-carboxylate (1.4 g, crude product) was synthesized by a method similar to that described in Step 1 of Example 22 as a yellow oil. MS (M+H) + =444.3.

[0433] Step 3. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (4)

[0434] By a method similar to that described in Step 2 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.1 g, crude product) was obtained as a bright yellow oil. MS (M+H) + =310.2.

[0435] Step 4. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (6)

[0436] By a method similar to that described in Step 3 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (650 mg, 1.51 mmol, 42.47% yield) was obtained as a yellow solid. MS (M+H) + =431.2.

[0437] Step 5. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-aminophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (7)

[0438] By a method similar to that described in Step 4 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(1-(4-aminophenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (650 mg, 1.62 mmol, 88.44% yield) was obtained as a gray solid. MS (M+H) + =401.3.

[0439] Step 6. Synthesis of tert-butyl ((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (9)

[0440] By a method similar to that described in Step 5 of Example 22, tert-butyl ((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (240 mg, 469.07 μmol, 93.94% yield) was obtained as a gray solid. MS (M+H) + =512.4.

[0441] Step 7. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (10)

[0442] 3-((4-(4-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (200 mg, crude, HCl salt) was synthesized by a method similar to that described in Step 6 of Example 22 as a cyan solid. MS (M+H) + =412.3.

[0443] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (Compound 24)

[0444] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-3-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-methoxybenzamide (78.9 mg, 91.30 μmol, 24.66% yield, 94.3% purity) was obtained as a gray solid. MS (M+H) + =815.5.

[0445] 1 H NMR (400MHz, DMSO-d6) δ=10.75(s,1H),8.30-8.27(m,1H),8.25-8.22(m,1H),8.21(s,1H),7.87(s,1H),7.47-7.44(m,2H),6.74(d,J=8.9Hz,2H) ,6.59(d,J=8.9Hz,2H),5.35(d,J=7.3Hz,1H),4.91-4.82(m,1H),4.22-4 .14(m,1H),4.03(t,J=13.6Hz,2H),3.92(s,3H),3.36(s,3H),3.07(d,J= 8.8Hz,2H),3.01-2.98(m,1H),2.78-2.69(m,1H),2.61-2.57(m,1H),2.5 6-2.54(m,1H),2.47-2.44(m,2H),2.44-2.39(m,3H),2.29(d,J=7.9Hz,2 H),2.14-2.07(m,1H),1.86-1.80(m,1H),1.72(d,J=11.3Hz,2H),1.64-1 .58(m,2H),1.42-1.34(m,3H),1.34-1.26(m,2H),1.23(d,J=6.8Hz,6H).

[0446] Example 25. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (Compound 25)

[0447]

[0448] Step 1. Synthesis of tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2)

[0449] To a solution of DMSO (5.50 g, 70.33 mmol, 5.50 mL) in DCM (50 mL), (COCl) (3.57 g, 28.13 mmol, 2.46 mL) was slowly added at -70 ° C, and the mixture was stirred for 0.5 hours at -70 ° C. Then, a solution of (1R, 5S, 6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3 g, 14.07 mmol) in DCM (5 mL) was added, and the mixture was stirred for 0.5 hours at -70 ° C. TEA (7.12 g, 70.33 mmol, 9.79 mL) was added, and the mixture was stirred for 0.5 hours at -70 ° C. By TLC (petroleum ether / EtOAc=2 / 1), it was confirmed that the starting material was completely consumed and a new spot was formed. The residue was diluted with saturated aqueous Na2SO3 (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g of Purification was performed on a silica gel flash column with a 0-30% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.7 g, 12.78 mmol, 90.86% yield) as a yellow oil. MS (M+H) + =212.3.

[0450] Step 2. Synthesis of tert-butyl (1R,5S,6s)-6-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (3)

[0451] To a suspension of methyl(triphenyl)phosphine bromide (6.85 g, 19.17 mmol) in THF (50 mL), KHMDS (1 M, 19.17 mL) was added under N2 and 0°C. After the mixture was stirred for 1 hour at 20°C, a solution of (1R, 5S, 6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.7 g, 12.78 mmol) in THF (2 mL) was added under N2 and -70°C. The mixture was warmed to -10°C and stirred at -10°C for 1 hour. By TLC (petroleum ether / EtOAc=2 / 1), it was confirmed that the starting material was completely consumed and a new spot was formed. The residue was diluted with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g of Purification was performed using a silica gel flash column with a 0-20% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl (1R,5S,6s)-6-vinyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.4 g, 11.47 mmol, 89.73% yield) as a yellow oil. MS (M+H) + =210.3.

[0452] Step 3. Synthesis of tert-butyl (1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4)

[0453] To a solution of (1R, 5S, 6s) -6-vinyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tert-butyl ester (2.4 g, 11.47 mmol) in THF (50 mL) cooled at 0 ° C, BH3-Me2S (10 M, 1.72 mL) solution was added under N2 conditions, and the mixture was stirred at 0 ° C for 30 minutes. The reactants were warmed to 20 ° C and stirred for 1 hour. After the mixture was carefully treated with NaOH (3 M, 9.60 mL), H2O2 (6.80 g, 59.95 mmol, 5.76 mL, 30% purity) was added at 0 ° C. The resulting mixture was stirred at 65 ° C for 1 hour. By TLC (petroleum ether / EtOAc = 2 / 1), it was confirmed that the starting material was completely consumed and a new spot was formed. The mixture was quenched by adding aqueous saturated Na2SO3 (100 mL) and adjusted to pH = 8 with 1N HCl. The resulting solution was extracted with EtOAc (50 mL × 3), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (40 g of Purification was performed using a silica gel flash column with a 0-30% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford tert-butyl (1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2 g, 5.28 mmol, 46.04% yield) as a white solid. MS (M+H) + =228.3.

[0454] Step 4. Synthesis of 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (5)

[0455] 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (0.9 g, crude product, HCl) was obtained as a colorless oil by a method similar to that described in Step 5 of Example 1. MS (M+H) + =128.2.

[0456] 1 H NMR (400MHz, CD3OD) δ = 3.64 (t, J = 6.4Hz, 2H), 3.42-3.37 (m, 4H), 1.71-1.62 (m, 2H), 1.53 (q, J = 6.5Hz, 2H), 0.97-0.87 (m, 1H).

[0457] Step 5. Synthesis of 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (6)

[0458] To a solution of 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)ethan-1-ol (0.9 g, 5.50 mmol, HCl) in H2O (20 mL) was added NaNO2 (1.14 g, 16.50 mmol) and AcOH (1.32 g, 22.00 mmol, 1.26 mL), and the resulting mixture was stirred at 20°C for 12 hours. TLC (EtOAc) confirmed complete consumption of the starting material and the formation of a new spot. The residue was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (1.2 g, crude product) as a yellow oil. MS (M+H) + =157.2.

[0459] Step 6. Synthesis of tert-butyl ((1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (7)

[0460] To a solution of 2-((1R,5S,6s)-3-nitroso-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol (0.6 g, 3.84 mmol) in THF (10 mL) and H₂O (2 mL) were added small amounts of NH₄Cl (821.98 mg, 15.37 mmol) and Zn (1.02 g, 15.53 mmol). The mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with THF (10 mL) and H₂O (10 mL). Boc₂O (2.52 g, 11.53 mmol, 2.65 mL) and NaHCO₃ (968.18 mg, 11.53 mmol) were added to the filtrate, and the mixture was stirred at 20°C for 12 hours. TLC (EtOAc) confirmed the formation of a new spot. The residue was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 5G Purification was performed on a silica gel flash column with a 0-60% EtOAc / petroleum ether gradient at 50 mL / min as the eluent to afford tert-butyl ((1R,5S,6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (0.2 g, 825.38 μmol, yield 21.48%) as a white solid. MS (M+H) + =243.3.

[0461] 1 H NMR (400MHz, CDCl3) δ = 5.37 (br s, 1H), 3.74-3.65 (m, 3H), 3.20 (d, J = 8.3Hz, 2H), 2.89 (d, J = 8.6Hz, 2H), 1.49-1.36 (m, 11H), 1.26-1.18 (m, 3H).

[0462] Step 7. Synthesis of 2-((1R,5S,6s)-3-((tert-Butyloxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (8)

[0463] To a solution of tert-butyl ((1R, 5S, 6s)-6-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-yl)carbamate (150 mg, 619.03 μmol) in DCM (5 mL) was added TEA (187.92 mg, 1.86 mmol, 258.48 μL) and TosCl (141.62 mg, 742.84 μmol) at 20°C, and the mixture was stirred for 16 hours at 20°C. The peak of the desired mass (80%) was confirmed by LCMS. The residue was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g of Purification was performed on a silica gel flash column with a 0-40% EtOAc / petroleum ether gradient at 60 mL / min as the eluent to afford 2-((1R,5S,6s)-3-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (130 mg, 327.87 μmol, 52.96% yield) as a yellow oil. MS (M+Na) + =419.2.

[0464] Step 8. Synthesis of tert-butyl ((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (10)

[0465] To a solution of 2-((1R,5S,6s)-3-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-6-yl)ethyl 4-methylbenzenesulfonate (130 mg, 327.87 μmol) and 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (130.00 mg, 400.24 μmol, HCl) in DMF (2 mL) were added KI (10.89 mg, 65.57 μmol) and DIPEA (127.12 mg, 983.61 μmol, 171.33 μL), and the mixture was stirred at 80°C for 2 hours. LCMS confirmed the presence of a major peak of the desired mass. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g of Purification was performed on a silica gel flash column with a 0-10% MeOH / EtOAc gradient at 60 mL / min as the eluent to afford tert-butyl ((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)carbamate (80 mg, 131.09 μmol, 39.98% yield, 84% purity) as a yellow oil. MS (M+H) + =513.4.

[0466] Step 9. Synthesis of 3-((4-(4-(2-((1R,5S,6s)-3-amino-3-azabicyclo[3.1.0]hexan-6-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (11)

[0467] 3-((4-(4-(2-((1R,5S,6s)-3-amino-3-azabicyclo[3.1.0]hexan-6-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (80 mg, 151.93 μmol, 97.36% yield, TFA) was obtained as a yellow oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =413.3.

[0468] Step 10. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (Compound 25)

[0469] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1R,5S,6s)-6-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)ethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-methoxybenzamide (13.7 mg, 15.28 μmol, 10.06% yield, 91% purity) was obtained as a brown solid. MS (M+H) + =816.4.

[0470] 1 H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 9.0Hz, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.51-7.41 (m, 2H), 6. 82(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),5.44(d,J=6.5Hz,1H),5.01-4.83(m,1H),4.30-4.21(m,1H),4.09(t,J=13.7Hz, 2H),3.98(s,3H),3.51-3.42(m,5H),3.39-3.31(m,3H),3.31-2.56(m,2H),3.19-3.06(m,2H),3.12-3.03(m,4H),2.85-2.7 5(m,1H),2.69-2.61(m,2H),2.21-2.12(m,1H),1.95-1.82(m,1H),1.47-1.40(m,2H),1.35-1.29(m,8H),1.18-1.12(m,1H).

[0471] Example 26. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 26)

[0472]

[0473] Step 1. Synthesis of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3)

[0474] A similar method to that described in Step 6 of Example 4 was used, except that acetone was replaced with DMF (50 mL). Tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3 g, 6.07 mmol, 79.03% yield, 94% purity) was obtained as a yellow solid. MS (M+H) + =465.4.

[0475] Step 2. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (4)

[0476] To a solution of tert-butyl ((1r,4r)-4-(((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (3 g, 6.46 mmol) in CF3CH2OH (100 mL) was slowly added Pd / C (500 mg, 10% purity) under N2. The suspension was degassed and washed three times with H2. The mixture was then stirred under H2 (15 Psi) at 25°C for 14 hours. TLC (DCM:MeOH = 10:1) confirmed the consumption of the starting material and detected a new spot. The mixture was filtered, and the filter cake was washed with EtOH (100 mL) and THF (100 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl ((1r,4r)-4-(((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (2.8 g, crude product) as a yellow oil. MS (M+H) + =435.4.

[0477] Step 3. Synthesis of tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (6)

[0478] By a method similar to that described in Step 5 of Example 22, tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (540 mg, 761.97 μmol, 33.11% yield, 77% purity) and tert-butyl ((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)carbamate (420 mg, 677.31 μmol, 29.44% yield, 88% purity) were obtained as cyan solids. MS (M+H) + =546.5.

[0479] Step 4. Synthesis of 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (7)

[0480] 3-((4-(4-((((1r,4r)-4-aminocyclohexyl)(methyl)amino)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (150 mg, crude product, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a dark brown oil. MS (M+H) + =446.5.

[0481] Step 5. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (Compound 26)

[0482] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-3-methoxybenzamide (29.8 mg, 34.05 μmol, 14.35% yield, 97% purity) was obtained as a gray solid. MS (M+H) + =849.4.

[0483] 1 H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.30 (d, J = 8.3Hz, 1H), 8.22 (s, 1H), 8.12-8.07 (m, 1H), 7.88 (s, 1H), 7.52-7 .46(m,2H),6.83(t,J=9.3Hz,1H),6.53-6.46(m,1H),6.43-6.38(m,1H),5.82-5.75(m,1H),4.92-4.83(m,1H),4.29 -4.20(m,1H),4.09-3.99(m,2H),3.93(s,3H),3.81-3.70(m,1H),3.34(s,3H),3.15-3.07(m,2H),2.78-2.68(m,1H) ,2.60-2.52(m,9H),2.11-2.04(m,1H),1.96-1.89(m,3H),1.86-1.72(m,4H),1.47-1.34(m,4H),1.29-1.17(m,9H).

[0484] Example 27. Synthesis of N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 27)

[0485]

[0486] Step 1. Synthesis of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-benzoic acid (3)

[0487] To a solution of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (650 mg, 2.35 mmol) and 4-amino-3-methoxy-benzoic acid (400.58 mg, 2.40 mmol) in H O (16 mL) and EtOH (4 mL) was added HCl (12 M, 293.67 μL), and the mixture was stirred at 100° C. for 16 hours. LCMS confirmed the desired mass peak (79%). The reaction mixture was filtered at 50°C and the filter cake was collected to obtain 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxy-benzoic acid (0.6 g, 1.44 mmol, yield 61.44%, purity 98%) as a brown solid. MS (M+H) + =408.1.

[0488] Step 2. Synthesis of N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 27)

[0489] N-((1r,4r)-4-(((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)(methyl)amino)cyclohexyl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (48.6 mg, 39.64 μmol, 5.89% yield, 96% purity, 3TFA) was obtained as a gray solid. MS (M+H) + =835.4.

[0490] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.92-8.75 (m, 1H), 8.31-8.14 (m, 4H), 7.56-7.45 (m, 2H), 7.01-6.86 (m, 1H),6.54(d,J=15.7Hz,1H),6.46(d,J=7.9Hz,1H),4.28-4.25(m,2H),4.22-4.21(m,1H),4.18-4.17(m,1H),3. 94(s,3H),3.87-3.80(m,1H),3.66(q,J=6.9Hz,2H),3.33(s,3H),3.29-3.16(m,4H),3.01-2.91(m,1H),2.83-2 .78(m,3H),2.78-2.69(m,2H),2.13-1.75(m,10H),1.74-1.60(m,2H),1.55-1.36(m,4H),1.21(t,J=7.0Hz,3H).

[0491] Example 28. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 28)

[0492]

[0493] Step 1. Synthesis of tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (2)

[0494] By a method similar to that described in Step 1 of Example 25, tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (2.5 g, crude product) was obtained as a yellow oil. MS (M+H) + =243.3.

[0495] Step 2. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (4)

[0496] By a method similar to that described in step 6 of Example 1, tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.2 g, 360.46 μmol, 56.17% yield, 96% purity) was obtained as a cyan solid. MS (M+H) + =533.4.

[0497] Step 3. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (5)

[0498] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (150 mg, 274.45 μmol, 97.46% yield, TFA) was obtained as a yellow oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =433.4.

[0499] Step 4. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 28)

[0500] N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (105.3 mg, 110.26 μmol, 40.18% yield, 98% purity, TFA) was obtained as a white solid. MS (M+H) + =822.4.

[0501] 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.90-9.61 (m, 1H), 9.58-9.37 (m, 1H), 8.39-8.15 (m, 3H), 7.56-7.38 (m, 2H), 6.90 (t, J =9.3Hz,1H),6.56(dd,J=2.1,14.9Hz,1H),6.49-6.42(m,1H),4.29-4.18(m,3H),3.95(s,3H),3.69-2.61(m,2H),3.61-3.54(m ,2H),3.33(s,3H),3.34-3.26(m,2H),3.25-3.11(m,6H),3.00-2.91(m,2H),2.92-2.85(m,2H),2.79-2.69(m,1H),2.67-2.61 (m,1H),2.12-2.04(m,1H),1.94-1.83(m,1H),1.81-1.74(m,2H),1.70-1.61(m,2H),1.45-1.36(m,3H),1.22(t,J=7.0Hz,3H).

[0502] Example 29. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 29)

[0503]

[0504] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (82 mg, 67.52 μmol, 31.62% yield, 97% purity, 3TFA salt) was synthesized as a white solid. MS (M+H) + =836.3.

[0505] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.81-9.61 (m, 1H), 9.58-9.34 (m, 1H), 8.35-8.12 (m, 3H), 7.54-7.36 (m,2H),6.90(t,J=9.4Hz,1H),6.55(dd,J=2.3,14.9Hz,1H),6.50-6.38(m,1H),4.94-4.83(m,1H),4.28(br dd,J=4.9,11.6Hz,1H),4.08(br s,2H),3.94(s,3H),3.57(br d,J=11.5Hz,2H),3.32(s,3H),3.28(br d,J=11.4Hz,2H),3.20(br d,J=8.8Hz,3H),3.17-3.10(m,3H),3.00-2.91(m,2H),2.90-2.79(m,2H),2.78-2.67(m,1H),2.63-2.54(m,1H),2. 13-2.02(m,1H),1.93-1.82(m,1H),1.81-1.71(m,2H),1.70-1.55(m,2H),1.49-1.30(m,3H),1.24(d,J=6.7Hz,6H).

[0506] Example 30. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 30)

[0507]

[0508] Step 1. Synthesis of tert-butyl 4-(2-(tosyl)ethyl)piperidine-1-carboxylate (2)

[0509] By a method similar to that described in Step 7 of Example 25, DMAP (26.64 mg, 218.04 μmol) was added and synthesized to give tert-butyl 4-(2-(tosyl)ethyl)piperidine-1-carboxylate (8.56 g, 19.64 mmol, 90.08% yield, 88% purity) as a bright yellow oil. MS (M-100+H) + =284.1.

[0510] Step 2. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3)

[0511] To a solution of tert-butyl 4-(2-(tosyl)ethyl)piperidine-1-carboxylate (5 g, 13.04 mmol) and benzyl piperidin-4-ylcarbamate (3.1 g, 13.23 mmol) in ACN (80 mL) was added KCO (3.60 g, 26.08 mmol) and KI (43.29 mg, 260.76 μmol), and the mixture was stirred for 16 hours under N gas and 60 ° C. By LCMS, it was confirmed that tert-butyl 4-(2-(tosyl)ethyl)piperidine-1-carboxylate was completely consumed, and 98% of the required mass was confirmed. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed on a silica gel flash column with a gradient of 25-100% EtOAc / petroleum ether to 10% MeOH / EtOAc at 200 mL / min to afford tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (5.53 g, 12.41 mmol, 95.19% yield) as a light brown solid. MS (M+H) + =446.4.

[0512] Step 3. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4)

[0513] Benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.7 g, HCl salt) was synthesized similarly to the method described in Step 5 of Example 1 as a light brown solid and used directly. MS (M+H) + =346.2.

[0514] Step 4. Synthesis of benzyl (1-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6)

[0515] A mixture of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.7 g, 17.54 mmol, HCl salt), 1,2-difluoro-4-nitrobenzene (5.58 g, 35.08 mmol, 3.88 mL), and KCO (7.27 g, 52.63 mmol) in DMF (70 mL) was stirred at 20°C for 16 hours. LCMS confirmed complete consumption of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate, and 39% of the desired mass was confirmed. The mixture was diluted with H2O (600 mL) and extracted with a mixture (EtOAc:MeOH = 10:1, 200 mL x 3). The combined organic layers were washed with brine (300 mL x 5), dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with a mixed solution (petroleum ether / EtOAc = 5 / 1, 40 mL) for 10 minutes, the suspension was filtered, and the filter cake was washed with a mixed solution (petroleum ether / EtOAc = 5 / 1, 40 mL). The filter cake was collected and dried under vacuum to obtain benzyl (1-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5.33 g, 11.00 mmol, yield 62.70%) as a yellow solid. MS (M+H) + =485.2.

[0516] Step 5. Synthesis of benzyl (1-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7)

[0517] Benzyl (1-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4.9 g, 10.78 mmol, 98.55% yield) was synthesized by a method similar to that described in Step 4 of Example 22 as a red solid. MS (M+H) + =455.2.

[0518] Step 6. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (8)

[0519] A method similar to that described in Step 5 of Example 22 was used to synthesize benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (480 mg, 610.95 μmol, 34.72% yield, 72% purity) as a gray solid. MS (M+H)+ =566.5.

[0520] Step 7. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (9)

[0521] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (195 mg, TFA salt) was obtained as a green oil by a method similar to that described in Step 2 of Example 4 and used directly. MS (M+H) + =432.2.

[0522] Step 8. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 30)

[0523] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (105.7 mg, 85.23 μmol, 23.83% yield, 97% purity, 3TFA salt) was synthesized as a light gray solid. MS (M+H) + =861.3.

[0524] 1H NMR (400MHz, DMSO-d6) δ = 10.82 (s, 1H), 9.59-9.32 (m, 1H), 8.47-8.35 (m, 1H), 8.33-8.25 (m, 2H), 8.23 ​​( d,J=8.7Hz,1H),7.60-7.44(m,2H),7.23-7.01(m,1H),6.68-6.55(m,1H),6.50(d,J=8.1Hz,1H),4.82-4 .74(m,1H),4.38-4.25(m,1H),4.22-3.98(m,3H),3.97-3.84(m,3H),3.58(d,J=11.1Hz,1H),3.45-1.13 (m,5H),3.20-2.87(m,4H),2.07-1.99(m,4H),1.99-1.76(m,8H),1.75-1.62(m,6H),1.61-1.40(m,8H).

[0525] Example 31. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 31)

[0526]

[0527] Step 1. Synthesis of tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidine-1-carboxylate (3)

[0528] To a solution of benzyl (7-azaspiro [3.5] nonane-2-yl) carbamate (2 g, 6.43 mmol, HCl) and tert-butyl 4- (2- (tosyl) ethyl) piperidine-1-carboxylate (3 g, 7.82 mmol) in DMSO (50 mL) was added DIPEA (2.49 g, 19.30 mmol, 3.36 mL) and the resulting mixture was stirred at 80 ° C for 16 hours. The peak of the desired mass (56%) was confirmed by LCMS. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (80 mL×3). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (50 g of Purification was performed on a silica gel flash column with a 0-100% EtOAc / petroleum ether gradient at 100 mL / min to afford tert-butyl 4-(2-(2-((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidine-1-carboxylate (2 g, 4.12 mmol, 64.00% yield, 100% purity) as a yellow oil. MS (M+H) + =486.3.

[0529] Step 2. Synthesis of benzyl (7-(2-(piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4)

[0530] Benzyl (7-(2-(piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.0 g, crude product, HCl) was synthesized by a method similar to that described in Step 5 of Example 1 as a yellow solid. MS (M+H) + =386.3.

[0531] Step 3. Synthesis of benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6)

[0532] Benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.24 mmol, 63.06% yield, 98% purity) was synthesized by a method similar to that described in Step 4 of Example 30 as a yellow oil. MS (M+H) + =525.4.

[0533] Step 4. Synthesis of tert-butyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7)

[0534] A mixture of benzyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.29 mmol) in TFA (18.42 g, 161.55 mmol, 12.00 mL) was stirred at 40°C for 2 hours. The mixture was concentrated, and the residue was diluted with THF (20 mL). Then, Boc2O (748.81 mg, 3.43 mmol, 788.22 μL) and TEA (694.36 mg, 6.86 mmol) were added, and the resulting mixture was stirred at 20°C for 2 hours. LCMS confirmed the desired mass (47%). The mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed on a silica gel flash column with a 0-100% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl (7-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.2 g, 2.20 mmol, 96.24% yield, 90% purity) as a yellow oil. MS (M+H) + =491.2.

[0535] Step 5. Synthesis of tert-butyl (7-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8)

[0536] By a method similar to that described in Step 4 of Example 22, tert-butyl (7-(2-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (0.82 g, 1.48 mmol, 60.41% yield, 83% purity) was obtained as a yellow oil. MS (M+H) + =461.4.

[0537] Step 6. Synthesis of tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (10)

[0538] By synthesizing in a manner similar to that described in Step 5 of Example 22, tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.5 g, crude product) was obtained as a brown solid. MS (M+H) + =572.5.

[0539] Step 7. Synthesis of 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (11)

[0540] 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1 g, crude, TFA) was obtained as a black oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =472.3.

[0541] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 31)

[0542] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (440.4 mg, 440.84 μmol, 25.82% yield, 99% purity, TFA) was obtained as a white solid. MS (M+H) + =875.4.

[0543] 1H NMR (400MHz, DMSO-d6) δ=10.81(s,1H),9.46-9.19(m,1H),8.54(d,J=6.9Hz,1H),8.50-8.37(m,1H),8.25(s,1H),8.22(d,J =8.3Hz,1H),7.57-7.49(m,2H),7.22-7.07(m,1H),6.66-6.56(m,1H),6.52(d,J=8.0Hz,1H),4.96-4.84(m,1H),4.51-4.39 (m,1H),4.37-4.30(m,1H),4.11(t,J=13.3Hz,2H),4.03-3.85(m,4H),3.49-3.32(m,6H),3.19-2.86(m,5H),2.85-2.59(m, 3H),2.43-2.34(m,1H),2.24-1.93(m,5H),1.92-1.75(m,6H),1.69-1.60(m,2H),1.58-1.49(m,3H),1.25(d,J=6.6Hz,6H).

[0544] Example 32. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 32)

[0545]

[0546] Step 1. Synthesis of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (2)

[0547] By a method similar to that described in step 4 of Example 30, tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (21 g, 64.55 mmol, 30.06% yield) was obtained as a yellow solid. MS (M+H) + =325.9.

[0548] 1 H NMR (400MHz, CDCl3) δ = 8.02 (t, J = 9.1Hz, 1H), 6.69-6.42 (m, 2H), 3.70-3.54 (m, 4H), 3.48-3.33 (m, 4H), 1.50 (s, 9H).

[0549] Step 2. Synthesis of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (3)

[0550] By synthesizing in a manner similar to that described in step 4 of Example 22, tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (19 g, crude product) was obtained as a brown solid. MS (M+H) + =296.1.

[0551] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (4)

[0552] A similar method to that described in Step 5 of Example 22 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (25 g, 61.51 mmol, 95.61% yield) as a green solid. MS (M+H) + =407.1.

[0553] 1 H NMR (400MHz, CDCl3) δ = 8.45 (s, 1H), 6.75-6.57 (m, 3H), 4.59-4.45 (m, 1H), 4.06-3.97 (m, 1H), 3.62-3.51 (m, 4H) ),3.04-2.92(m,4H),2.88-2.79(m,1H),2.78-2.66(m,1H),2.51-2.43(m,1H),2.00-1.88(m,1H),1.48(s,9H).

[0554] Step 4. Synthesis of 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (5)

[0555] 3-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (21 g, crude product, HCl) was synthesized by a method similar to that described in Step 5 of Example 1 as a green solid. MS (M+H) + =306.9.

[0556] Step 5. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (6)

[0557] A similar method to that described in Step 3 of Example 23 was used to synthesize tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (2.9 g, 5.44 mmol, 37.33% yield) as a brown solid. MS (M+H) + =533.3.

[0558] Step 6. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7)

[0559] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.4 g, crude, HCl) was obtained as a green solid by a method similar to that described in Step 4. MS (M+H) + =433.2.

[0560] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 32)

[0561] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (2.43 g, 2.75 mmol, 61.43% yield, 97.4% purity) was synthesized as an off-white solid. MS (M+H) + =862.5.

[0562] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.34-8.24 (m, 2H), 8.12 (d, J = 7.8Hz, 1H), 7.96 (s, 1H), 7.55 -7.46(m,2H),6.81-6.69(m,2H),6.63-6.55(m,1H),5.12-5.02(m,1H),4.82-4.71(m,1H),4.32-4.2 1(m,1H),4.05(t,J=14.1Hz,2H),3.94(s,3H),3.84-3.71(m,1H),3.37-3.34(m,2H),3.04-2.85(m,6 H),2.80-2.70(m,1H),2.62-2.45(m,10H),2.14-1.88(m,6H),1.84-1.67(m,4H),1.67-1.52(m,6H).

[0563] Example 33. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 33)

[0564]

[0565] Step 1. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (3)

[0566] A similar method to that described in Step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (7.8 g, 14.64 mmol, 55.78% yield) as a gray solid. MS (M+H) + =533.3.

[0567] Step 2. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (4)

[0568] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.1 g, crude, TFA) was obtained as a green oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =433.2.

[0569] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 33)

[0570] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (1.30 g, 1.52 mmol, 49.40% yield, 98.0% purity) was obtained as an off-white solid. MS (M+H) + =836.5.

[0571] 1H NMR (400MHz, DMSO-d6)δ=10.86-10.77(m,1H),9.25(s,1H),8.35-8.28(m,1H),8.22(s,1H),7.91-7.84(m,1H),7.47-7.39( m,2H),6.79-6.69(m,2H),6.62-6.54(m,1H),5.11-5.03(m,1H),4.88(t,J=13.2Hz,1H),4.32-4.22(m,1H),4.08-4.00(m,2H ),3.93(s,3H),3.34-3.31(m,4H),3.04-2.93(m,6H),2.79-2.68(m,3H),2.61-2.51(m,2H),2.47-2.43(m,2H),2.37-2.29(m ,2H),2.13-2.06(m,1H),2.00-1.90(m,1H),1.76-1.66(m,2H),1.46-1.38(m,2H),1.34-1.27(m,3H),1.25(d,J=6.5Hz,6H).

[0572] Example 34. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 34)

[0573]

[0574] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (1.2 g, 2.68 mmol) in DMF (16 mL) were added EDCI (960.00 mg, 5.01 mmol), HOBt (660.00 mg, 4.88 mmol), DIPEA (2.23 g, 17.22 mmol, 3.00 mL), and 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (2.30 g, 4.21 mmol, TFA) at 20° C. The mixture was stirred under N2 gas at 20° C. for 16 hours. By LCMS, the peak of the desired mass (48%) was confirmed. The reaction mixture was diluted with H2O (30 mL), and the mixture was extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage; 20 g of Purification was performed using a silica gel flash column (eluent: 0-10% MeOH:DCM gradient, 60 mL / min). The product was further purified by Prep-HPLC (column: Phenomene x luna C18 150×25 mm×10 μm; mobile phase: [water (TFA)-ACN]; gradient: 21%-51% B over 10 minutes, column temperature: 30°C). The eluate was lyophilized and diluted with HCl (1 M, 40 mL). The mixture was added dropwise to Na2CO3 (1 M, 70 mL) at 0°C. The suspension was filtered, and the filter cake was washed with H2O (80 mL x 3) and then lyophilized to obtain 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (656.9 mg, 740.01 μmol, yield 27.59%, purity 97.1%) as an off-white solid. MS (M+H) + =862.5.

[0575] 1H NMR (400MHz, DMSO-d6)δ=10.86-10.76(m,1H),9.28(s,1H),8.35-8.22(m,2H),7.97(s,1H),7.49-7.35(m,2H),6.81- 6.68(m,2H),6.62-6.56(m,1H),5.10-5.03(m,1H),4.82-4.72(m,1H),4.31-4.22(m,1H),4.11-4.00(m,2H),3.93(s, 3H),3.37-3.33(m,4H),3.04-2.87(m,6H),2.83-2.69(m,3H),2.62-2.51(m,2H),2.49-2.44(m,2H),2.40-2.30(m,2H) ),2.13-2.06(m,1H),2.01-1.89(m,3H),1.77-1.66(m,4H),1.65-1.55(m,4H),1.47-1.37(m,2H),1.36-1.23(m,3H).

[0576] Example 35. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 35)

[0577]

[0578] Step 1. Synthesis of ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropionate (2)

[0579] At 20 ° C, a solution of ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropionate (44.00 g, 111.72 mmol) in THF (900 mL) was stirred until it became a transparent solution. The H2 back pressure regulator was adjusted to 1 MPa, and the flow rate of H2 was adjusted to 95 mL / min, and a fixed bed Pt / C (30 g, purity 1%) was heated to 50 ° C. Then, the solution was pumped into the reactor at a flow rate of 3 mL / min. After the reaction was completed, the pipeline was washed with THF (100 mL) and all the reaction solution was collected. The mass was confirmed by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropionate (42.00 g, crude product) as a light yellow oil. MS (M+H) + =309.1.

[0580] Step 2. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3)

[0581] A mixture of ethyl 3-((5-amino-2-chloropyrimidin-4-yl)(ethyl)amino)-2,2-difluoropropanoate (42.00 g, 136.05 mmol) in TFA (50 mL) was stirred at 50°C for 4 hours. LCMS confirmed the presence of a main peak (90%) of the desired mass. The mixture was concentrated, and the residue was diluted with EtOAc (500 mL), then washed with NaHCO₃ (100 mL x 2) and brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (100 mL) at 25°C for 10 minutes and filtered. The filter cake was collected and dried to obtain 2-chloro-9-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (26.00 g, 98.00 mmol, yield 72.04%, purity 99%) as a light yellow solid. MS (M+H) + =263.1.

[0582] 1 H NMR (400MHz, DMSO-d6) δ = 7.92 (s, 1H), 7.90-7.84 (m, 1H), 3.93 (t, J = 10.4Hz, 2H), 3.89-3.81 (m, 2H), 1.31 (t, J = 6.8Hz, 3H).

[0583] Step 3. Synthesis of 2-chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (4)

[0584] 2-Chloro-9-ethyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (25.00 g, 85.84 mmol, 86.72% yield, 95% purity) was obtained as a white solid by a method similar to that described in Step 8 of Example 4. MS (M+H) + =277.1.

[0585] 1 H NMR (400MHz, DMSO-d6) δ = 8.31 (s, 1H), 4.26 (t, J = 12.8Hz, 2H), 3.69-3.58 (m, 2H), 3.33 (s, 3H), 1.16 (t, J = 7.2Hz, 3H).

[0586] Step 4. Synthesis of methyl 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoate and 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (6 & 7)

[0587] A mixture of 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (3.4 g, 5.68 mmol, 19.63% yield, 71% purity) and methyl 4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoate (7 g, 10.83 mmol, 37.47% yield, 68% purity) was obtained as a pale yellow solid. MS (M+H) + =426.2, 440.3.

[0588] Step 5. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 35)

[0589] N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzamide (1.40 g, 1.64 mmol, 36.42% yield, 98.1% purity) was obtained as a gray solid. MS (M+H) + =840.4.

[0590] 1 H NMR (400MHz, DMSO-d6) δ = 8.38 (d, J = 14.4Hz, 1H), 8.07 (s, 1H), 7.93-7.86 (m, 1H), 7.81 (s, 1H), 7.56 (d, J = 9.2Hz ,1H),7.47(d,J=16.8Hz,1H),6.75-6.60(m,3H),4.53-4.44(m,1H),4.06-3.95(m,6H),3.75-3.66(m,2H),3.42 (s,3H),3.33-3.23(m,2H),3.14-3.27(m,4H),2.93-2.83(m,1H),2.80-2.67(m,1H),2.66-2.56(m,6H),2.54-2 .41(m,3H),2.05-1.92(m,1H),1.82-1.74(m,2H),1.57-1.45(m,4H),1.43-1.38(m,1H),1.36(d,J=6.8Hz,3H).

[0591] Example 36. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 36)

[0592]

[0593] Step 1. Synthesis of benzyl (7-((1-(4-((tert-Butoxycarbonyl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3)

[0594] A mixture of tert-butyl (4-bromo-2-fluorophenyl)carbamate (7 g, 24.13 mmol), benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8.37 g, 20.51 mmol, HCl salt), CsCO (23.58 g, 72.38 mmol), and BrettPhos Pd G (1.09 g, 1.21 mmol) in dioxane (100 mL) was degassed and purged with N three times. The mixture was then stirred under N at 100° C. for 16 hours. LCMS confirmed that 38% of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate remained, and a peak of the desired mass (30%) was confirmed. The reaction mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g Purification was performed on a silica gel flash column with a 20-80% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford benzyl (7-((1-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.5 g, 3.87 mmol, 16.06% yield, 90% purity) as a yellow solid. MS (M+H) + =581.5.

[0595] Step 2. Synthesis of benzyl (7-((1-(4-amino-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4)

[0596] Benzyl (7-((1-(4-amino-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.2 g, 3.66 mmol, 85.06% yield, 80% purity) was synthesized by a method similar to that described in Step 6 of Example 3 as a yellow solid. MS (M+H) + =481.3.

[0597] Step 3. Synthesis of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6)

[0598] Benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.3 g, 3.65 mmol, 99.78% yield, 94% purity) was synthesized by a method similar to that described in Step 5 of Example 22 as a brown solid. MS (M+H) + =592.5.

[0599] Step 4. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7)

[0600] 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (1.2 g, crude, TFA salt) was synthesized by a method similar to that described in Step 2 of Example 4 as a brown oil. MS (M+H) + =458.3.

[0601] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 36)

[0602] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (467.50 mg, 374.28 μmol, 41.50% yield, 98.5% purity, 3TFA) was obtained as a gray solid. MS (M+H) + =887.6.

[0603] 1 H NMR (400MHz, DMSO-d6) δ = 10.83 (s, 1H), 9.15-8.98 (m, 1H), 8.54-8.48 (m, 1H), 8.29-8.13 (m, 3H), 7.53- 7.47(m,2H),7.24-6.79(m,3H),4.83-4.73(m,1H),4.47-4.36(m,2H),4.12-4.03(m,2H),3.94(s,3H), 3.59-3.51(m,2H),3.47-3.36(m,2H),3.33(s,3H),3.10-3.04(m,2H),3.00-2.91(m,2H),2.89-2.70(m ,2H),2.62-2.54(m,1H),2.41-2.34(m,1H),2.21-2.13(m,1H),2.09-1.67(m,16H),1.65-1.43(m,6H).

[0604] Example 37. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 37)

[0605]

[0606] Step 1. Synthesis of tert-butyl (4-(4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate (3)

[0607] A similar method to that described in Step 3 of Example 3 was used to synthesize tert-butyl (4-(4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate (3.3 g, 5.95 mmol, 64.92% yield) as a yellow solid. MS (M+H) + =555.4.

[0608] Step 2. Synthesis of benzyl (1-(2-(1-(4-amino-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4)

[0609] Benzyl (1-(2-(1-(4-amino-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, crude, HCl) was synthesized by a method similar to that described in Step 7 of Example 7 as a yellow solid. MS (M+H) + =455.2.

[0610] Step 3. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6)

[0611] Benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.5 g, 2.65 mmol, 52.08% yield, 100% purity) was synthesized by a method similar to that described in Step 3 of Example 36 as a cyan solid. MS (M+H) + =566.3.

[0612] Step 4. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (7)

[0613] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (1.35 g, crude, TFA) was obtained as a brown oil by a method similar to that described in Step 4 of Example 36. MS (M+H) + =432.3.

[0614] Step 5. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 37)

[0615] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (403.3 mg, 468.12 μmol, 18.92% yield, 99% purity) was synthesized as a white solid. MS (M+H) + =853.5.

[0616] 1 H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.34-8.22 (m, 2H), 7.98 (s, 1H), 7.20 (d, J = 6.6Hz, 1H), 6.79-6.69 (m,2H),6.63-6.55(m,1H),5.05(d,J=6.5Hz,1H),4.95-4.80(m,1H),4.32-4.24(m,1H),4.07(t,J=13.4H z,2H),3.92(s,3H),3.49-3.37(m,2H),3.35-3.34(m,3H),2.98-2.64(m,3H),2.64-2.53(m,6H),2.53-2. 46(m,2H),2.15-2.00(m,2H),2.00-1.82(m,3H),1.79-1.70(m,3H),1.64-1.34(m,4H),1.32-1.25(m,8H).

[0617] Example 38. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 38)

[0618]

[0619] Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (2)

[0620] To a solution of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2 g, 5.83 mmol, HCl salt) in DCM (30 mL) was added TEA (1.77 g, 17.50 mmol, 2.44 mL), DMAP (71.28 mg, 583.44 μmol), and (Boc)2O (1.53 g, 7.00 mmol, 1.61 mL). The mixture was stirred at 20°C for 1.5 hours. LCMS confirmed complete consumption of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione and confirmed a major peak of the desired mass. The residue was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with water (30 mL) and dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (25 g of Purification was performed using a silica gel flash column with a 0-50% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1.8 g, 4.43 mmol, 75.91% yield) as a cyan solid. MS (M+H) + =407.3.

[0621] Step 2. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (3)

[0622] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (700 mg, 1.72 mmol) in DCM (10 mL) were added HCHO (698.90 mg, 8.61 mmol, 641.19 μL, 37% purity) and AcOH (103.42 mg, 1.72 mmol, 98.59 μL). After 30 minutes, NaBH(OAc)3 (1.10 g, 5.17 mmol) was added to the reaction mixture. The mixture was stirred at 20°C for 16 hours. LCMS confirmed that tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate remained at ~20% and multiple new peaks appeared on the LCMS, confirming ~73% of the desired compound. HCHO (279.56 mg, 3.44 mmol, 256.48 μL, 37% purity) and NaBH(Oac)3 (1.10 g, 5.17 mmol) were added to the reaction mixture. The mixture was stirred for 3 hours at 20°C. By LCMS, it was confirmed that tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate was completely consumed, and a main peak of the desired mass was confirmed. The residue was diluted with NaHCO3 solution (30 mL) and extracted with DCM (20 mL×3). The combined organic layer was washed with water (20 mL), dried over Na2SO4, and then concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g of Purification was performed on a silica gel flash column with a 0-50% EtOAc / petroleum ether gradient at 80 mL / min as the eluent to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (720 mg, 1.71 mmol, 99.43% yield) as a cyan solid. MS (M+H) + =421.2.

[0623] Step 3. Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (4)

[0624] 3-((3-fluoro-4-(piperazin-1-yl)phenyl)(methyl)amino)piperidine-2,6-dione (305 mg, 854.77 μmol, 99.84% yield, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a cyan solid. MS (M+H) + =321.2.

[0625] Step 4. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (6)

[0626] A method similar to that described in step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (270 mg, 414.87 μmol, 58.05% yield, 84% purity) as a bright yellow oil. MS (M+H) + =547.5.

[0627] Step 5. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (7)

[0628] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)(methyl)amino)piperidine-2,6-dione (138 mg, 246.17 μmol, 99.69% yield, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a yellow oil. MS (M+H) + =447.3.

[0629] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 38)

[0630] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (32.85 mg, 37.88 μmol, 23.13% yield, 98% purity) was obtained as a white solid. MS (M+H) + =850.5.

[0631] 1 H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 9.26 (s, 1H), 8.30 (d, J = 8.1Hz, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.47-7.38 (m, 2H) ,6.98-6.84(m,1H),6.75-6.62(m,1H),6.60-6.48(m,1H),4.93-4.85(m,1H),4.84-4.76(m,1H),4.04(t,J=13.6Hz,2H), 3.93(s,3H),3.32-3.31(m,3H),3.06-2.95(m,3H),2.95-2.84(m,3H),2.84-2.69(m,4H),2.69(s,3H),2.59-2.52(m,2H ),2.46-2.21(m,5H),1.90-1.82(m,1H),1.77-1.67(m,2H),1.54-1.35(m,2H),1.35-1.26(m,3H),1.24(d,J=6.7Hz,6H).

[0632] Example 39. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 39)

[0633]

[0634] Step 1. Synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene (2)

[0635] 1,2-difluoro-4-methoxy-5-nitrobenzene (2.3 g, 12.16 mmol, 85.18% yield) was obtained as a yellow solid by a method similar to that described in Step 1 of Example 7. MS (M+H) + =190.1.

[0636] Step 2. Synthesis of tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4)

[0637] By a method similar to that described in Step 4 of Example 30, MeCN (30 mL) was replaced with DMF to obtain tert-butyl 4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate (2.2 g, 6.19 mmol, 50.90% yield) as a yellow solid. MS (M+H) + =356.4.

[0638] Step 3. Synthesis of tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (5)

[0639] A method similar to that described in Step 4 of Example 22 was used to synthesize tert-butyl 4-(4-amino-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (1 g, 3.07 mmol, 99.29% yield) as a purple solid. MS (M+H) + =326.4.

[0640] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (7)

[0641] A similar method to that described in Step 5 of Example 22 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (1.02 g, 2.34 mmol, 95.05% yield) as a green solid. MS (M+H) + =437.2.

[0642] Step 5. Synthesis of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8)

[0643] 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (550 mg, crude product, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a cyan solid. MS (M+H) + =337.1.

[0644] Step 6. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (10)

[0645] A method similar to that described in Step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (340 mg, 604.26 μmol, 45.06% yield) as a bright yellow solid. MS (M+H) + =563.3.

[0646] Step 7. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (11)

[0647] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (350 mg, crude product, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a brown oil. MS (M+H) + =463.3.

[0648] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 39)

[0649] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (120.4 mg, 133.48 μmol, 33.09% yield, 96% purity) was obtained as a white solid. MS (M+H) + =866.4.

[0650] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.24 (s, 1H), 8.30 (d, J = 7.8Hz, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 7.49-7.37 (m, 2H), 6.61(d,J=7.9Hz,1H),6.54(d,J=14.5Hz,1H),5.08(d,J=6.4Hz,1H),4.93-4.82(m,1H),4.31-4.20(m,1H),4.03(t,J=13. 5Hz,2H),3.93(s,3H),3.79(s,3H),3.30(s,3H),3.08-2.94(m,3H),2.94-2.86(m,4H),2.85-2.69(m,4H),2.42-2.26(m,4 H),2.16-2.09(m,1H),1.97-1.88(m,1H),1.76-1.68(m,2H),1.46-1.38(m,2H),1.37-1.27(m,4H),1.24(d,J=6.7Hz,6H).

[0651] Example 40. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 40)

[0652]

[0653] Step 1. Synthesis of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2)

[0654] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate (500 mg, 1.15 mmol) in dioxane (1 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 20 ° C for 3 hours. By LCMS, it was confirmed that tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazine-1-carboxylate was completely consumed. The solvent was removed by concentrating the reaction mixture under reduced pressure to obtain 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (500 mg, crude product, HCl salt) as a cyan solid. MS (M+H)+ =337.1.

[0655] Step 2. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (4)

[0656] To a solution of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (500 mg, 1.34 mmol, HCl salt) and tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (487.46 mg, 2.01 mmol) in DCM (10 mL) were added TEA (135.71 mg, 1.34 mmol, 186.67 μL) and 4A MS (50 mg, 134.11 μmol). After 30 minutes, NaBH(OAc) (852.72 mg, 4.02 mmol) was added to the reaction mixture. The mixture was stirred at 20°C for 16 hours. By LCMS, it was confirmed that 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was completely consumed and a main peak of the desired mass was confirmed. The residue was diluted with NaHCO3 solution (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with water (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (20 g of Purification was performed on a silica gel flash column with a 10-20% MeOH / EtOAc gradient at 80 mL / min as the eluent to afford tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (390 mg, 693.12 μmol, 51.68% yield) as a bright yellow solid. MS (M+H) + =563.3.

[0657] Step 3. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (5)

[0658] To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (390 mg, 693.12 μmol) in DCM (6 mL) was added TFA (3.07 g, 26.93 mmol, 2 mL). The mixture was stirred at 20 °C for 1 hour. LCMS confirmed ~3% of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate remaining and ~75% of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (410 mg, crude product, TFA salt) as a brown oil. MS (M+H) + =463.2.

[0659] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 40)

[0660] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (210 mg, 469.34 μmol) in DMF (4 mL) were added HATU (267.69 mg, 704.01 μmol), DIPEA (303.29 mg, 2.35 mmol, 408.75 μL), and 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (405.92 mg, 704.01 μmol, TFA salt). The mixture was stirred at 20° C. for 2 hours. By LCMS, it was confirmed that 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazine-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione was completely consumed and a main peak of the desired mass was confirmed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g The product was purified by silica gel flash column, eluent: 10-20% MeOH / EtOAc gradient @ 80 mL / min) and prep-HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 34%-64% B over The reaction mixture was purified again (10 minutes) and the eluted product was lyophilized to obtain 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (111.7 mg, 123.47 μmol, yield: 26.31%, purity: 98.6%) as a pink solid. MS (M+H) + =892.5.

[0661] 1H NMR (400MHz, DMSO-d6) δ = 10.96-10.73 (m, 1H), 9.28 (s, 1H), 8.30-8.21 (m, 2H), 7.96 (s, 1H), 7.45-7.37 (m, 2H), 6.60 (d, J = 8. 2Hz,1H),6.54(d,J=14.4Hz,1H),5.09(d,J=6.5Hz,1H),4.83-4.69(m,1H),4.30-4.19(m,1H),4.05(t,J=14.0Hz,2H),3.93( s,3H),3.79(s,3H),3.33-3.32(m,3H),3.04-2.96(m,2H),2.95-2.86(m,4H),2.85-2.72(m,3H),2.62-2.51(m,4H),2.40-2. 30(m,3H),2.16-2.09(m,1H),1.99-1.88(m,3H),1.75-1.66(m,4H),1.64-1.55(m,4H),1.47-1.38(m,2H),1.36-1.24(m,3H).

[0662] Example 41. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 41)

[0663]

[0664] Step 1. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2)

[0665] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.15 g, HCl salt) was synthesized similarly to that described in Step 5 of Example 1 as a light brown solid and used directly. MS (M+H) + =463.2.

[0666] Step 2. Synthesis of N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 41)

[0667] N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (78.7 mg, 64.53 μmol, 13.14% yield, 97.9% purity, 3TFA salt) was synthesized as an off-white solid. MS (M+H) + =852.3.

[0668] 1 H NMR (400MHz, DMSO-d6) δ = 10.49 (s, 1H), 9.92-9.69 (m, 1H), 9.66-9.36 (m, 1H), 8.42-8.30 (m, 1H), 8.28-8.12 (m, 2H), 7. 51-7.33(m,2H),6.69-6.45(m,2H),4.31-4.19(m,3H),3.94(s,3H),3.81(s,3H),3.68-3.64(m,2H),3.57(d,J=11.4Hz, 2H),3.35-3.30(m,5H),3.25-3.11(m,6H),3.08-2.98(m,2H),2.87-2.84(m,2H),2.82-2.73(m,1H),2.59-2.56(m,1H) ,2.15-2.06(m,1H),2.01-1.89(m,1H),1.85-1.75(m,2H),1.70-1.60(m,2H),1.45-1.30(m,3H),1.21(t,J=7.0Hz,3H).

[0669] Example 42. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 42)

[0670]

[0671] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (1.61 g, 3.47 mmol) in DMF (30 mL) were added HATU (1.58 g, 4.16 mmol) and DIPEA (1.34 g, 10.41 mmol, 1.81 mL). The resulting mixture was stirred at 20° C. for 1 hour, and then 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2 g, 3.47 mmol, TFA salt) was added, and the mixture was stirred at 20° C. for 2 hours. By LCMS, the peak of the desired mass (66%) was confirmed. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 40g Purification was performed on a silica gel flash column with a 0-10% MeOH / EtOAc gradient at 100 mL / min as eluent to obtain 1.7 g of a product mixed with impurities, which was then crushed with ACN (50 mL) and filtered. The filter cake was collected to obtain 1.6 g of the desired product as a brown solid. The product was purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B over The mixture was purified again after 10 minutes (10 minutes), and the eluted product was lyophilized to obtain 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.16 g, 1.12 mmol, 32.20% yield, 99% purity, TFA salt) as a white solid. MS (M+H) + =910.4.

[0672] 1 H NMR (400MHz, DMSO-d6) δ = 10.86 (s, 1H), 9.61-9.49 (m, 1H), 9.25 (br s,1H),8.31(s,1H),8.24(d,J=13.0Hz,1H),8.15(s,1H),7.16(d,J=6.5Hz,1H),6.66-6.56(m,2H),4.87-4.80(m,1H),4.29(br dd,J=4.8,11.9Hz,1H),4.10(br t,J=13.9Hz,2H),3.92(s,3H),3.82(s,3H),3.57(br d,J=11.1Hz,2H),3.38-3.31(m,5H),3.23-3.03(m,8H),2.87-2.68(m,3H),2.61-2.54 (m,1H),2.16-2.07(m,1H),2.02-1.91(m,3H),1.82-1.60(m,10H),1.44-1.25(m,3H).

[0673] Example 43. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 43)

[0674] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (803 mg, 796.60 μmol, 20.88% yield, 99% purity, TFA salt) was synthesized as a yellow solid. MS (M+H) + =884.4.

[0675] 1 H NMR (400MHz, DMSO-d6) δ = 10.86 (s, 1H), 9.66-9.48 (m, 1H), 9.23 (br s,1H),8.34-8.20(m,2H),8.11(s,1H),7.16(d,J=6.6Hz,1H),6.70-6.50(m,2H),4.93-4.88(m,1H),4.29(br dd,J=5.1,11.9Hz,1H),4.09(br t,J=13.3Hz,2H),3.92(s,3H),3.82(s,3H),3.57(br d,J=11.6Hz,2H),3.34(s,5H),3.26-2.99(m,8H),2.85-2.66(m,3H),2.57(br s,1H),2.16-2.06(m,1H),2.02-1.87(m,1H),1.82-1.57(m,4H),1.45-1.30(m,3H),1.27(d,J=6.6Hz,6H).

[0676] Example 44. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (Compound 44)

[0677]

[0678] Step 1. Synthesis of 4-bromo-3-fluoro-2-methoxyaniline (2)

[0679] In AcOH (30mL) solution of 3-fluoro-2-methoxyaniline (8g, 56.68mmol) was added dropwise a mixture of Br2 (7.25g, 45.34mmol, 2.34mL) in AcOH (30mL), and the resulting mixture was stirred for 0.5 hours at 20°C. By TLC (SiO2, petroleum ether: EtOAc = 5:1), it was confirmed that the remaining trace starting material and the main spot with high polarity were detected. The suspension was filtered and the filter cake was washed with petroleum ether (50mL) and a mixture (petroleum ether: EtOAc = 3:1, 20mL). The filter cake was collected and dried under vacuum and purified by flash silica gel chromatography (20g of Purification was performed using a silica gel flash column with a 3-10% EtOAc / petroleum ether gradient at 200 mL / min, and the extract was concentrated in vacuo to afford 4-bromo-3-fluoro-2-methoxyaniline (8 g, 29.09 mmol, 51.32% yield, 80% purity) as an off-white solid. MS (M+H) + =220.0.

[0680] Step 2. Synthesis of methyl 4-amino-2-fluoro-3-methoxybenzoate (3)

[0681] To a solution of 4-bromo-3-fluoro-2-methoxyaniline (8 g, 29.09 mmol) and TEA (23.99 g, 237.09 mmol, 33 mL) in MeOH (100 mL) and DMF (50 mL) was added Pd(dppf)Cl2·CH2Cl2 (2.7 g, 3.31 mmol) under N2 atmosphere. The suspension was degassed under vacuum and purged with CO2 several times. The mixture was stirred at 80°C under CO2 (50 psi) for 120 hours. LCMS confirmed complete consumption of the starting material and 40% of the desired mass. The mixture was filtered, and the filter cake was washed with MeOH (300 mL). The filtrate was concentrated in vacuo to remove the MeOH, and the residue was diluted with brine (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 4), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (80 g of Purification was performed using a silica gel flash column with a 10-12% EtOAc / petroleum ether gradient at 200 mL / min as the eluent to afford methyl 4-amino-2-fluoro-3-methoxybenzoate (3.13 g, 15.71 mmol, 54.03% yield) as an off-white solid. MS (M+H) + =200.4.

[0682] 1 H NMR (400MHz, DMSO-d6) δ = 7.36 (t, J = 8.3Hz, 1H), 6.49 (dd, J = 1.1, 8.8Hz, 1H), 6.09 (s, 2H), 3.74 (d, J = 5.4Hz, 6H).

[0683] Step 3. Synthesis of methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (5)

[0684] A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6 g, 18.94 mmol), methyl 4-amino-2-fluoro-3-methoxybenzoate (3.30 g, 16.57 mmol), Pd2(dba)3 (1 g, 1.09 mmol), Xantphos (1 g, 1.73 mmol) and K3PO4 (12.00 g, 56.53 mmol) in dioxane (100 mL) was stirred at 100 °C under N2 gas for 16 hours. By LCMS, it was confirmed that 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one was completely consumed and 64% of the desired mass was confirmed. The mixture was diluted with brine (300 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed using a silica gel flash column with a 15-35% EtOAc / petroleum ether gradient at 200 mL / min as the eluent to afford methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (6.17 g, 12.87 mmol, 67.93% yield) as a light brown solid. MS (M+H) + =480.3.

[0685] Step 4. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoic acid (6)

[0686] A mixture of methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-3-methoxybenzoate (6.17 g, 12.87 mmol) and NaOH (2M, 30 mL) in MeOH (30 mL) and THF (30 mL) was stirred at 20°C for 12 hours. LCMS confirmed complete consumption of the starting material and the desired mass. The organic solvent was removed by concentrating the reaction mixture under vacuum, and HCl solution (12M) was added to the residue to adjust the pH to <2. ACN (20 mL) and EtOAc (20 mL) were added to the suspension, and the resulting mixture was stirred at 15°C for 10 minutes. The suspension was filtered. The filter cake was washed with EtOAc (20 mL), collected, and dried. The filter cake was diluted with HCl solution (12M, 30 mL) and concentrated in vacuo at 75 ° C. The residue was crushed with a mixture (MeCN: EtOAc = 1: 3, 60 mL) for 10 minutes and the suspension was filtered, and then the filter cake was washed with a mixture (MeCN: EtOAc = 1: 3, 40 mL). The filter cake was collected and dried in vacuo to give 4- ((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,4] diazepine-2-yl) amino) -2-fluoro-3-methoxybenzoic acid (5.64 g, 12.12 mmol, yield 94.16%) as an off-white solid. MS (M+H) + =466.3.

[0687] Step 5. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (Compound 44)

[0688] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-3-methoxybenzamide (522.2 mg, 567.84 μmol, 61.82% yield, 98.95% purity) was obtained as a white solid. MS (M+H) + =910.5.

[0689] 1 H NMR (400MHz, DMSO-d6) δ = 10.58 (s, 1H), 8.92-8.62 (m, 1H), 8.27 (s, 1H), 8.16-7.95 (m, 2H), 7.34-6.98 (m, 1H), 6.64 (d, J = 8.1Hz, 1H), 6.55(d,J=14.1Hz,1H),5.01(d,J=6.4Hz,1H),4.87-4.67(m,1H),4.29-4.17(m,1H),4.02(t,J=14.0Hz,2H),3.95(s,3H),3.82(s,3H) ,3.36(s,3H),3.04-2.88(m,6H),2.86-2.77(m,1H),2.76-2.63(m,2H),2.63-2.57(m,2H),2.56(s,3H),2.45-1.99(m,2H),2.25-2.16 (m,1H),1.98(dd,J=4.7,10.9Hz,2H),1.95-1.87(m,1H),1.82-1.68(m,4H),1.67-1.57(m,4H),1.53-1.41(m,2H),1.41-1.27(m,3H).

[0690] Example 45. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (Compound 45)

[0691]

[0692] Step 1. Synthesis of 4-amino-5-fluoro-2-methoxybenzonitrile (2)

[0693] To a solution of MeOH (23.75 g, 741.35 mmol, 30.00 mL) in THF (100 mL) was added t-BuOK (1 M, 160.00 mL) dropwise at 0 ° C. under N2 gas, and the mixture was stirred at 20 ° C. for 0.5 hours. Then, 4-amino-2,5-difluorobenzonitrile (10 g, 64.89 mmol) was added, and the resulting mixture was stirred at 70 ° C. for 3 hours. By LCMS, it was confirmed that the starting material was completely consumed and 99% of the required mass was confirmed. Most of the solvent was removed by vacuum concentration of the mixture. The residue was diluted with H2O (300 mL) and extracted with MTBE (150 mL×4). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (40 g of Purification was performed using a silica gel flash column with an 8-28% EtOAc / petroleum ether gradient at 200 mL / min as the eluent to afford 4-amino-5-fluoro-2-methoxybenzonitrile (9.85 g, 59.28 mmol, 91.37% yield) as a gray solid. MS (M+H) + =167.5.

[0694] Step 2. Synthesis of 4-amino-5-fluoro-2-methoxybenzoic acid (3)

[0695] A mixture of 4-amino-5-fluoro-2-methoxybenzonitrile (2.98 g, 17.94 mmol), NaOH (8 M, 16 mL) and EtOH (15 mL) was placed in a sealed can and stirred at 110°C for 20 hours. LCMS confirmed complete consumption of the starting material and the desired mass was detected. After cooling to room temperature, it was combined with the mixture from three batches, most of the solvent was removed by vacuum concentration, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was acidified to pH = 4 with HCl solution (6 M), and the resulting mixture was extracted with a mixture (EtOAc:MeOH = 20:1, 200 mL x 5), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column (DCM:MeOH=10:1) to give 4-amino-5-fluoro-2-methoxybenzoic acid (10.73 g) as a light brown solid, which was used directly. MS (M+H) + =186.1.

[0696] Step 3. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-5-fluoro-2-methoxybenzoic acid (4)

[0697] By a method similar to that described in Step 3 of Example 44, K₃PO₄ was replaced with K₂CO₃ (4.00 g, 28.94 mmol) 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)-5-fluoro-2-methoxybenzoic acid (3.15 g, 7.17 mmol, 52.10% yield) as a gray solid. MS (M+H) + =440.3.

[0698] 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (s, 1H), 8.30 (s, 1H), 7.71 (d, J = 6.6Hz, 1H), 7.59 (d, J = 11.1Hz, 1 H), 5.04-4.93 (m, 1H), 4.17 (t, J = 12.8Hz, 2H), 3.85 (s, 3H), 3.37 (s, 3H), 1.21 (d, J = 6.7Hz, 6H).

[0699] Step 4. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (Compound 45)

[0700] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxybenzamide (660.01 mg, 727.64 μmol, 53.42% yield, 97.45% purity) was obtained as a bright pink solid. MS (M+H) + =884.5.

[0701] 1 H NMR (400MHz, DMSO-d6) δ=10.69-10.44(m,1H),8.79-8.67(m,1H),8.64-8.40(m,1H),8.20(s,1H),7.79(d,J=6.4Hz,1H),7.56-7.41(m,1H),6 .63(d,J=8.1Hz,1H),6.54(d,J=14.3Hz,1H),5.00(d,J=6.4Hz,1H),4.97-4.80(m,1H),4.29-4.16(m,1H),3.98(t,J=13.4Hz,2H),3.90(s,3H) ,3.80(s,3H),3.34(s,3H),3.01(d,J=1.1Hz,2H),2.99-2.88(m,4H),2 .86-2.76(m,1H),2.76-2.63(m,2H),2.62-2.53(m,2H),2.54-2.50(m, 3H),2.43-2.35(m,2H),2.24-2.15(m,1H),1.96-1.85(m,1H),1.79-1. 64(m,2H),1.50-1.40(m,2H),1.40-1.26(m,3H),1.20(d,J=6.6Hz,6H).

[0702] Example 46. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidinyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidinyl)-4-methoxy-pyridine-2-carboxamide (Compound 46)

[0703]

[0704] Step 1. Synthesis of 7,7-difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2)

[0705] To 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (5.00 g, 17.20 mmol) and (4-methoxyphenyl)methanamine (3.54 g, 25.80 mmol) in t-BuOH (5 mL) was added DIPEA (4.45 g, 34.40 mmol). The mixture was stirred at 100°C for 26 hours. LCMS confirmed the desired compound at approximately 74%. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (30 mL) at 25° C. for 10 minutes to give 7,7-difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (5.20 g, 7.97 mmol, 46.34% yield, 60% purity). MS (M+H) + =392.2.

[0706] Step 2. Synthesis of 2-amino-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (3)

[0707] 7,7-difluoro-9-isopropyl-2-((4-methoxybenzyl)amino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (5.20 g, 7.97 mmol) was stirred in TFA (50 mL) at 25° C. for 16 hours. LCMS confirmed ~51% of the desired compound. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was diluted with EtOAc (200 mL) and washed with saturated NaHCO solution (30 mL×2), then dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (30 mL) at 25°C for 10 minutes to give 2-amino-7,7-difluoro-9-isopropyl-5-methyl-8H-pyrimido[4,5-b][1,4]diazepin-6-one (2.30 g, 5.94 mmol, yield 74.46%, purity 70%) as a light yellow solid. MS (M+H) + =272.1.

[0708] Step 3. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid methyl ester (5)

[0709] A similar method to that described in Step 3 of Example 3 was used to synthesize 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid methyl ester (1.25 g, 2.72 mmol, 62.03% yield, 95% purity) as a light yellow solid. MS (M+H) + =437.2.

[0710] Step 4. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid (6)

[0711] To a solution of methyl 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylate (1.25 g, 2.72 mmol) in MeOH (10 mL) and THF (10 mL) was added NaOH / H₂O (2 M, 10 mL). The mixture was stirred at 25°C for 16 hours. LCMS confirmed ~91% of the desired compound. The mixture was adjusted to pH 2 with HCl / dioxane (2 M) and then concentrated to afford 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxy-pyridine-2-carboxylic acid (2 g, crude) as a yellow solid. The crude product was used directly without further purification. MS (M+H) + =423.2.

[0712] Step 5. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidinyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidinyl)-4-methoxy-pyridine-2-carboxamide (Compound 46)

[0713] By a method similar to that described in step 10 of Example 2, 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxo-3-piperidinyl)amino)-2-fluoro-5-methoxy-phenyl)piperazin-1-yl)ethyl)-1-piperidinyl)-4-methoxy-pyridine-2-carboxamide (702 mg, 795.18 μmol, yield 27.99%, purity 98.2%) was obtained as a light yellow solid. MS (M+H) + =867.4.

[0714] 1 H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 9.35 (s, 1H), 9.10 (s, 1H), 8.21-8.16 (m, 2H), 7.62 (s, 1H), 6.10 (d, J = 8.0Hz, 1H), 6 .54(d,J=14.4Hz,w1H),5.13-5.05(m,1H),4.85-4.74(m,1H),4.30-4.20(m,1H),4.08-3.95(m,5H),3.79(s,3H),3.32-3. 29(m,5H),3.00-2.85(m,6H),2.85-2.75(m,1H),2.75-2.65(m,2H),2.59-2.54(m,1H),2.40-2.30(m,2H),2.17-2.08(m,1 H),1.98-1.84(m,1H),1.77-1.65(m,2H),1.47-1.37(m,2H),1.35-1.31(m,3H),1.29-1.23(m,1H),1.19(d,J=6.4Hz,6H).

[0715] Example 47. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (Compound 47)

[0716]

[0717] Step 1. Synthesis of 9-cyclopentyl-2-((2,4-dimethoxybenzyl)amino)-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2)

[0718] By a method similar to that described in Step 1 of Example 46, PMBNH2 was replaced with DMBNH2 (13.36 g, 79.88 mmol, 12.00 mL) to obtain 9-cyclopentyl-2-((2,4-dimethoxybenzyl)amino)-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (13 g, crude product) as a yellow solid. MS (M+H) + =448.3.

[0719] Step 2. Synthesis of 2-amino-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3)

[0720] 2-Amino-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6.13 g, 20.21 mmol, 69.55% yield, 98% purity) was synthesized by a method similar to that described in Step 2 of Example 46 as a yellow solid. MS (M+H) + =298.2.

[0721] Step 3. Synthesis of methyl 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinate (5)

[0722] By a method similar to that described in Step 3 of Example 46, Cs2CO3 was replaced with K3PO4 (12.96 g, 61.08 mmol) to obtain methyl 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinate (7.61 g, 16.13 mmol, 79.51% yield, 98% purity) as a yellow solid. MS (M+H) + =463.2.

[0723] Step 4. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (6)

[0724] 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (6.46 g, 13.11 mmol, 79.66% yield, 91% purity) was synthesized by a method similar to that described in Step 4 of Example 46 as a white solid. MS (M+H) + =449.3.

[0725] Step 5. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (Compound 47)

[0726] 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-4-methoxypicolinamide (149.8 mg, 166.41 μmol, 4.97% yield, 99% purity) was synthesized as a yellow solid. MS (M+H) + =893.4.

[0727] 1H NMR (400MHz, DMSO-d6) δ=10.84(s,1H),9.33(s,1H),9.01(s,1H),8.36(s,1H),8.22(s,1H),7.62(s,1H),6.61(d,J=8.1Hz ,1H),6.54(d,J=14.5Hz,1H),5.08(d,J=6.4Hz,1H),4.70-4.58(m,1H),4.30-4.20(m,1H),4.06-3.93(m,5H),3.79(s,3H), 3.32(s,3H),3.31-3.25(m,4H),3.01-2.87(m,6H),2.84-2.75(m,1H),2.72-264(m,2H),2.58-2.53(m,1H),2.35(t,J=7.1 Hz,2H),2.17-2.08(m,1H),1.96-1.80(m,3H),1.75-1.61(m,4H),1.59-1.47(m,4H),1.45-1.38(m,2H),1.36-1.26(m,3H).

[0728] Example 48. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 48)

[0729]

[0730] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3)

[0731] MeCN (24 mL) was added and synthesized similarly to the method described in Step 3 of Example 23 to obtain tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (1.59 g, 2.77 mmol, 34.41% yield, 98% purity) as a gray solid. MS (M+H) + =563.4.

[0732] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (4)

[0733] By a method similar to that described in Step 5 of Example 1, replacing dioxane with DCM (10 mL), 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.4 g, crude product, HCl) was obtained as a gray solid. MS (M+H) + =463.3.

[0734] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 48)

[0735] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (1.65 g, 1.84 mmol, 68.49% yield, 99.4% purity) was obtained as a yellow solid. MS (M+H) + =892.6.

[0736] 1H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.31-8.22 (m, 2H), 8.18-8.06 (m, 1H), 7.96 (s, 1H) ,7.53-7.43(m,2H),6.64-6.49(m,2H),5.09(d,J=6.7Hz,1H),4.82-4.69(m,1H),4.29-4.2 1(m,1H),4.04(t,J=13.9Hz,2H),3.94(s,3H),3.84-3.72(m,4H),3.34-3.33(m,6H),2.96- 2.86(m,6H),2.83-2.73(m,1H),2.64-2.52(m,6H),2.16-1.86(m,6H),1.84-1.51(m,10H).

[0737] Example 49. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 49)

[0738]

[0739] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3)

[0740] By synthesizing the product similarly to the method described in Step 3 of Example 23, tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (4.5 g, 8.00 mmol, 49.69% yield) was obtained as a cyan solid. MS (M+H) + =563.3.

[0741] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (4)

[0742] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2 g, 3.47 mmol, 97.59% yield, TFA salt) was synthesized by a method similar to that described in Step 3 of Example 3 as a brown oil. MS (M+H) + =463.3.

[0743] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 49)

[0744] By a method similar to that described in Step 10 of Example 2, 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (1.67 g, 1.81 mmol, 52.30% yield, 99% purity) was obtained as a cyan solid. MS (M+H) + =910.4.

[0745] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (br s, 1H), 8.30 (s, 1H), 8.25 (d, J = 13.3Hz, 1H), 8.04 (s, 1H), 7.89 (br dd,J=2.8,7.3Hz,1H),7.20(d,J=6.6Hz,1H),6.60(d,J=8.1Hz,1H),6.55(d,J=14.3Hz,1H),5.09(br d,J=6.4Hz,1H),4.83(br t,J=8.1Hz,1H),4.32-4.18(m,1H),4.08(br t,J=13.9Hz,2H),3.92(s,3H),3.83-3.72(m,4H),3.31(br s,2H),2.93-2.76(m,7H),2.59-2.51(m,6H),2.49-2.42(m,4H),2.16-1.90(m,6H),1.84-1.70(m,4H),1.67-1.51(m,6H).

[0746] Example 50. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 50)

[0747]

[0748] Step 1. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3)

[0749] A method similar to that described in Step 6 of Example 1 was used to synthesize tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (7.7 g, 16.93 mmol, 81.90% yield, 98% purity) as a white solid. MS (M+H) + =446.3.

[0750] Step 2. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4)

[0751] Benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6.5 g, crude product, HCl) was synthesized by a method similar to that described in Step 5 of Example 1 as a white solid. MS (M+H) + =346.1.

[0752] 1 H NMR (400MHz, CD3OD) δ = 7.44-7.19 (m, 5H), 5.22-4.96 (m, 2H), 3.73 -3.62(m,4H),3.47-3.36(m,2H),3.25-3.14(m,2H),3.14-2.89(m,4H),2.19-1.93(m,4H),1.90-1.66(m,4H),1.56-1.37(m,2H).

[0753] Step 3. Synthesis of benzyl (1-(2-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6)

[0754] Benzyl (1-(2-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, 5.83 mmol, 34.26% yield, 100% purity) was synthesized by a method similar to that described in Step 2 of Example 7 as a yellow solid. MS (M+H) + =515.3.

[0755] Step 4. Synthesis of benzyl (1-(2-(1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7)

[0756] Benzyl (1-(2-(1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5.6 g, 10.75 mmol, 80.15% yield, 93% purity) was synthesized by a method similar to that described in Step 1 of Example 35 as a brown solid. MS (M+H) + =485.2.

[0757] Step 5. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (9)

[0758] Benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (3 g, 4.63 mmol, 74.84% yield, 92% purity) was synthesized by a method similar to that described in Step 5 of Example 22 as a brown solid. MS (M+H) + =596.2.

[0759] Step 6. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (10)

[0760] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2.5 g, crude, TFA) was obtained as a brown oil by a method similar to that described in Step 2 of Example 4. MS (M+H) + =462.3.

[0761] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (Compound 50)

[0762] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide (507.3 mg, 561.92 μmol, 41.34% yield, 97.8% purity) was obtained as a purple solid. MS (M+H) + =883.4.

[0763] 1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H), 8.34-8.24 (m, 2H), 7.97 (s, 1H), 7.93-7.80 (m, 1H), 7.20 (d, J = 6.8Hz, 1H), 6.60(d,J=8.1Hz,1H),6.53(d,J=14.3Hz,1H),5.08(d,J=6.8Hz,1H),4.95-4.85(m,1H),4.29-4.20(m,1H),4.07(t ,J=13.6Hz,2H),3.92(s,3H),3.78(s,3H),3.34(s,3H),3.18-3.11(m,2H),2.86-2.76(m,2H),2.66-2.53(m,4H),2 .40-2.26(m,2H),2.16-2.08(m,1H),2.04-1.89(m,3H),1.85-1.72(m,4H),1.63-1.51(m,2H),1.44-1.24(m,12H).

[0764] Example 51. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 51)

[0765]

[0766] Step 1. Synthesis of benzyl (7-((1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3)

[0767] Benzyl (7-((1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (11.26 g, 19.16 mmol, 90.33% yield, 92% purity) was synthesized by a method similar to that described in Step 4 of Example 30 as a yellow oil. MS (M+H) + =541.4.

[0768] Step 2. Synthesis of benzyl (7-((1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4)

[0769] Benzyl (7-((1-(4-amino-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (9.14 g, crude product) was synthesized by a method similar to that described in Step 4 of Example 22 as a red oil. MS (M+H) + =511.3.

[0770] Step 3. Synthesis of benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6)

[0771] TBAI (1.87 g, 5.08 mmol) was added and synthesized in a manner similar to that described in Step 5 of Example 22 to give benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.8 g, 2.78 mmol, 16.43% yield, 96% purity) as a gray solid. MS (M+H) + =622.3.

[0772] Step 4. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7)

[0773] Under N₂, a solution of Pd / C (1 g, 10% purity) in THF (60 mL) was added with Boc₂O (3.58 g, 16.41 mmol, 3.77 mL), AcOH (340 mg, 5.66 mmol, 324.12 μL), and benzyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6.8 g, 10.94 mmol) in THF (100 mL). The mixture was stirred at 25° C. under H₂ (45 psi) for 28 hours. The desired mass was detected by LCMS. The mixture was filtered, and the filter cake was washed with THF (500 mL). The filtrate was concentrated under reduced pressure (25° C.). The residue was diluted with EtOAc (100 mL) and saturated aqueous NaHCO₃ (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO₃ (50 mL) and water (50 mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and then diluted with MTBE / EtOH = 4 / 1 (65 mL). The mixture was stirred at 25°C for 14 hours. The filter cake was collected and triturated with MTBE / EtOH = 4 / 1 (30 mL, twice) and then filtered. The filter cake was collected and dried to obtain tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4.74 g, 8.07 mmol, 73.74% yield) as a cyan solid. The filtrate was concentrated under reduced pressure and triturated with MTBE / EtOH = 4 / 1 (20 mL) at 25° C. for 14 hours. The mixture was filtered, and the filter cake was washed with MTBE / EtOH=4 / 1 (10 mL). The filter cake was collected to give tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (680 mg, 1.16 mmol, yield 10.58%, purity 100%) as a cyan solid. MS (M+H) + =588.3.

[0774] Step 5. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (8)

[0775] 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.83 g, crude, TFA) was obtained as a yellow oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =488.2.

[0776] Step 6. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 51)

[0777] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (1.18 g, 1.27 mmol, 51.66% yield, 98.7% purity) was obtained as a yellow solid. MS (M+H) + =917.6.

[0778] 1H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.42 (d, J = 7.3Hz, 1H), 8.29-8.25 (m, 2H), 7.96 (s, 1H), 7.51-7.46 (m, 2H), 6.60 (d,J=8.2Hz,1H),6.52(d,J=14.2Hz,1H),5.07(d,J=7.0Hz,1H),4.82-4.71(m,1H),4.44-4.35(m,1H),4.29-4.20(m,1H ),4.04(t,J=14.0Hz,2H),3.94(s,3H),3.77(s,3H),3.33(s,3H),3.17-3.10(m,2H),2.84-2.75(m,1H),2.64-2.54(m, 3H),2.35-2.09(m,9H),1.99-1.88(m,3H),1.85-1.78(m,2H),1.77-1.67(m,4H),1.65-1.52(m,9H),1.29-1.17(m,2H).

[0779] Example 52. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 52)

[0780] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (905.6 mg, 968.38 μmol, 38.68% yield, 97.2% purity) was obtained as a yellow solid. MS (M+H) + =909.5.

[0781] 1H NMR (400MHz, DMSO-d6) δ=10.90-10.77(m,1H),8.31-8.16(m,3H),7.96(s,1H),7.19(d,J=6.7Hz,1H),6.59(d,J =8.2Hz,1H),6.52(d,J=14.3Hz,1H),5.06(d,J=6.2Hz,1H),4.94-4.85(m,1H),4.43-4.31(m,1H),4.29-4.21(m ,1H),4.11-4.01(m,2H),3.91(s,3H),3.77(s,3H),3.31-3.27(m,3H),3.17-3.09(m,2H),2.86-2.75(m,1H),2. 64-2.53(m,3H),2.36-2.08(m,9H),1.97-1.84(m,1H),1.83-1.71(m,4H),1.66-1.49(m,5H),1.33-1.15(m,8H).

[0782] Example 53. Synthesis of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-methoxypicolinamide (Compound 53)

[0783] To a solution of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (1.5 g, 3.55 mmol) and HATU (1.62 g, 4.26 mmol) in DMF (20 mL) was added DIPEA (4.59 g, 35.51 mmol, 6.19 mL) at 25 °C and the mixture was stirred for 15 min. Then, a solution of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (2.4 g, 3.99 mmol, TFA) in DMF (20 mL) was added, and the mixture was stirred at 25° C. for 3 hours. LCMS confirmed 53% of the desired mass remaining and 27% of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione. Then, a solution of 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-4-methoxypicolinic acid (450 mg, 1.07 mmol), HATU (419 mg, 1.10 mmol) and DIPEA (371.00 mg, 2.87 mmol, 0.5 mL) in DMF (5 mL) was added and the mixture was stirred at 25° C. for 1 hour. LCMS confirmed 77% of the desired mass. The mixture was diluted with EtOAc (50 mL) and diluted with saturated aqueous NaHCO3 (100 mL), then extracted with EtOAc (20 mL×3), and the combined organic layers were washed with brine (30 mL×2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (20 g of Purification was performed using a silica gel flash column with a 7-13% MeOH / DCM gradient at 100 mL / min. The product was diluted with 1N HCl (60 mL), and the mixture was stirred at 25°C for 10 minutes. The mixture was washed with EtOAc (30 mL x 3), and the aqueous phase was slowly added to a saturated aqueous NaHCO solution (200 mL). The mixture was then filtered, and the filter cake was washed with deionized water (30 mL x 3). The filter cake was collected and the solvent was removed under reduced pressure to give 5-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-4-methoxypicolinamide (2.08 g, 2.30 mmol, 64.74% yield, 98.6% purity) as a white solid. MS (M+H) + =892.6.

[0784] 1 H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.12 (s, 1H), 8.83-8.71 (m, 1H), 8.23-8.14 (m, 2H), 7.64 (s, 1H) ),6.59(d,J=8.1Hz,1H),6.53(d,J=14.1Hz,1H),5.11-5.04(m,1H),4.85-4.75(m,1H),4.49-4.35(m, 1H),4.30-4.21(m,1H),4.08-3.95(m,5H),3.78(s,3H),3.32(s,3H),3.18-3.10(m,2H),2.86-2.73(m ,1H),2.66-2.55(m,4H),2.30-2.05(m,7H),1.99-1.70(m,7H),1.65-1.48(m,4H),1.29-1.14(m,8H).

[0785] Example 54. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 54)

[0786]

[0787] Step 1. Synthesis of tert-butyl 4-(2-fluoro-3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3)

[0788] A similar method to that described in Step 4 of Example 30 was used to synthesize tert-butyl 4-(2-fluoro-3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (16.3 g, 43.58 mmol, 82.41% yield, 95% purity) as a yellow solid. MS (Mt-Bu+H) + =300.1.

[0789] Step 2. Synthesis of tert-butyl 4-(4-amino-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (4)

[0790] MeOH (160 mL) was added and the reaction was performed similarly to the method described in Step 1 of Example 35 to obtain tert-butyl 4-(4-amino-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (14 g, 43.03 mmol, 95.56% yield) as a red solid. MS (M+H) + =326.1.

[0791] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (6)

[0792] A similar method to that described in Step 5 of Example 22 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazine-1-carboxylate (5.3 g, 12.02 mmol, 78.23% yield, 99% purity) as a cyan solid. MS (M+H) + =437.2.

[0793] Step 4. Synthesis of 3-((3-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7)

[0794] 3-((3-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (5 g, crude product, HCl) was synthesized by a method similar to that described in Step 5 of Example 1 as a cyan solid. MS (M+H) + =337.1.

[0795] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9)

[0796] A similar method to that described in Step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.4 g, 2.39 mmol, 44.53% yield, 96% purity) as a cyan solid. MS (M+H) + =563.3.

[0797] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (10)

[0798] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-3-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (1.3 g, 2.25 mmol, 97.59% yield, TFA) was synthesized by a method similar to that described in Step 6 of Example 3 as a brown oil. MS (M+H) + =463.4.

[0799] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 54)

[0800] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (481.7 mg, 524.37 μmol, 23.26% yield, 97.1% purity) was obtained as a white solid. MS (M+H) + =892.4.

[0801] 1 H NMR (400MHz, DMSO-d6) δ=10.85(s,1H),9.29(s,1H),8.31-8.19(m,2H),7.97(s,1H),7.49-7.37(m,2H),6.64(t,J=8.3 Hz,1H),6.46(d,J=8.5Hz,1H),5.26(s,1H),4.82-4.72(m,1H),4.36-4.24(m,1H),4.05(t,J=13.9Hz,2H),3.93(s,3H) ,3.78(s,3H),3.33(s,3H),3.09-2.97(m,3H),2.95-2.86(m,3H),2.84-2.72(m,4H),2.61-2.52(m,3H),2.49-2.25(m, 3H),2.16-2.07(m,1H),2.05-1.87(m,3H),1.79-1.68(m,4H),1.65-1.55(m,4H),1.53-1.39(m,2H),1.38-1.23(m,3H).

[0802] Example 55. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 55)

[0803]

[0804] Step 1. Synthesis of 1,3-difluoro-2-methoxy-4-nitrobenzene (2)

[0805] To a solution of 2,6-difluoro-3-nitrophenol (5 g, 28.56 mmol) in DMF (70 mL) was added K2CO3 (7.89 g, 57.11 mmol) and MeI (6.16 g, 43.37 mmol, 2.7 mL), and the mixture was stirred at 25°C for 14 hours. By TLC (petroleum ether: EtOAc = 1:0), the consumption of the starting material was confirmed, and a new spot was detected. The mixture was diluted with EtOAc (50 mL) and brine (100 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain 1,3-difluoro-2-methoxy-4-nitrobenzene (6 g, crude product) as a yellow oil.

[0806] Step 2. Synthesis of tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (4)

[0807] To a solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (6 g, 31.73 mmol) and K2CO3 (5.26 g, 38.07 mmol) in DMF (200 mL) was added tert-butyl piperazine-1-carboxylate (5.4 g, 28.99 mmol), and the mixture was stirred at 100 ° C for 1 hour. The required mass was confirmed by LCMS. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3), and the combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was crushed with MTBE (50 mL) for 14 hours at 25 ° C. The mixture was filtered and the filter cake was washed with MTBE (10 mL). The filter cake was collected and the solvent was removed under reduced pressure to obtain 4.74 g of a product with a purity of 97%. The filtrate was concentrated under reduced pressure and the Purification was performed using a silica gel flash column with a 10-20% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to obtain 3.46 g of product. Two batches of product were combined to obtain tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (8.2 g, 22.38 mmol, 70.55% yield, 97% purity) as a yellow solid. MS (M+H) + =356.2.

[0808] 1H NMR (400MHz, DMSO-d6) δ = 7.85 (dd, J = 8.5, 9.4Hz, 1H), 6.88 (dd, J = 1.5, 9.5Hz, 1H), 3.83 (s, 3H), 3.53-3.46 (m, 4H), 3.31-3.27 (m, 4H), 1.42 (s, 9H).

[0809] Step 3. Synthesis of tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (5)

[0810] To a solution of tert-butyl 4-(3-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (8.2 g, 23.08 mmol) and NH4Cl (3.70 g, 69.22 mmol) in EtOH (150 mL) and H2O (50 mL) was added Fe (3.87 g, 69.23 mmol), and the mixture was stirred at 80°C for 1 hour. LCMS confirmed 84% of the desired mass. The mixture (80°C) was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and adjusted to pH = 8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (50 mL×3), and the combined organic layers were washed with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (7.6 g, crude product) as a yellow solid. MS (M+H) + =326.2.

[0811] Step 4. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (7)

[0812] A solution of tert-butyl 4-(4-amino-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (8.5 g, 26.12 mmol), 3-bromopiperidine-2,6-dione (10.03 g, 52.25 mmol), TBAI (964.92 mg, 2.61 mmol) and NaHCO3 (8.78 g, 104.49 mmol, 4.07 mL) in MeCN (20 mL) was stirred at 80 ° C for 28 hours. By LCMS, 84% of the required mass was confirmed. The mixture was diluted with EtOAc (200 mL) and filtered. The filter cake was washed with EtOAc (30 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (80 g of Purification was performed using a silica gel flash column with a 40-80% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (8.73 g, 17.40 mmol, 66.61% yield, 87% purity) as a cyan solid. MS (M+H) + =437.3.

[0813] Step 5. Synthesis of 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8)

[0814] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (4 g, 7.97 mmol) in DCM (50 mL) was added HCl / dioxane (2 M, 100 mL), and the mixture was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure (25° C.) to give 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.8 g, crude product, HCl) as a cyan solid. MS (M+H) + =337.2.

[0815] Step 6. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (10)

[0816] To a solution of 3-((2-fluoro-3-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.6 g, 9.66 mmol, HCl) in DMF (60 mL) and DCM (60 mL) were added TEA (3.14 g, 31.04 mmol, 4.32 mL) and MgSO4 (2.32 g, 19.31 mmol), followed by tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (3.04 g, 12.55 mmol), and the mixture was stirred at 25° C. for 0.5 h. NaBH(OAc)3 (4.09 g, 19.31 mmol) was added, and the mixture was stirred at 25° C. for 14 h. Tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (1.1 g, 4.54 mmol) was added and the mixture was stirred at 25° C. for 1 hour. 70% of the desired mass was confirmed by LCMS. The mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40 g of Silica gel flash column, eluent (Eluent) is 10-20% MeOH / EtOAc gradient (gradient @ 100mL / min) and purified by reverse phase HPLC (0.1% TFA condition, column: 330g flash column Welch Ultimate XB_C18 20-40 μm; 20-40 μm; 120A solvent (Solvent) was used to dissolve the sample; approximately 3.00 g of the sample was dissolved in 100 mL of MeCN; flow rate: 100 mL / min; mobile phase: MeCN / H2O; gradient (B%): 30-50% over 45 min; % min (ISCO Instrument) was used for further purification, and the elution was lyophilized to obtain tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2.7 g, 3.83 mmol, 39.67% yield, 96% purity, TFA) as a cyan solid. MS (M+H) + =563.4.

[0817] Step 7. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (11)

[0818] To a solution of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (2.7 g, 4.80 mmol) in DCM (10 mL) was added TFA (8.29 g, 72.70 mmol, 5.4 mL), and the mixture was stirred at 25° C. for 4 hours. LCMS confirmed 93% of the desired mass. The mixture was concentrated under reduced pressure to give 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (2.78 g, crude, TFA) as a cyan oil. MS (M+H) + =463.4.

[0819] Step 8. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 55)

[0820] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid (1.6 g, 3.58 mmol) and HATU (1.63 g, 4.29 mmol) in DMF (10 mL) was added DIPEA (4.62 g, 35.76 mmol, 6.23 mL), and the mixture was stirred at 15° C. for 0.5 h. Then, a solution of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazine-1-yl)-2-fluoro-3-methoxyphenyl)amino)piperidine-2,6-dione (2.78 g, 4.83 mmol, TFA) in DMF (10 mL) was added at 0°C, and the mixture was stirred at 15°C for 1 hour. LCMS confirmed 55% of the desired mass. The mixture was diluted with water (10 mL) and saturated aqueous NaHCO3 (30 mL), and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 3 g of the product. The product (1 g) was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 15%-45% B for more than 10 minutes) and the eluted product was lyophilized to obtain 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (312.40 mg, 273.34 μmol, yield 7.64%, purity 98%, 2TFA) as a yellow solid. MS (M+H) + =892.6.

[0821] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.79-9.31 (m, 2H), 8.30-8.12 (m, 3H), 7.53-7.38 (m, 2H), 6.6 6-6.60(m,1H),6.55-6.47(m,1H),4.84-4.75(m,1H),4.37-4.30(m,1H),4.13-4.04(m,2H),3.93(s,3 H),3.86(s,3H),3.61-3.55(m,2H),3.45-3.37(m,2H),3.33(s,3H),3.26-3.09(m,6H),2.95-2.83(m, 4H),2.80-2.70(m,1H),2.62-2.56(m,1H),2.09-1.88(m,4H),1.81-1.54(m,10H),1.44-1.31(m,3H).

[0822] The product (2 g) was purified by flash silica gel chromatography (20 g of Silica gel flash column, eluent (Eluent) is 10% MeOH / EtOAc and 10% MeOH / DCM gradient (gradient) @ 100mL / min) purification. Under the condition of 15 ℃, the product is crushed with MTBE / EtOH=2 / 1 (30mL) for 14 hours. The mixture is filtered and the filter cake is washed with MTBE / EtOH=2:1 (10mL). After collecting the filter cake, it is diluted with 1N HCl (30mL). The mixture is slowly added to a saturated aqueous solution of NaHCO3 (200mL) and a large amount of white precipitate is formed. The suspension is filtered and the filter cake is washed with water (50mL). The filter cake is collected and the solvent is removed by freeze-drying under reduced pressure. Under the condition of 15 ℃, the product is crushed with water (50mL) for 0.5 hours. The suspension is filtered and the filter cake is washed with water (20mL). The filter cake was collected, and the solvent was lyophilized and removed under reduced pressure 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)-3-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (328 mg, 349.34 μmol, yield 9.77%, purity 95%) as a yellow solid. MS (M+H) + =892.6.

[0823] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.27 (s, 1H), 8.30-8.23 (m, 2H), 7.96 (s, 1H), 7.45-7.39 (m, 2H), 6.60-6.55 (m, 1H) ),6.52-6.44(m,1H),5.27(d,J=6.6Hz,1H),4.82-4.71(m,1H),4.35-4.25(m,1H),4.04(t,J=13.8Hz,2H),3.93(s,3H),3 .82(s,3H),3.35-3.15(m,5H),3.04-2.97(m,2H),2.94-2.82(m,4H),2.81-2.69(m,3H),2.61-2.53(m,3H),2.39-2.30(m ,2H),2.12-2.01(m,1H),2.01-1.88(m,3H),1.79-1.66(m,4H),1.65-1.52(m,4H),1.48-1.37(m,2H),1.35-1.24(m,3H).

[0824] Example 56. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 56)

[0825]

[0826] Step 1. Synthesis of tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (3)

[0827] A similar method to that described in Step 2 of Example 7 was used to synthesize tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (7.95 g, 22.37 mmol, 42.74% yield) as a yellow solid. MS (M+H) + =356.3.

[0828] 1 H NMR (400MHz, CD3OD) δ = 7.61 (d, J = 7.2Hz, 1H), 6.83 (d, J = 13.6Hz, 1H), 3.92 (s, 3H), 3.66-3.50 (m, 4H), 3.26-3.15 (m, 4H), 1.48 (s, 9H).

[0829] Step 2. Synthesis of tert-butyl 4-(4-amino-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (4)

[0830] To a mixture of Pd / C (2 g, 10% purity) in THF (60 mL) and MeOH (60 mL) was added tert-butyl 4-(5-fluoro-2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (7.95 g, 22.37 mmol) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred for 16 hours under H2 (50 psi) at 25°C. Complete consumption of the starting material was confirmed by LCMS, and 76% of the desired mass was confirmed. The mixture was filtered, and the filter cake was washed with MeOH (200 mL) and THF (200 mL). The filtrate was concentrated in vacuo. The residue was triturated with a mixture (EtOAc: petroleum ether = 1:15, 80 mL) for 10 minutes, and the suspension was filtered, the filter cake was washed with petroleum ether (30 mL), and the filter cake was collected and dried to obtain tert-butyl 4-(4-amino-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (6.56 g, 20.16 mmol, yield 90.12%) as a purple solid. MS (M+H) + =326.4.

[0831] 1 H NMR (400MHz, DMSO-d6) δ = 6.66 (d, J = 12.9Hz, 1H), 6.46 (d, J = 8.6Hz, 1H), 4.79 (s, 2H), 3.72 (s, 3H), 3.52-3.40 (m, 4H), 2.84-2.73 (m, 4H), 1.45 (s, 9H).

[0832] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (6)

[0833] A method similar to that described in Step 3 of Example 51 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazine-1-carboxylate (2.9 g, 6.64 mmol, 32.95% yield) as a gray solid. MS (M+H) + =437.3.

[0834] Step 4. Synthesis of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7)

[0835] 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.65 g, HCl salt) was synthesized similarly to the method described in Step 5 of Example 1 as a purple solid and used directly. MS (M+H) + =337.2.

[0836] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9)

[0837] A mixture of 3-((2-fluoro-5-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (3.55 g, 9.52 mmol, HCl salt), TEA (5.45 g, 53.88 mmol, 7.5 mL), tert-butyl (4-(2-oxoethyl)piperidin-1-yl)carbamate (4 g, 16.51 mmol) and MgSO4 (4 g, 33.23 mmol) in DCM (120 mL) and DMF (120 mL) was stirred at 20°C for 16 hours. NaBH(OAc)3 (6.5 g, 30.67 mmol) was then added portionwise and the resulting mixture was stirred at 20°C for 4 hours. By LCMS, it was confirmed that there was 37% of 3-((2-fluoro-5-methoxy-4-(piperazine-1-yl)phenyl)amino)piperidine-2,6-dione remaining, and 54% of the required mass was confirmed. At 20° C., the mixture was further stirred for 12 hours, and by LCMS, it was confirmed that 3-((2-fluoro-5-methoxy-4-(piperazine-1-yl)phenyl)amino)piperidine-2,6-dione was completely consumed, and 92% of the required mass was confirmed. The mixture was quenched by adding H2O (400mL) to the mixture and treated with NaHCO3 solution so that the pH was adjusted to>7 and extracted with a mixture (DCM:MeOH=10:1, 200mL×3). The combined organic layers were washed with brine (300mL×5), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (20 g of Purification was performed by silica gel flash column, eluent: 100% EtOAc to 6% MeOH / DCM gradient @ 150 mL / min) and by flash silica gel chromatography (20 g of The residue was purified again using a silica gel flash column (eluent: 100% EtOAc to 6% MeOH / DCM gradient @ 150 mL / min) to afford tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.62 g, 2.88 mmol, 30.24% yield) as a cyan solid. MS (M+H) + =563.5.

[0838] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-5-methoxyphenyl)amino)piperidine-2,6-dione (10)

[0839] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2-fluoro-5-methoxyphenyl)amino)piperidine-2,6-dione (2.32 g, 3% TFA salt) was obtained as a green viscous substance by a method similar to that described in Step 6 of Example 3 and used directly. MS (M+H) + =463.3.

[0840] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 56)

[0841] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (710.60 mg, 783.83 μmol, 62.71% yield, 98.39% purity) was obtained as an off-white solid. MS (M+H) + =892.5.

[0842] 1H NMR (400MHz, DMSO-d6) δ=10.78(s,1H),9.31-9.14(m,1H),8.33-8.18(m,2H),7.96(s,1H),7.50-7.30(m,2H),6.67(d,J= 13.4Hz,1H),6.48(d,J=8.6Hz,1H),5.26-5.09(m,1H),4.82-4.69(m,1H),4.45-4.33(m,1H),4.13-3.99(m,2H),3.93(s,3 H),3.72(s,3H),3.32(s,3H),3.00(d,J=9.9Hz,2H),2.90-2.78(m,4H),2.78-2.67(m,3H),2.60-2.54(m,1H),2.39-2.28( m,3H),2.14-1.95(m,3H),1.95-1.83(m,2H),1.76-1.67(m,4H),1.67-1.49(m,5H),1.45-1.37(m,2H),1.37-1.04(m,4H).

[0843] Example 57. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 57)

[0844]

[0845] Step 1. Synthesis of tert-butyl 4-(2,5-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3)

[0846] A similar method to that described in step 4 of Example 30 was used to synthesize tert-butyl 4-(2,5-difluoro-4-nitrophenyl)piperazine-1-carboxylate (1.3 g, 3.75 mmol, 66.38% yield, 99% purity) as a yellow solid. MS (M+H-Boc) + =244.2.

[0847] 1 H NMR (400MHz, CDCl3) δ=7.83 (dd, J=7.1, 12.8Hz, 1H), 6.64 (dd, J=7.2, 13.0Hz, 1H), 3.71-3.51 (m, 4H), 3.35-3.16 (m, 4H), 1.49 (s, 9H).

[0848] Step 2. Synthesis of tert-butyl 4-(4-amino-2,5-difluorophenyl)piperazine-1-carboxylate (4)

[0849] A similar method to that described in Step 4 of Example 22 was used to synthesize tert-butyl 4-(4-amino-2,5-difluorophenyl)piperazine-1-carboxylate (1.1 g, 3.16 mmol, 83.44% yield, 90% purity) as a yellow oil. MS (M+H-Boc) + =214.0.

[0850] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazine-1-carboxylate (6)

[0851] A method similar to that described in Step 5 of Example 22 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazine-1-carboxylate (1.2 g, 2.43 mmol, 69.26% yield, 86% purity) as a brown solid. MS (M+H) + =425.3.

[0852] Step 4. Synthesis of 3-((2,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7)

[0853] 3-((2,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (0.8 g, crude product, HCl) was synthesized by a method similar to that described in Step 2 of Example 48 as a cyan solid. MS (M+H) + =325.2.

[0854] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9)

[0855] A similar method to that described in step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (0.23 g, 396.81 μmol, 16.09% yield, 95% purity) as a gray solid. MS (M+H) + =551.3.

[0856] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (10)

[0857] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (0.17 g, 301.13 μmol, 97.54% yield, TFA) was synthesized by a method similar to that described in Step 6 of Example 3 as a yellow oil. MS (M+H) + =451.2.

[0858] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 57)

[0859] A similar method to that described in Step 10 of Example 2 was used to synthesize 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (72.6 mg, 72.31 μmol, 24.01% yield, 99% purity, TFA) as a white solid. MS (M+H) + =880.4.

[0860] 1H NMR (400MHz, DMSO-d6)δ=10.81(s,1H),9.82-9.61(m,1H),9.58-9.39(m,1H),8.33-8.11(m,3H),7.53-7.38(m,2H),7.08-6.89(m,1H),6.79(br dd,J=8.2,14.3Hz,1H),4.82-4.76(m,1H),4.39(br t,J=8.2Hz,1H),4.09(br t,J=13.9Hz,2H),3.94(s,3H),3.62-3.54(m 2H),3.33(s,5H),3.26-3.09(m,6H),3.02-2.81(m,4H),2.79-2.69(m,1H),2 .07-1.99(m,2H),1.99-1.90(m,2H),1.84-1.54(m,11H),1.42-1.36(m,3H).

[0861] Example 58. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 58)

[0862]

[0863] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (110.4 mg, 97.65 μmol, 40.84% ​​yield, 95.7% purity, 2TFA) was obtained as a white solid. MS (M+H) + =854.4.

[0864] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.69-9.32 (m, 2H), 8.27 (br d,J=8.2Hz,1H),8.23(s,1H),8.17-8.10(m,1H),7.50-7.41(m,2H),6.97(dd,J=8.3,13.0Hz,1 H),6.78(dd,J=8.4,14.6Hz,1H),5.75-5.51(m,1H),4.92-4.85(m,1H),4.40-4.36(m,1H),4.1 0-4.04(m,2H),3.93(s,3H),3.61-3.52(m,2H),3.37-3.29(m,5H),3.24-3.07(m,6H),3.00-2. 90(m,2H),2.87-2.74(m,2H),2.73-2.54(m,1H),2.07-1.99(m,2H),1.80-1.70(m,2H),1.64(br s, 2H), 1.45-1.30 (m, 3H), 1.24 (d, J = 6.7Hz, 6H).

[0865] Example 59. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 59)

[0866]

[0867] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.52 g, 1.66 mmol, 35.97% yield, 98% purity) was synthesized as a yellow solid. MS (M+H) + =898.4.

[0868] 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 8.28-8.21 (m, 1H), 8.04 (s, 1H), 7.14 (d, J = 6.4Hz, 1H), 6.84 (br dd,J=8.1,13.0Hz,1H),6.73(brdd,J=8.2,14.6Hz,1H),5.49(br d,J=8.4Hz,1H),4.88-4.77(m,1H),4.38-4.31(m,1H),4.08(br t,J=13.9Hz,2H),3.91(s,3H),3.33(s,3H),3.09-2.98(m 2H),2.95-2.84(m,5H),2.77-2.62(m,5H),2.39-2.30(m,2H),2.09-1.92(m,5H),1.77-1.59(m,9H),1.44-1.27(m,5H).

[0869] Example 60. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (Compound 60)

[0870] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluoro-5-methoxybenzamide (1.60 g, 1.79 mmol, 65.04% yield, 97.4% purity) was synthesized as a yellow solid. MS (M+H) + =872.4.

[0871] 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.98 (d, J = 1.8Hz, 1H), 8.33-8.16 (m, 2H), 7.97 ( s,1H),7.14(d,J=6.5Hz,1H),6.84(dd,J=8.1,13.1Hz,1H),6.78-6.68(m,1H),5.49(br d,J=8.1Hz,1H),4.90(td,J=6.6,13.4Hz,1H),4.42-4.28(m,1H),4.06(br t,J=13.4Hz,2H),3.91(s,3H),3.39-3.31(m,5H),3.10-3.01(m,2H),2.91-2.81(m,4H),2.80-2.56(m,4H),2.4 8-2.41(m,2H),2.39-2.28(m,2H),2.12-1.96(m,2H),1.78-1.70(m,2H),1.47-1.38(m,2H),1.36-1.21(m,9H).

[0872] Example 61. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 61)

[0873]

[0874] Step 1. Synthesis of benzyl (7-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3)

[0875] Benzyl (7-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.9 g, 7.19 mmol, 97.84% yield) was obtained as a yellow oil by a method similar to that described in Step 4 of Example 30. MS (M+H) + =543.3.

[0876] Step 2. Synthesis of benzyl (7-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4)

[0877] Benzyl (7-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (3.6 g, 7.02 mmol, 97.71% yield) was obtained as a brown oil by a method similar to that described in Step 4 of Example 22. MS (M+H) + =513.3.

[0878] Step 3. Synthesis of benzyl (7-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (6)

[0879] Benzyl (7-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1 g, 1.25 mmol, 35.51% yield) was obtained as a brown oil by a method similar to that described in Step 3 of Example 1. MS (M+H) + =802.2.

[0880] Step 4. Synthesis of tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7)

[0881] Pd(OH)2 (0.5 g, 712.07 μmol, 20% purity) was added and synthesized in a manner similar to that described in Step 4 of Example 51 to obtain tert-butyl (7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (400 mg, 678.29 μmol, 77.71% yield) as a cyan solid. MS (M+H) + =590.4.

[0882] Step 5. Synthesis of 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (8)

[0883] 3-((4-(4-(2-(2-amino-7-azaspiro[3.5]nonan-7-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (500 mg, 828.33 μmol, 97.70% yield, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a brown oil. MS (M+H) + =490.3.

[0884] Step 6. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 61)

[0885] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (299.4 mg, 325.22 μmol, 39.26% yield, 97% purity) was obtained as a white solid. MS (M+H) + =893.4.

[0886] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.45-8.38 (m, 1H), 8.30 (d, J = 8.4Hz, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.54-7.46 (m, 2H),6.87-6.78(m,1H),6.76-6.66(m,1H),5.49-5.42(m,1H),4.95-4.82(m,1H),4.46-4.29(m,2H),4.09-3.99(m,2H),3. 94(s,3H),3.33-3.32(m,3H),3.18-3.05(m,2H),2.80-2.65(m,1H),2.60-2.51(m,3H),2.34-2.11(m,8H),2.08-1.97(m,2 H),1.84-1.77(m,2H),1.75-1.68(m,2H),1.61-1.51(m,4H),1.42-1.35(m,2H),1.34-1.27(m,2H),1.24(d,J=6.7Hz,7H).

[0887] Example 62. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 62)

[0888]

[0889] Step 1. Synthesis of tert-butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (3)

[0890] tert-Butyl 4-(2-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)ethyl)piperidine-1-carboxylate (16 g, crude product) was synthesized by a method similar to that described in Step 6 of Example 1 as a white solid. MS (M+H) + =446.4.

[0891] Step 2. Synthesis of benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (4)

[0892] Benzyl (1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (10 g, crude product, HCl) was synthesized by a method similar to that described in Step 2 of Example 48 as a white solid. MS (M+H) + =346.3.

[0893] Step 3. Synthesis of benzyl (1-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (6)

[0894] Benzyl (1-(2-(1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (5 g, 9.45 mmol, 72.20% yield, 95% purity) was synthesized by a method similar to that described in Step 4 of Example 30 as a yellow solid. MS (M+H) + =503.3.

[0895] Step 4. Synthesis of benzyl (1-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (7)

[0896] Benzyl (1-(2-(1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.48 g, 3.13 mmol, 62.96% yield, 100% purity) was synthesized by a method similar to that described in Step 4 of Example 22 as a yellow solid. MS (M+H) + =473.3.

[0897] Step 5. Synthesis of benzyl (1-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (9)

[0898] Benzyl (1-(2-(1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (1.26 g, 1.65 mmol, 78.15% yield) was synthesized by a method similar to that described in Step 1 of Example 36 as a yellow solid. MS (M+H) + =762.4.

[0899] Step 6. Synthesis of benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (10)

[0900] Benzyl (1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)carbamate (440 mg, 800.51 μmol, 57.54% yield, 100% purity) was synthesized by a method similar to that described in Step 4 of Example 61 as a cyan solid. MS (M+H) + =550.4.

[0901] Step 7. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (11)

[0902] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (450 mg, crude, TFA) was obtained as a cyan oil by a method similar to that described in Step 6 of Example 3. MS (M+H) + =450.4.

[0903] Step 8. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 62)

[0904] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (237.1 mg, 272.43 μmol, 35.88% yield, 98% purity) was synthesized as a white solid. MS (M+H) + =853.5.

[0905] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30 (d, J = 8.2Hz, 1H), 8.22 (s, 1H), 8.10 (d, J = 7.7Hz, 1H), 7.87 (s, 1H), 7.54-7.45 (m, 2H), 6. 83(dd,J=8.1,13.1Hz,1H),6.71(dd,J=8.4,14.3Hz,1H),5.49-5.42(m,1H),4.94-4.81(m,1H),4.39-4.29(m,1H),4.03(t,J=13.6Hz ,2H),3.93(s,3H),3.83-3.71(m,1H),3.26(s,3H),3.16-3.08(m,2H),2.93-2.85(m,2H),2.78-2.66(m,1H),2.59-2.52(m,3H),2.35 -2.28(m,2H),2.07-2.00(m,2H),1.98-1.88(m,2H),1.82-1.69(m,4H),1.63-1.51(m,2H),1.45-1.28(m,5H),1.24(d,J=6.7Hz,6H).

[0906] Example 63. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 63)

[0907] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (130.7 mg, 145.73 μmol, 17.16% yield, 98% purity) was obtained as a gray solid. MS (M+H) + =879.5.

[0908] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.30-8.23 (m, 2H), 8.11 (d, J = 7.7Hz, 1H), 7.96 (s, 1H), 7.53-7.44 (m, 2H), 6.8 3(dd,J=8.1,13.2Hz,1H),6.71(dd,J=8.3,14.3Hz,1H),5.48-5.43(m,1H),4.83-4.70(m,1H),4.38-4.28(m,1H),4.04 (t,J=14.1Hz,2H),3.93(s,3H),3.84-3.70(m,1H),3.32(s,3H),3.17-3.08(m,2H),2.93-2.85(m,2H),2.79-2.66(m,1 H),2.60-2.53(m,3H),2.36-2.29(m,2H),2.09-1.86(m,6H),1.82-1.67(m,6H),1.65-1.53(m,6H),1.45-1.22(m,5H).

[0909] Example 64. Synthesis of N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (Compound 64)

[0910] N-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-4-((9-ethyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzamide (258.3 mg, 304.83 μmol, 35.48% yield, 99% purity) was synthesized as a gray solid. MS (M+H) + =839.4.

[0911] 1H NMR (400MHz, DMSO-d6) δ=10.79(s,1H),8.31(d,J=8.3Hz,1H),8.23(s,1H),8.10(d,J=7.7Hz,1H),7.89(s,1H),7.55-7.47(m,2H ),6.83(dd,J=8.1,13.3Hz,1H),6.72(dd,J=8.4,14.4Hz,1H),5.49-5.43(m,1H),4.38-4.30(m,1H),4.17(t,J=13.4Hz,2H),3.9 4(s,3H),3.82-3.72(m,1H),3.69-3.60(m,2H),3.33(s,3H),3.17-3.09(m,2H),2.94-2.85(m,2H),2.79-2.68(m,1H),2.60-2.5 3(m,3H),2.36-2.27(m,2H),2.07-1.89(m,4H),1.83-1.70(m,4H),1.64-1.52(m,2H),1.46-1.25(m,5H),1.22(t,J=7.0Hz,3H).

[0912] Example 65. Synthesis of 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 65)

[0913]

[0914] Step 1. Synthesis of tert-butyl 2-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoyl)hydrazine-1-carboxylate (2)

[0915] A similar method to that described in Step 10 of Example 2 was used to synthesize tert-butyl 2-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoyl)hydrazine-1-carboxylate (7.6 g, 13.40 mmol, 99.91% yield, 99% purity) as a yellow solid. MS (M+H) + =562.3.

[0916] Step 2. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (3)

[0917] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (3 g, 6.50 mmol, 48.04% yield, 100% purity) was obtained as a yellow solid by a method similar to that described in Step 6 of Example 3. MS (M+H) + =462.2.

[0918] Step 3. Synthesis of N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (5)

[0919] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.5 g, 5.42 mmol) in DCM (100 mL) was added DIPEA (1.39 g, 10.74 mmol, 1.87 mL) at 0°C, followed by the slow addition of a solution of 2-chloroacetyl chloride (490 mg, 4.34 mmol, 345.56 μL) in DCM (5 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h. LCMS confirmed 21% of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide, and 72% of the desired mass. A solution of 2-chloroacetyl chloride (95 mg, 841.14 μmol, 67.00 μL) in DCM (1 mL) was added, and the mixture was further stirred at 0°C for 0.5 hours. LCMS confirmed 8% of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide, and 84% of the desired mass. A solution of 2-chloroacetyl chloride (110 mg, 973.95 μmol, 77.57 μL) in DCM (1 mL) was added and the mixture was further stirred at 0°C for 0.5 hours. The mixture was diluted with water (50 mL) and extracted with DCM (20 mL). The organic layer was washed with water (20 mL) and dried over Na2SO4, then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by flash silica gel chromatography (20 g of Purification was performed using a silica gel flash column with an 80-100% EtOAc / petroleum ether gradient at 100 mL / min as the eluent to afford N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.5 g, 4.23 mmol, 78.06% yield, 91% purity) as a yellow solid. MS (M+H) + =538.2.

[0920] Step 4. Synthesis of 2-((4-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (6)

[0921] To a solution of N'-(2-chloroacetyl)-4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.4 g, 4.46 mmol) in toluene (50 mL) was slowly added POCl3 (13.16 g, 85.83 mmol, 8 mL) at 25°C, and the mixture was stirred under N2 and 80°C for 14 hours. LCMS confirmed the presence of remaining starting material. POCl3 (13.16 g, 85.83 mmol, 8 mL) was additionally added at 25°C, and the mixture was further stirred under N2 and 80°C for 38 hours. The suspension became clear. The mixture was combined with another batch (0.1 g scale) and concentrated under reduced pressure. The crude product was diluted with DCM (100 mL) and then slowly poured into a saturated NaHCO3 solution (100 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and water (50 mL) and dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to give 2-((4-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2.16 g, crude product) as a red solid. MS (M+H) + =520.2.

[0922] Step 5. Synthesis of tert-butyl 4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (7C)

[0923] A similar method to that described in Step 5 of Example 56 was used to synthesize tert-butyl 4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (8.6 g, 16.06 mmol, 57.93% yield, 100% purity) as a gray solid. MS (M+H) + =536.5.

[0924] Step 6. Synthesis of 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7)

[0925] 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (8 g, crude, HCl salt) was synthesized by a method similar to that described in Step 2 of Example 48 as a gray solid. MS (M+H) + =436.3.

[0926] Step 7. Synthesis of 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 65)

[0927] Two batches of product were obtained by a method similar to that described in Step 8 of Example 25. Batch 1: 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione as a yellow solid (1.81 g, 1.96 mmol, 59.91% yield, 99.3% purity). Batch 2: 3-((4-(4-(2-(1-((5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione as a yellow solid (628 mg, 670.38 μmol, 20.54% yield, 98% purity). MS (M+H) + =919.7.

[0928] 1H NMR (400MHz, DMSO-d6) δ=10.78(s,1H),8.43(d,J=8.4Hz,1H),8.28(s,1H),8.11(s,1H),7.60-7.49(m,2H),6.81(br dd,J=7.8,13.2Hz,1H),6.71(br dd,J=8.1,14.7Hz,1H),5.49-5.44(m,1H),4.83-4.72(m,1H),4.37-4.27(m,1H),4.04(br t,J=13.8Hz,2H),3.98(s,3H),3.82(s,2H),3.37(s,3H),2.90-2.78(m,6H),2.76-2.65(m,1H),2.58-2.52(m,1H),2.47-2.4 1(m,3H),2.33-2.26(m,2H),2.14-2.05(m,2H),2.04-1.89(m,4H),1.72-1.53(m,9H),1.39-1.31(m,2H),1.28-1.10(m,3H).

[0929] Example 66. Synthesis of 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 66)

[0930]

[0931] Step 1. Synthesis of 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2)

[0932] To a solution of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxybenzohydrazide (2.1 g, 4.55 mmol) in dioxane (40 mL) was added a solution of NaHCO (1.15 g, 13.66 mmol, 531.45 μL) in H₂O (20 mL), followed by the addition of BrCN (1.05 g, 9.91 mmol, 727.65 μL). The mixture was stirred at 25°C under N₂ for 13 hours. The mixture was filtered, and the filter cake was washed with MTBE (30 mL) and water (30 mL). The filter cake was collected and dried under reduced pressure to obtain 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (1.81 g, 3.53 mmol, yield 77.67%, purity 95%) as a yellow solid. The filtrate was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was diluted with MTBE (10 mL) and stirred at 25°C for 0.5 hours. The suspension was filtered, and the filter cake was washed with MTBE (10 mL) and water (10 mL). The filter cake was collected and dried under reduced pressure to give 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (380 mg, crude product) as a yellow solid. MS (M+H) + =487.3.

[0933] Step 2. Synthesis of 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (3)

[0934] To a solution of CuBr (1.80 g, 12.55 mmol, 382.17 μL) in CAN (20 mL) was added t-BuONO (1.28 g, 12.41 mmol, 1.48 mL), followed by a solution of 2-((4-(5-amino-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (2 g, 4.11 mmol) in CAN (90 mL). The resulting mixture was stirred at 60°C for 1 hour. LCMS confirmed the desired mass. The mixture was cooled to 25°C and adjusted to pH ~8 with saturated NaHCO3. The mixture was filtered, and the filter cake was washed with THF (100 mL) and EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude product was diluted with water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4, and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by flash silica gel chromatography (12 g of Purification was performed on a silica gel flash column with a 0-10% MeOH / EtOAc gradient at 100 mL / min as the eluent to afford 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.6 g, 1.09 mmol, 26.52% yield) as a yellow solid. MS (M+H) + =550.3.

[0935] Step 3. Synthesis of 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (Compound 66)

[0936] To a solution of 3-((2,5-difluoro-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1 g, 2.12 mmol, HCl salt) and KCO (603.33 mg, 4.37 mmol, 279.45 μL) in DMF (10 mL) was added 2-((4-(5-bromo-1,3,4-oxadiazol-2-yl)-2-methoxyphenyl)amino)-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.6 g, 1.09 mmol). The resulting mixture was stirred at 50°C for 14 hours. LCMS confirmed the presence of a peak of the desired mass (82%). The mixture was diluted with EtOAc (10 mL) and water (30 mL). The mixture was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g of The product was purified by silica gel flash column (eluent: 10-20% MeOH / DCM gradient @ 50 mL / min) and repurified by prep-TLC (EtOAc / MeOH = 10 / 1). The product, mixed with impurities, was repurified by prep-HPLC (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [water (TFA)-ACN]; gradient: 25%-55% B over 10 minutes). The eluted material was lyophilized to obtain 3-((4-(4-(2-(1-(5-(4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione as a cyan solid (568.5 mg, 544.52 μmol, 49.95% yield, 97.6% purity, TFA). MS (M+H) + =905.6.

[0937] 1H NMR (400MHz, CD3OD) δ=8.33(d,J=8.4Hz,1H),8.16(s,1H),7.58-7.56(m,1H),7.52(dd,J=1.8,8.5Hz,1H),6.89(dd,J=7.7,12 .6Hz,1H),6.72(dd,J=7.9,13.8Hz,1H),4.99-4.93(m,1H),4.31(dd,J=5.0,12.4Hz,1H),4.14-4.05(m,4H),4.03(s,3H),3.6 6(brd,J=12.4Hz,2H),3.46-3.39(m,5H),3.30-3.24(m,4H),3.22-3.14(m,2H),3.11-3.02(m,2H),2.87-2.78(m,1H),2.75-2 .68(m,1H),2.33-2.25(m,1H),2.10-1.99(m,3H),1.94-1.87(m,2H),1.84-1.75(m,4H),1.74-1.64(m,5H),1.50-1.38(m,2H).

[0938] Example 67. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 67)

[0939]

[0940] Step 1. Synthesis of tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (3)

[0941] A method similar to that described in step 3 of Example 23 was used to synthesize tert-butyl (1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (4 g, 7.12 mmol, 39.51% yield, 98% purity) as a white solid. MS (M+H) + =551.5.

[0942] Step 2. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (4)

[0943] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (3 g, 5.31 mmol, 97.54% yield, TFA salt) was synthesized by a method similar to that described in Step 3 of Example 3 as a yellow oil. MS (M+H) + =451.3.

[0944] Step 3. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (Compound 67)

[0945] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide (1.81 g, 2.04 mmol, 38.37% yield, 99% purity) was synthesized as a white solid. MS (M+H) + =880.4.

[0946] 1H NMR (400MHz, CD3OD) δ = 8.50 (d, J = 8.2Hz, 1H), 8.20 (s, 1H), 7.60-7.49 (m, 2H), 6.85 (dd, J = 7.7, 13.0 Hz,1H),6.78-6.64(m,1H),4.30(dd,J=4.8,12.5Hz,1H),4.20-4.09(m,1H),4.08-3.98(m,5H),3.61 -3.49(m,1H),3.42(s,3H),3.24-3.18(m,2H),3.12-3.00(m,6H),2.93-2.72(m,9H),2.36-2.29(m, 1H),2.26-2.17(m,2H),2.14-2.06(m,2H),2.05-1.92(m,3H),1.88-1.81(m,2H),1.79-1.59(m,5H).

[0947] Example 68. Synthesis of 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-4-methoxypicolinamide (Compound 68)

[0948] 5-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-4-methoxypicolinamide (0.7637 g, 858.25 μmol, 40.38% yield, 99% purity) was obtained as a yellow solid. MS (M+H) + =881.4.

[0949] 1H NMR (400MHz, DMSO-d6) δ = 10.81 (s, 1H), 9.05 (s, 1H), 8.81 (br d, J = 7.9Hz, 1H), 8.62 (br s,1H),8.24(s,1H),7.71(s,1H),6.97(dd,J=8.0,12.9Hz,1H),6.79(dd,J=8.2,14.4Hz,1H),5.84-5.59(m,1H),4.73-4.61(m,1H),4.39(br t,J=8.6Hz,1H),4.22-3.91(m,6H),3.64-3.43(m,6H),3.43-3.28(m,6H),3.28-2.92(m, 7H),2.79-2.66(m,1H),2.62-2.54(m,1H),2.12-1.92(m,6H),1.89-1.81(m,2H),1.66(br s,2H),1.61-1.47(m,4H).

[0950] Example 69. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 69)

[0951]

[0952] Step 1. Synthesis of benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2)

[0953] Benzyl (7-(piperidin-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (23 g, crude product, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a colorless oil. MS (M+H) + =372.2.

[0954] Step 2. Synthesis of benzyl (7-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (4)

[0955] Benzyl (7-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (20 g, 37.84 mmol, 79.87% yield) was synthesized by a method similar to that described in Step 3 of Example 62 as a yellow solid. MS (M+H) + =529.3.

[0956] Step 3. Synthesis of benzyl (7-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (5)

[0957] Benzyl (7-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (20 g) was synthesized in a manner similar to that described in Step 4 of Example 62 as a yellow solid. MS (M+H) + =499.3.

[0958] Step 4. Synthesis of benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (7)

[0959] Benzyl (7-((1-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (16 g, 20.31 mmol, 72.32% yield) was obtained as a brown oil by a method similar to that described in Step 5 of Example 62. MS (M+H) + =788.4.

[0960] Step 5. Synthesis of tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (8)

[0961] By synthesizing in a manner similar to that described in Step 6 of Example 62, tert-butyl (7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2 g) was obtained as a cyan solid. MS (M+H) + =576.3.

[0962] Step 6. Synthesis of 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (9)

[0963] 3-((4-(4-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)amino)piperidine-2,6-dione (1.78 g, 3.48 mmol, 100.00% yield, HCl salt) was synthesized by a method similar to that described in Step 2 of Example 48 as a cyan solid. MS (M+H) + =476.2.

[0964] Step 7. Synthesis of 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (Compound 69)

[0965] 4-((7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-2-fluoro-5-methoxybenzamide (233.6 mg, 252.63 μmol, 22.66% yield, 97% purity) was obtained as a yellow solid. MS (M+H) + =897.2.

[0966] 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.36-8.21 (m, 3H), 7.98 (s, 1H), 7.21 (d, J = 6.6Hz, 1H), 6.90- 6.79(m,1H),6.78-6.67(m,1H),5.50(d,J=8.0Hz,1H),4.95-4.86(m,1H),4.49-4.30(m,2H),4.07(t ,J=13.4Hz,2H),3.92(s,3H),3.33-3.32(m,3H),3.18-3.13(m,2H),3.06-2.84(m,2H),2.79-2.65(m ,2H),2.63-2.52(m,5H),2.35-2.10(m,3H),2.09-1.96(m,3H),1.95-1.59(m,9H),1.47-1.22(m,8H).

[0967] Example 70. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (Compound 70)

[0968]

[0969] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(7-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,5-difluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-methoxybenzamide (274 mg, 296.71 μmol, 11.69% yield, 98% purity) was obtained as a white solid. MS (M+H) + =905.5.

[0970] 1H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 8.42 (br d, J = 6.9Hz, 1H), 8.30-8.23 (m, 2H), 7.96 (s, 1H), 7.51-7.44 (m, 2H), 6.87-6.66 (m, 2H), 5.46 (br d,J=8.6Hz,1H),4.82-4.71(m,1H),4.46-4.28(m,2H),4.04(br t,J=13.9Hz,2H),3.94(s,3H),3.31(s,3H),3.18-3.08(m,2H),2.80-2.66(m,1H),2.61-2.52(m,3 H),2.36-2.09(m,7H),2.08-1.90(m,5H),1.87-1.68(m,6H),1.66-1.48(m,9H),1.31-1.14(m,2H).

[0971] Example 71. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 71)

[0972]

[0973] Step 1. Synthesis of tert-butyl 4-(2,3-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3)

[0974] A method similar to that described in step 4 of Example 30 was used to synthesize tert-butyl 4-(2,3-difluoro-4-nitrophenyl)piperazine-1-carboxylate (4.8 g, 13.56 mmol, 48.03% yield, 97% purity) as a white solid. MS (M+H-55) + =288.0.

[0975] 1 H NMR (400MHz, CDCl3) δ = 7.91-7.77 (m, 1H), 6.66 (br t, J = 8.4Hz, 1H), 3.61-3.59 (m, 4H), 3.30-3.28 (m, 4H), 1.49-1.46 (m, 9H).

[0976] Step 2. Synthesis of tert-butyl 4-(4-amino-2,3-difluorophenyl)piperazine-1-carboxylate (4)

[0977] A method similar to that described in step 4 of Example 22 was used to synthesize tert-butyl 4-(4-amino-2,3-difluorophenyl)piperazine-1-carboxylate (4.6 g, 12.48 mmol, 89.25% yield, 85% purity) as a brown solid. MS (M+H) + =314.0.

[0978] Step 3. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazine-1-carboxylate (6)

[0979] A similar method to that described in Step 5 of Example 22 was used to synthesize tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazine-1-carboxylate (2.7 g, 5.85 mmol, 39.87% yield, 92% purity) as a cyan solid. MS (M+H) + =425.2.

[0980] 1 H NMR (400MHz, CDCl3) δ = 8.37 (br s, 1H), 6.61 (br t, J = 7.9Hz, 1H), 6.40 (br t, J = 8.1Hz, 1H), 4.75-4.57 (m, 1H), 4.10-4.06 (m, 1H), 3.59 (br d,J=4.4Hz,4H),2.93(brd,J=4.4Hz,4H),2.94-2.76(m,1H),2.65-2.27(m,2H),2.05-1.91(m,1H),1.50(s,9H).

[0981] Step 4. Synthesis of 3-((2,3-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (7)

[0982] 3-((2,3-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (2.3 g, crude product, HCl salt) was synthesized by a method similar to that described in Step 5 of Example 1 as a cyan solid. MS (M+H) + =325.1.

[0983] Step 5. Synthesis of tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (9)

[0984] A similar method to that described in Step 6 of Example 1 was used to synthesize tert-butyl (4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)carbamate (1.05 g, 1.72 mmol, 26.92% yield, 90% purity) as a yellow solid. MS (M+H) + =551.3.

[0985] Step 6. Synthesis of 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,3-difluorophenyl)amino)piperidine-2,6-dione (10)

[0986] 3-((4-(4-(2-(1-aminopiperidin-4-yl)ethyl)piperazin-1-yl)-2,3-difluorophenyl)amino)piperidine-2,6-dione (1.08 g, crude product, TFA salt) was synthesized by a method similar to that described in Step 6 of Example 3 as a brown oil. MS (M+H) + =451.2.

[0987] Step 7. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (Compound 71)

[0988] 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-N-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-3-methoxybenzamide (899 mg, 980.79 μmol, 51.27% yield, 96% purity) was obtained as a white solid. MS (M+H) + =880.4.

[0989] 1H NMR (400MHz, DMSO-d6) δ = 10.82 (s, 1H), 9.90-9.56 (m, 2H), 8.34-8.13 (m, 3H), 7.54-7.37 (m ,2H),6.80-6.68(m,1H),6.66-6.53(m,1H),4.81-4.76(m,1H),4.43-4.38(m,1H),4.08(br t,J=13.6Hz,2H),3.94(s,3H),3.60-3.52(m,2H),3.40-3.29(m,5H),3.28-3.09(m,6H),3.07-2. 82(m,4H),2.81-2.65(m,1H),2.63-2.54(m,1H),2.10-1.87(m,5H),1.83-1.52(m,10H),1.39(br s,2H).

[0990] Example 72. Synthesis of N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-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)-2-fluoro-5-methoxybenzamide (Compound 72)

[0991]

[0992] Step 1. Synthesis of tert-butyl 4-(5-chloro-2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (2)

[0993] By synthesizing in a manner similar to that described in step 4 of Example 30, tert-butyl 4-(5-chloro-2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (19 g, crude product) was obtained as a yellow solid. MS (M-100+H) + =260.2.

[0994] Step 2. Synthesis of tert-butyl 4-(4-amino-5-chloro-2-fluorophenyl)piperazine-1-carboxylate (3)

[0995] By synthesizing in a manner similar to that described in Step 4 of Example 22, tert-butyl 4-(4-amino-5-chloro-2-fluorophenyl)piperazine-1-carboxylate (16.66 g, crude product) was obtained as a yellow oil. MS (M+H) + =330.2.

[0996] Step 3. Synthesis of tert-butyl 4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (5)

[0997] A similar method to that described in Step 3 of Example 51 was used to synthesize tert-butyl 4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (15 g, 30.62 mmol, 60.61% yield, 90% purity) as a yellow solid. MS (M+H) + =441.2.

[0998] Step 4. Synthesis of 3-((2-chloro-5-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (6)

[0999] 3-((2-chloro-5-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (11.6 g, crude product, HCl) was synthesized by a method similar to that described in Step 2 of Example 48 as a cyan solid. MS (M+H) + =341.3.

[1000] Step 5. Synthesis of tert-butyl (1-(2-hydroxyethyl)piperidin-4-yl)carbamate (7B)

[1001] By a method similar to that described in step 2 of Example 7, tert-butyl (1-(2-hydroxyethyl)piperidin-4-yl)carbamate (25 g, 102.32 mmol, 81.97% yield) was obtained as a white solid. MS (M+H) + =245.3.

[1002] Step 6. Synthesis of tert-butyl (1-(2-chloroethyl)piperidin-4-yl)carbamate (7)

[1003] To a solution of tert-butyl (1-(2-hydroxyethyl)piperidin-4-yl)carbamate (3 g, 12.28 mmol) in DCM (30 mL) was added Py (1.94 g, 24.56 mmol, 1.98 mL) and then SOCl (2.19 g, 18.42 mmol, 1.34 mL) was added at 0°C. The mixture was stirred for 2 hours at 20°C. By TLC (DCM / MeOH=10 / 1), the consumption of the starting material was confirmed and the formation of a new spot was confirmed. The reaction mixture was diluted with DCM (150 mL) and H2O (150 mL) and then adjusted to pH~8 with saturated NaHCO3 at 0°C. The DCM layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was diluted with hexane (100 mL) and concentrated in vacuo at 40-50°C to remove pyridine, yielding tert-butyl (1-(2-chloroethyl)piperidin-4-yl)carbamate (3.3 g, crude product) as a yellow solid. MS (M+H) + =263.8.

[1004] Step 7. Synthesis of tert-butyl (1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (8)

[1005] By a method similar to that described in Step 1 of Example 48, tert-butyl (1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)carbamate (2.55 g, 4.50 mmol, 33.93% yield) was obtained as a dark blue solid. MS (M+H) + =567.3.

[1006] Step 8. Synthesis of 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-chloro-5-fluorophenyl)amino)piperidine-2,6-dione (9)

[1007] 3-((4-(4-(2-(4-aminopiperidin-1-yl)ethyl)piperazin-1-yl)-2-chloro-5-fluorophenyl)amino)piperidine-2,6-dione (3.4 g, crude product, HCl) was obtained as a gray solid by a method similar to that described in Step 4. MS (M+H) + =467.3.

[1008] Step 9. Synthesis of N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-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)-2-fluoro-5-methoxybenzamide (Compound 72)

[1009] N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-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)-2-fluoro-5-methoxybenzamide (1.33 g, 1.47 mmol, 49.59% yield, 98% purity) was synthesized as a yellow solid. MS (M+H) + =888.4.

[1010] 1 H NMR (400MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.32-8.24 (m, 2H), 8.15-7.80 (m, 2H), 7.19 (d, J = 6.6Hz, 1H), 7 .02-6.95(m,1H),6.77(d,J=14.8Hz,1H),5.43-5.37(m,1H),4.95-4.85(m,1H),4.45-4.36(m,1H),4.0 6(t,J=13.4Hz,2H),3.92(s,3H),3.41-3.36(m,3H),3.33(s,3H),2.96-2.85(m,4H),2.82-2.71(m,1H ),2.64-2.53(m,11H),2.11-1.99(m,3H),1.88-1.71(m,2H),1.67-1.47(m,1H),1.26(d,J=6.7Hz,6H).

[1011] Example 73. Synthesis of N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-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-methoxybenzamide (Compound 73)

[1012] N-(1-(2-(4-(5-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)-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-methoxybenzamide (1.53 g, 1.64 mmol, 54.51% yield, 98% purity) was synthesized as a yellow solid. MS (M+H) + =914.5.

[1013] 1 H NMR (400MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.35-8.21 (m, 2H), 8.13-7.92 (m, 2H), 7.19 (d, J = 6.8 Hz,1H),6.99(d,J=8.8Hz,1H),6.77(d,J=14.8Hz,1H),5.44-5.37(m,1H),4.88-4.77(m,1H), 4.46-4.36(m,1H),4.08(t,J=13.8Hz,2H),3.92(s,3H),3.55-3.48(m,4H),3.33(s,3H),2.9 5-2.87(m,4H),2.83-2.73(m,1H),2.69-2.51(m,11H),2.12-1.88(m,6H),1.80-1.55(m,7H).

[1014] Example 74. Synthesis of 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,...

Claims

1. A compound represented by the following chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: [Chemical Formula I] ULM-Connector-PTM, In the chemical formula I, ULM is a moiety represented by the following chemical formula 1: [Chemical formula 1] PTM is a moiety represented by the following chemical formula 2: [Chemical formula 2] The linker is a group that chemically connects the ULM and PTM; X is CH or N; V is -NR V - or single key; R V is -H or -CH3; Ring U is phenyl or 5- to 6-membered heteroaryl, {wherein one or more H on the phenyl or 5- to 6-membered heteroaryl ring can be replaced by R U replace}; R U For -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Aminoalkyl, -C 1-3 Haloalkyl, -C 1-3 Alkoxy, -CN or -halo; Y1 is CR Y or N; Y2 to Y4 are each independently CR Y ; R Y -H, -C 1-3 Alkyl, -C 1-3 Alkoxy or -halo; R1 is -C 1-4 Alkyl or 5- to 6-membered cycloalkyl; R2 and R3 are each independently -H, -C 1-3 Alkyl or -halo; R4 is -C 1-3 alkyl.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: ULM is a moiety represented by the following Chemical Formula 1-1, Chemical Formula 1-2, or Chemical Formula 1-3: [Chemical formula 1-1] [Chemical formula 1-2] [Chemical formula 1-3] R V is -H or -CH3; Ring U is phenyl or pyridyl, {wherein one or more H on the phenyl or pyridyl ring can be replaced by R U replace}; R U For -C 1-3 Alkyl, -C 1-3 Alkoxy, -CN or -halo.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: ULM is: R U1 and R U2 Each independently is -C 1-3 Alkyl, -C 1-3 Alkoxy, -CN or -halo.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: ULM is: R U1 and R U2 Each independently is -C 1-3 Alkyl, -C 1-3 Alkoxy, -CN or -halo.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The PTMs are: Y1 is CR Y or N; Y2 to Y4 are each independently CR Y ; R Y -H, -C 1-3 Alkoxy or -halo; R1 is -C 1-4 Alkyl or 5- to 6-membered cycloalkyl.

6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Connector: -L U -L1-L2-L P -; L U is a heterocycloalkyl group, {wherein the heterocycloalkyl group contains one or more N atoms in the ring, and one or more H atoms in the heterocycloalkyl group can be replaced by -C 1-4 Alkyl, -C 1-4 alkoxy or -halo substituted}; L1 is -(CH2) X1 -、-(CH2) X2 -NH-(CH2) X3 -、-(CH2) X2 -N(C 1-4 Alkyl)-(CH2) X3 - or a single bond, {wherein, each of X1 to X3 is independently 0, 1, 2, 3 or 4}; L2 is a cycloalkyl or heterocycloalkyl group, {wherein the heterocycloalkyl group contains one or more N atoms on the ring, and one or more H atoms on the cycloalkyl or heterocycloalkyl ring can be replaced by -C 1-4 Alkyl, -C 1-4 alkoxy or -halo substituted}; L P It is -NH-C(=O)- or -(CH2)p-heteroaryl, {wherein, the -C(=O)- of the -NH-C(=O)- or the heteroaryl of the -(CH2)p-heteroaryl is connected to PTM, the heteroaryl contains N and O atoms in the ring, and p is 0, 1, 2 or 3}.

7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L U is a 4- to 12-membered heterocycloalkyl group, {wherein the 4- to 12-membered heterocycloalkyl group is a monocyclic, bridged bicyclic or spirocyclic ring, the 4- to 12-membered heterocycloalkyl group contains one or more N atoms on the ring, the N atoms are directly connected to the ULM, and one or more H atoms on the 4- to 12-membered heterocycloalkyl ring can be replaced by -C 1-4 alkyl or -halo substituted}; L1 is -(CH2) X1 -、-(CH2) X2 -N(C 1-4 Alkyl)-(CH2) X3 - or a single bond, {wherein, each of X1 to X3 is independently 0, 1, 2 or 3}; L2 is a 4- to 6-membered cycloalkyl or a 4- to 12-membered heterocycloalkyl, {wherein the 4- to 12-membered heterocycloalkyl is a monocyclic, bridged bicyclic or spirocyclic ring, the 4- to 12-membered heterocycloalkyl contains one or more N atoms on the ring, and one or more H atoms on the 4- to 6-membered cycloalkyl or 4- to 12-membered heterocycloalkyl ring can be replaced by -C 1-4 alkyl or -halo substituted}; L P It is -NH-C(=O)- or -(CH2)p-1,3,4-oxadiazole, {wherein, the -C(=O)- of the -NH-C(=O)- or the 1,3,4-oxadiazole of the -(CH2)p-1,3,4-oxadiazole is connected to PTM, and the p is 0 or 1}.

8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Chemical Formula I is selected from the group consisting of the following compounds:

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for preventing or treating cancer, benign tumors or neurological diseases, characterized in that: The pharmaceutical composition comprises the compound according to any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A method for treating or preventing cancer, benign tumors or neurological diseases, characterized in that: The method comprises the following steps: A therapeutically effective amount of the compound of any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

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

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

14. Use of the compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing cancer, benign tumors or neurological diseases.

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