Degradation agent targeting BET and / or CBP / p300 protein and application thereof

Abstract

The invention provides a degradation agent targeting BET and / or CBP / p300 protein and application thereof. The structure of the degradation agent is shown as a formula I and a formula II. The degradation agent provided by the invention can effectively degrade BET and CBP / p300 protein at the same time, realizes effective inhibition on tumor cells, and has a potential disease treatment effect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a degradation agent targeting BET and / or CBP / p300 protein and application thereof. Background Art

[0002] Epigenetic mechanisms are essential for maintaining the homeostasis of gene expression in normal cells, while epigenetic dysregulation in tumor cells can lead to overexpression of tumor cell oncogenes and silencing of tumor suppressor genes. Among them, bromodomains are epigenetic "readers". Bromodomain and extraterminal domain (BET) proteins are important epigenetic regulatory proteins and transcriptional regulatory proteins, which are closely related to biological processes such as cell growth, proliferation, differentiation, apoptosis and necrosis. The BET protein family is overexpressed in a variety of tumor cells and participates in regulating the occurrence and development of tumors. It has become an important target for cancer treatment. Cyclic AMP response element binding protein (CBP) and E1A binding protein (EP300 or p300) both contain bromodomains, are highly homologous in amino acid sequences, and have similar structures and functions. They are usually referred to as CBP / p300. CBP / p300 induces histone H3 lysine 27 acetylation (H3K27ac) and cooperates with BRD4 to activate gene transcription. CBP / p300 is overexpressed in tumor cells, activating oncogene transcription, inducing cancer cell proliferation, survival, tumorigenesis, metastasis, immune escape, and drug resistance. Based on the fact that both BET and CBP / p300 proteins contain bromodomains and their important functions in the occurrence and development of cancer, dual-target inhibitors of BET and CBP / p300 have been developed and many studies have shown that they have anti-tumor activity in a variety of solid tumors and hematological tumors. However, since BET and CBP / p300 contain multiple domains encoding different functions, targeting their bromodomains with current inhibitors may lead to incomplete inhibition of their oncogenic activity. Therefore, targeted protein degradation strategies that more completely inhibit their oncogenic functions may produce more effective treatments, and the development of new dual-target inhibitors of BET and CBP / p300 is urgent. Summary of the invention

[0003] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a degradation agent targeting BET and / or CBP / p300 protein and its application. The degradation agent provided by the present invention can effectively degrade BET and CBP / p300 protein at the same time, and effectively inhibit tumor cells, and has potential disease treatment effect.

[0004] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0005] In a first aspect, the present invention provides a degrader targeting BET and / or CBP / p300 protein, wherein the structure of the degrader is selected from Formula I or Formula II:

[0006]

[0007] wherein the linking group is selected from

[0008] Any one of , n is selected from an integer of 1-15, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0009] E3 ubiquitin ligase ligands are selected from

[0010] Any one of .

[0011] The hydrophobic tag is selected from Any one of .

[0012] Indicates the group attachment site.

[0013] The above-mentioned compounds with specific structures can effectively achieve the simultaneous degradation of BET and CBP / p300 proteins, and have excellent technical effects.

[0014] Preferably, the linking group is selected from n is selected from integers of 1-15.

[0015] Preferably, n is an integer of 2-12.

[0016] Preferably, the E3 ubiquitin ligase ligand is selected from

[0017] Preferably, the hydrophobic tag is selected from

[0018] Preferably, the degradation agent is selected from any one of the structural compounds in Table 1.

[0019] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one degradation agent as described above.

[0020] The pharmaceutical composition can be applied to various routes of administration, typical but non-limiting examples of which are oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, by lumbar puncture, transurethral, ​​transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implant), etc. The pharmaceutical composition of the present invention can be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration used. The composition of the present invention can be administered in the following ways: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, oral, intranasal, liposome, etc. Oral pharmaceutical compositions can be solid, gel or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules and bulk powders. These preparations can optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners and flavoring agents, etc. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar and carboxymethylcellulose. The pharmaceutical composition of the present invention is administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection. The injection can be prepared in any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolving or suspending in a liquid before injection, or an emulsion. Examples of pharmaceutically acceptable carriers that can be used for the injection of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection; examples of non-aqueous carriers include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and dextrose; buffers include phosphates and citrates.

[0021] The pharmaceutical composition of the present invention can also be prepared as a sterile lyophilized powder injection by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, then aseptically filtering the solution under standard conditions known to those skilled in the art, followed by freeze drying to obtain the desired preparation.

[0022] In a third aspect, the present invention provides use of the above-described degradation agent or the above-described pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to BET and / or CBP / p300 overexpression.

[0023] In a fourth aspect, the present invention also provides the use of the above-mentioned degradation agent or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating cancer, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.

[0024] Cancers that can be treated by the drug include adrenal tumors, acoustic neuroma, acromelanoma, acrohidroma, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenal cortical carcinoma, adult T-cell leukemia / lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, angiomyolipoma, angiosarcoma, astrocytoma, atypical malformed rod-shaped tumors, B-cell chronic lymphocytic leukemia, B-cell prolymphocytes, Leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, germ cell tumor, bone tumor, brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine tumor, endodermal sinus tumor, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblasts cell tumor, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, granular cell tumor, male cell tumor, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancer, hemangiopericytoma malignant tumor, hepatoblastoma, cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, infiltrative lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, fatal midline cancer, leukemia, testicular interstitial cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, maltoid lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumors, medullary breast cancer, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer, mesothelioma, metastatic cell carcinoma, mixed Muehl tumors, myxoid tumors, multiple myeloma, muscle tissue tumors, mycosis fungoides, myxoma, myxosarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroma, eye cancer, eosinophilic, optic nerve sheath meningioma, tumors, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid cancer, tumor paraganglioma, pineal cell tumor, pituitary cell tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma,Peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyomas, rhabdomyosarcomas, rectal cancer, sarcomas, seminoma, trophoblastic tumors, skin cancer, small round cell tumors, small cell carcinomas, soft tissue sarcomas, somatostatinomas, spinal cord tumors, splenic marginal zone lymphomas, squamous cell carcinomas, synovial sarcomas, small intestine cancer, squamous cell carcinomas, gastric cancer, T-cell lymphomas, testicular cancer, thyroid cancer, transitional cell carcinomas, laryngeal cancer, urachal cancer, genitourinary cancer, uterine cancer, verrucous carcinomas, optic pathway gliomas, vulvar cancer or vaginal cancer, etc. ,

[0025] The treatable cell proliferative disorders include benign soft tissue tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, seborrheic keratomas, gastric polyps, thyroid nodules, hepatic hemangiomas, vocal cord nodules, polyps, cysts, pilonidal disease, cutaneous fibromas, Pilar cysts or pyogenic granulomas, etc.

[0026] Inflammatory diseases that can be treated by the drug include inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease, Guillain-Barré syndrome, mycosis fungoides or acute inflammatory response, etc.

[0027] The viral infections that can be treated by the drug include human papillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection, etc.

[0028] The neurodegenerative diseases that can be treated by the drug include Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis or spinal muscular atrophy, etc.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention provides a degrader with a specific structure targeting BET and / or CBP / p300 proteins, which can effectively degrade BET and CBP / p300 proteins at the same time and effectively inhibit tumor cells, and has potential disease treatment effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the degradation result diagram of BET and CBP targets of some compounds in Table 3 in MV4;11 cells. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0033] The present invention provides compounds V1-V22, H1-H14, C1-C59, whose structures are shown in Table 1:

[0034] Table 1 Compound structures

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] The preparation method is as follows: Synthesis of Example 1-V1

[0042]

[0043] Step 1: Synthesis of 5-bromo-1,3-dimethylpyridin-2(1H)-one (Intermediate 2)

[0044] 5-Bromo-3-methylpyridin-2-ol (5 g, 26.6 mmol) and potassium carbonate (7.2 g, 52.4 mmol) were added to DMF (15 mL), potassium iodide (5.3 g, 37.2 mmol) was added thereto, and the mixture was stirred at 20°C overnight. The mixture was extracted three times with ethyl acetate, the organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 4.87 g (91%) of a yellow solid. 1H NMR (400MHz, CDCl3) δ7.30 (d, J=2.4Hz, 1H), 7.25 (d, J=2.4Hz, 1H), 3.52 (s, 3H), 2.14 (s, 3H).

[0045] Step 2: Synthesis of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2(1H)-one (Intermediate 3)

[0046] A mixture of 5-bromo-1,3-dimethylpyridin-2(1H)-one (1 g, 4.95 mmol), bipyridinyl borate (2.26 g, 8.9 mmol), potassium acetate (1.46 g, 14.9 mmol) and Pd(dppf)Cl2 (180 mg, 0.25 mmol) in dioxane (10 mL) was stirred at 85° C. overnight under nitrogen protection. The mixture was filtered through celite, concentrated, and column chromatography was performed to obtain 1.2 g (100%) of a white solid. 1 H NMR (400MHz, CDCl3) δ7.65 (d, J=2.0Hz, 1H), 7.48 (dt, J=2.4, 1.2Hz, 1H), 3.55 (s, 3H), 2.12 (s, 3H), 1.30 (s, 12H).

[0047] Step 3: Synthesis of 5-bromo-2-nitro-N-(2-(trifluoromethoxy)ethyl)aniline (Intermediate 5)

[0048] A mixture of 2-(trifluoromethoxy)ethane-1-amine hydrochloride (752.8 mg, 4.55 mmol), DIPEA (2.35 g, 18.2 mmol) in DMSO (6 mL) was stirred at 20° C. for 10 min, 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.45 mmol) was slowly added thereto, and the mixture was stirred overnight at 20° C. The mixture was poured into a small amount of ice water, solid precipitated, filtered, and dried to obtain 1.67 g (100%) of yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 8.06 (d, J=9.2Hz, 1H), 7.02 (d, J=2.0Hz, 1H), 6.85 (dd, J=9.2, 2.0Hz, 1H), 4.23 (t, J=5.2Hz, 2H), 3.65 (q, J=5.6Hz, 2H).

[0049] Step 4: Synthesis of 1,3-dimethyl-5-(4-nitro-3-((2-(trifluoromethoxy)ethyl)amino)phenyl)pyridin-2(1H)-one (Intermediate 6)

[0050] Pd(PPh3)4 (176 mg, 0.15 mmol) was added to 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2(1H)-one (1 g, 3.04 mmol), 5-bromo-2-nitro-N-(2-(trifluoromethoxy)ethyl)aniline (1.14 g, 4.56 mmol), cesium carbonate (2.08 g, 6.38 mmol) in DME (8 mL) and water (0.4 mL), and the mixture was reacted at 85° C. overnight under nitrogen protection. The mixture was extracted with ethyl acetate, the organic phases were combined, washed once with saturated brine, concentrated, and column chromatography to obtain 840 mg (75%) of a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.37–8.27 (m, 1H), 8.20 (d, J=8.8Hz, 1H), 7.53–7.45 (m, 2H), 6.82 (s, 1H), 6. 75 (dd, J=8.8, 2.0Hz, 1H), 4.26 (d, J=5.2Hz, 2H), 3.73 (q, J=5.6Hz, 2H), 3.63 (s, 3H), 2.22 (s, 3H).

[0051] Step 5: Synthesis of 5-(4-amino-3-((2-(trifluoromethoxy)ethyl)amino)phenyl)-1,3-dimethylpyridin-2(1H)-one (Intermediate 7)

[0052] To a mixture of 1,3-dimethyl-5-(4-nitro-3-((2-(trifluoromethoxy)ethyl)amino)phenyl)pyridin-2(1H)-one (2 g, 5.39 mmol) in THF (50 mL) and water (50 mL) was added Na2S2O4 (9.38 g, 53.9 mmol) and aqueous ammonia (3.77 g, 107.8 mmol) and stirred overnight at 20°C. The mixture was concentrated and extracted with dichloromethane. The organic phases were combined, washed once with 1 mol / L sodium hydroxide solution and once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 1.39 g (76%) of a white solid. 1 H NMR (400MHz, CDCl3) δ7.73–7.63 (m, 1H), 7.48–7.43 (m, 2H), 7.28 (d, J=2.6Hz, 1H), 6.77 (d, J= 1.2Hz, 2H), 6.65 (s, 1H), 4.23 (t, J=5.2Hz, 2H), 3.61 (s, 3H), 3.51–3.43 (m, 2H), 2.21 (s, 3H).

[0053] Step 6: Synthesis of (9H-fluoren-9-yl)methyl-4-((4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((2-(trifluoromethoxy)ethyl)amino)phenyl)carbamoyl)piperidine-1-carboxylate (Intermediate 8)

[0054] To a mixture of 1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carboxylic acid (3.15 g, 9.24 mmol) in dichloromethane (30 mL) were added DIPEA (1.67 g, 12.94 mmol), HATU (4.22 g, 11.09 mmol), HOAt (1.51 g, 11.09 mol) and stirred at 20° C. for 15 min, followed by the addition of 5-(4-amino-3-((2-(trifluoromethoxy)ethyl)amino)phenyl)-1,3-dimethylpyridin-2(1H)-one (3.25 g, 9.24 mmol) and stirred overnight at 20° C. The mixture was spin-dried and purified by column chromatography to give 2.24 g (36%) of a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J=2.8Hz, 1H), 7.90 (d, J=7.2Hz, 2H), 7.81 (dd, J=2.8, 1.2Hz, 1H), 7.76 (d, J=2.0Hz, 1H), 7.66 (d, J=7.2Hz, 2H), 7.59 (d, J=8.4Hz, 1H), 7.45–7.32 (m, 5H), 4.69 (t, J= 5.2Hz, 2H), 4.44 (t, J=4.8Hz, 2H), 4.41–4.34 (m, 2H), 4.31 (t, J=6.4Hz, 1H), 4.03 (d, J=35.2Hz, 2H ), 3.54(s, 3H), 3.27–3.18(m, 1H), 2.96(s, 2H), 2.11(s, 3H), 1.83(d, J=12.8Hz, 2H), 1.70(m, 2H).

[0055] Step 7: Synthesis of methyl (9H-fluoro-9-yl)-4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (Intermediate 9)

[0056] A mixture of (9H-fluoren-9-yl)methyl-4-((4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((2-(trifluoromethoxy)ethyl)amino)phenyl)carbamoyl)piperidine-1-carboxylate (2.24 g) and acetic acid (10 mL) was reacted at 100° C. overnight. The mixture was spin-dried, water was added, and saturated sodium bicarbonate solution was added under ice bath to neutralize, and dichloromethane was extracted, the organic phases were combined, washed once with saturated brine, spin-dried, and column chromatography was performed to obtain 1.24 g (57%) of a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J=2.8Hz, 1H), 7.90 (dt, J=7.6, 0.8Hz, 2H), 7.81 (dd, J=2.8, 1.2 Hz, 1H), 7.77–7.75 (m, 1H), 7.68–7.64 (m, 2H), 7.61–7.57 (m, 1H), 7.45–7.32 (m, 5H), 4.69 (t, J= 4.8Hz, 2H), 4.44(t, J=4.8Hz, 2H), 4.38(s, 2H), 4.31(t, J=6.4Hz, 1H), 4.14–3.92(m, 2H), 3.54( s, 3H), 3.27–3.17 (m, 1H), 2.96 (m, 2H), 2.15–2.08 (s, 3H), 1.83 (d, J=12.8Hz, 2H), 1.70 (m, 2H).

[0057] Step 8: Synthesis of 1,3-dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (Intermediate 10)

[0058] Methyl (9H-fluoro-9-yl)-4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (500 mg) was dissolved in dichloromethane (3 mL) and methanol (1 mL), piperidine (1 mL) was added under ice bath and stirred overnight at 20°C. The mixture was dried by spin drying and column chromatography to give 310 mg (94%) of a white solid.

[0059] 1H NMR (400MHz, CDCl3) δ7.77 (d, J=8.4Hz, 1H), 7.53 (dd, J=2.4, 1.2Hz, 1H), 7.39 (d, J= 2.4Hz, 1H), 7.31 (dd, J=8.4, 1.6Hz, 1H), 7.26 (s, 1H), 4.51 (t, J=5.2Hz, 2H), 4.31 (t, J=5.2Hz, 2H), 3.64 (s, 3H), 3.27 (dt, J=12.8, 3.2Hz, 2H), 3.01 (tt, J=11.2, 3.6Hz, 1 H), 2.79 (td, J=12.4, 2.8Hz, 2H), 2.24 (s, 3H), 2.06–1.94 (m, 2H), 1.93–1.88 (m, 2H).

[0060] Step 9: Synthesis of 4-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (Intermediate 12)

[0061] A mixture of (2R,4S)-1-(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (100 mg, 0.23 mmol) and succinic anhydride (46 mg, 0.46 mmol) in pyridine (5 mL) was stirred at 20°C overnight. The mixture was concentrated and column chromatography gave 73 mg (73%) of a white solid. 1 H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 7.34 (s, 4H), 4.54 (m, 4H), 4.30 (d, J=15.6Hz, 1H), 4. 05(m, 1H), 3.67(m, 1H), 2.67(m, 1H), 2.36–2.65(m, 6H), 2.36–2.12(m, 2H), 0.96(s, 9H).

[0062] Step 10: (2S,4R)-1-((R)-2-(4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(2-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V1)

[0063] 4-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (72 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL), and EDCI (32 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (22 mg, 0.17 mmol) and 1,3-dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (60 mg, 0.14 mmol) were added thereto under ice bath, and the mixture was stirred at 20°C overnight. The mixture was spin-dried and extracted with EA. The organic phases were combined, washed once with saturated brine, spin-dried, and purified by column chromatography to obtain 10 mg (8%) of a white solid. 1 H NMR (400MHz, CDCl3) δ8.66 (d, J=1.6Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J=28.0, 8.4Hz, 1H), 7.53–7.49 (m , 1H), 7.40–7.29 (m, 7H), 7.25 (d, J=2.0Hz, 1H), 4.82–4.73 (m, 2H), 4.63–4.45 (m, 5H), 4.37–4.23 (m, 3H), 4.07 (t, J=11.8Hz, 2H), 3.64 (s, 3H), 3.62–3.56 (m, 1H), 3.22–3.05 (m, 2H), 2.85–2.53 (m, 3H), 2 .50 (d, J=4.0Hz, 3H), 2.46–2.40 (m, 2H), 2.26–2.23 (m, 3H), 2.22–1.80 (m, 6H), 0.96 (d, J=2.8Hz, 9H).

[0064] Example 2: (2S, 4R)-1-((R)-2-(5-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazo-2-yl)piperidin-1-yl)-5-oxopentanyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V2). Compound V2 was synthesized by the method of Example 1. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.70 (dd, J=8.4, 5.6Hz, 1H), 7.52 (s, 1H), 7.39 (d, J=2.8Hz, 1H), 7. 36–7.29(m, 5H), 6.91(s, 1H), 4.76(m, 2H), 4.60–4.44(m, 4H), 4.40–4.26(m, 3H), 4.21–3.99(m, 2H), 3. 64 (s, 3H), 3.61 (d, J = 15.2Hz, 1H), 3.15 (d, J = 20.4Hz, 1H), 2.70 (s, 1H), 2.50 (m, 5H), 2.42 (d, J = 7.2Hz, 2H), 2.33 (t, J=6.8Hz, 2H), 2.25 (s, 3H), 2.18 (dd, J=15.6, 8.0Hz, 2H), 2.06–1.74 (m, 6H), 0.97 (s, 9H).

[0065] Example 3-Synthesis of V3

[0066]

[0067] Step 1: 6-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (Intermediate 14)

[0068] Adipic acid (102 mg, 0.7 mmol) was dissolved in DCM (2 mL) and DMF (1 mL), and EDCI (65 mg, 0.34 mmol), HOAt (76 mg, 0.56 mmol) and NMM (142 mg, 1.4 mmol) and (2R, 4S)-1-(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (120 mg, 0.28 mmol) were added thereto under ice bath and stirred overnight at 20°C. The mixture was concentrated and extracted three times with ethyl acetate, the organic phases were combined, washed three times with water, washed once with saturated brine, and dried by spin drying. 84 mg (54%) of white solid was obtained by column chromatography. 1H NMR (400MHz, CDCl3) δ8.67 (s, 1H), 7.40 (d, J=6.0Hz, 1H), 7.37–7.30 (m, 4H), 7.28–7.26 (m, 1H), 4.72–4.60 (m, 2H), 4.53 (s, 1H), 4.28 (dd, J=15 .2, 4.8Hz, 1H), 4.12 (d, J=11.6Hz, 1H), 3.76–3.64 (m, 1H), 2.48 (s, 3H) , 2.30–2.15(m, 4H), 1.63–1.51(m, 4H), 1.31–1.21(m, 3H), 0.95(s, 9H).

[0069] Step 2: (2S,4R)-1-((R)-2-(6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-(methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V3)

[0070] 6-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (84 mg) was dissolved in DCM (3 mL), and EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), DIPEA (24 mg, 0.18 mmol) and 1,3-dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (65 mg, 0.15 mmol) were added thereto under ice bath and stirred at 20°C overnight. The mixture was spin-dried and extracted with EA. The organic phases were combined, washed once with saturated brine, spin-dried, and purified by column chromatography to obtain 12 mg (8%) of a white solid.

[0071] 1H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.71 (dd, J=8.4, 5.6Hz, 1H), 7.55–7.45 (m, 2H), 7.39 (d, J=2.8Hz, 1H) , 7.37–7.28 (m, 6H), 6.52 (m, 1H), 4.80–4.66 (m, 2H), 4.66–4.45 (m, 4H), 4.37–4.26 (m, 3H), 4.06 (q, J=13 .3, 12.8Hz, 2H), 3.64 (s, 3H), 3.60 (s, 1H), 3.26–3.05 (m, 2H), 2.70 (ddd, J=18.0, 12.8, 5.6Hz, 1H), 2.49 (s, 3H), 2.42–2.28 (m, 3H), 2.24 (s, 3H), 2.19–2.05 (m, 2H), 2.02–1.85 (m, 2H), 1.64 (m, 4H), 0.95 (s, 9H).

[0072] Example 4: (2S, 4R)-1-((R)-2-(7-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-oxoheptylamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V4). Compound V4 was synthesized by the method of Example 3. 1 H NMR (400MHz, CDCl3) δ8.64 (d, J=2.0Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.57–7.51 (m, 2H), 7.40 (d, J=2.8Hz, 1H) , 7.35–7.27 (m, 7H), 4.72 (t, J=8.4Hz, 1H), 4.57–4.48 (m, 5H), 4.36–4.28 (m, 3H), 4.09–4.00 (m, 2H), 3.66–3. 60(m, 6H), 3.18–3.10(m, 2H), 2.68(t, J=12.8Hz, 1H), 2.48(d, J=4.0Hz, 4H), 2.44–2.28(m, 2H), 2.23(s, 3H), 2.19–2.05(m, 2H), 1.99–1.84(m, 2H), 1.70–1.56(m, 4H), 1.50–1.38(m, 2H), 1.37–1.29(m, 2H), 0.94(s, 9H).

[0073] Example 5: (2S, 4R)-1-((R)-2-(8-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-8-oxooctylamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V5). Compound V5 was synthesized by the method of Example 3. 1 H NMR (400MHz, CDCl3) δ8.65 (d, J=2.8Hz, 1H), 7.73 (dd, J=8.4, 2.8Hz, 1H), 7.61–7.50 (m, 2H), 7.39 (d, J=2.6Hz, 1H), 7.35 (d, J=2.0Hz, 4H), 7.31 (dt, J=8.4, 2.0Hz, 1H), 4.77–4.67 (m, 2H), 4.61–4.47 (m, 5H), 4.44–4.35 (m, 1H), 4.32 (t, J=5.2Hz , 2H), 4.10–4.00(m, 2H), 3.64(s, 3H), 3.66–3.57(m, 1H), 3.23–3.06(m, 2H), 2.68(m, 1H), 2.49(s, 3H), 2.47–2.41(m, 1H) , 2.40–2.30 (m, 2H), 2.24 (s, 3H), 2.21–2.11 (m, 4H), 2.08 (s, 3H), 2.02–1.86 (m, 3H), 1.61 (m, 5H), 0.94 (d, J=5.2Hz, 9H).

[0074] Example 6: (2S, 4R)-1-((R)-2-(9-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-9-oxononanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V6). Compound V6 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.63 (d, J=5.8Hz, 1H), 7.75–7.69 (m, 1H), 7.54–7.50 (m, 1H), 7.39 (d, J=2.4Hz, 1H) , 7.36–7.28 (m, 7H), 6.28 (t, J=9.0Hz, 1H), 4.74–4.63 (m, 2H), 4.62–4.47 (m, 6H), 4.34–4.29 (m, 2H), 4.14 –3.97(m, 3H), 3.63(s, 3H), 3.21–3.04(m, 2H), 2.76–2.60(m, 1H), 2.48(s, 3H), 2.44–2.25(m, 2H), 2.23(s , 3H), 2.18–2.04 (m, 2H), 2.01–1.82 (m, 4H), 1.76–1.48 (m, 6H), 1.38–1.27 (m, 6H), 0.95 (d, J=9.2Hz, 9H).

[0075] Example 7: (2S, 4R)-1-((R)-2-(10-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-10-oxodecanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V7). Compound V7 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.64 (d, J=1.6Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.56–7.47 (m, 2H), 7.39 (d, J=2.8Hz, 1H), 7.33 (s, 4H), 7.30 (dd , J=8.4, 1.6Hz, 1H), 7.26 (s, 1H), 6.30 (dd, J=29.2, 8.8Hz, 1H), 4.71 (q, J=8.0, 6.8Hz, 2H), 4.61–4.47 (m, 6H), 4.36–4.27 (m, 3H), 4. 04 (d, J=12.0Hz, 3H), 3.69 (q, J=7.2Hz, 3H), 3.63 (s, 3H), 3.60 (t, J=3.2Hz, 1H), 3.24–3.04 (m, 2H), 2.75–2.63 (m, 1H), 2.48 (d, J=1. 6Hz, 3H), 2.46–2.40(m, 1H), 2.38–2.26(m, 3H), 2.23(s, 3H), 2.21–2.05(m, 5H), 2.05–1.85(m, 4H), 1.67–1.51(m, 4H), 0.93(s, 9H).

[0076] Example 8: (2S, 4R)-1-((R)-2-(11-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-11-oxoundecanoyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V8). Compound V8 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.52 (dd, J=2.4, 1.2Hz, 1H), 7.47 (m, 1H), 7.39 (d, J=2.4Hz, 1H), 7 .36–7.28(m, 5H), 7.26(s, 1H), 6.23(dd, J=8.8, 5.6Hz, 1H), 4.79–4.65(m, 2H), 4.60–4.49(m, 5H), 4.34(dt, J=14.4, 5.6Hz, 3H), 4.05 (d, J=11.6Hz, 3H), 3.63 (s, 3H), 3.62–3.58 (m, 1H), 3.20–3.58 (m, 2H), 2.68 (s, 1H), 2.49 (s, 3H), 2.49–2.40 (m, 1H) ), 2.38–2.26(m, 2H), 2.23(s, 3H), 2.20–2.06(m, 5H), 2.02–1.86(m, 3H), 1.66–1.50(m, 4H), 1.35–1.25(m, 8H), 0.93(s, 9H).

[0077] Example 9: (2S, 4R)-1-((R)-2-(12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-12-oxododecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V9). Compound V9 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.52 (q, J=1.2Hz, 1H), 7.43 (t, J=6.0Hz, 1H), 7.39 (d, J=2.4Hz, 1H ), 7.37–7.26 (m, 6H), 6.20 (dd, J=8.8, 4.4Hz, 1H), 4.77–4.65 (m, 2H), 4.58–4.45 (m, 5H), 4.39–4.28 (m, 3H), 4.06 (d, J=11.2 Hz, 2H), 3.63 (s, 3H), 3.60 (d, J=3.6Hz, 1H), 3.24–3.05 (m, 2H), 2.82–2.63 (m, 1H), 2.49 (s, 3H), 2.48–2.41 (m, 1H), 2.34 (td , J=6.8, 2.8Hz, 2H), 2.23 (s, 3H), 2.20–2.06 (m, 6H), 2.01–1.85 (m, 3H), 1.65–1.51 (m, 4H), 1.34–1.20 (m, 10H), 0.93 (s, 9H).

[0078] Example 10: (2S, 4R)-1-((R)-2-(13-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-13-oxotridecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V10). Compound V10 was synthesized by the method of Example 3. 1H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.52 (d, J = 2.4Hz, 1H), 7.45–7.29 (m, 7H), 7.26 (s, 1H), 6.23 (d d, J=8.8, 4.0Hz, 1H), 4.75 (d, J=13.6Hz, 1H), 4.68 (t, J=8.0Hz, 1H), 4.62–4.45 (m, 5H), 4.40–4.25 (m, 3H), 4.04 (d, 2H), 3.62 (s, 3H), 3.60 (d, J=6.0Hz, 1H), 3.22–3.05 (m, 2H), 2.77–2.66 (m, 1H), 2.48 (s, 3H), 2.46–2.41 (m, 1H), 2.34 (dd, J=9 .2, 6.0Hz, 2H), 2.22(s, 3H), 2.20–2.04(m, 4H), 2.05–1.84(m, 3H), 1.68–1.50(m, 4H), 1.34–1.19(m, 14H), 0.92(s, 9H).

[0079] Example 11: (2S, 4R)-1-((R)-2-(14-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-14-oxotetradecanoyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V11). Compound V11 was synthesized by the method of Reference Example 3. 1 H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.52–7.50 (m, 1H), 7.44–7.37 (m, 2H), 7.35–7. 27(m, 5H), 7.25(s, 1H), 6.19(dd, J=8.8, 4.4Hz, 1H), 4.79–4.62(m, 2H), 4.61–4.46(m, 5H), 4.39–4.26(m , 3H), 4.04 (d, J=11.0Hz, 2H), 3.61 (s, 3H), 3.22–3.04 (m, 2H), 2.74–2.67 (m, 1H), 2.48 (s, 3H), 2.33 (td, J=6.8, 2.8Hz, 2H), 2.21 (s, 3H), 2.16–1.85 (m, 7H), 1.64–1.50 (m, 4H), 1.38–1.23 (m, 18H), 0.92 (s, 9H).

[0080] Example 12: (2S, 4R)-1-((R)-2-(15-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-15-oxopentadecanoyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V12). Compound V12 was synthesized by the method of Reference Example 3. 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.53 (t, J=2.8, 1.2Hz, 1H), 7.44–7.38 (m, 2H), 7.36–7.26 (m, 6H), 6 .18 (dd, J=8.8, 3.2Hz, 1H), 4.76 (d, J=13.6Hz, 1H), 4.69 (t, J=8.0Hz, 1H), 4.58–4.46 (m, 5H), 4.32 (p, J=5.2Hz, 3H), 4.06 (d, J =11.6Hz, 2H), 3.63 (s, 4H), 3.61–3.57 (m, 1H), 3.24–3.07 (m, 2H), 2.72 (dt, J = 13.9, 7.8Hz, 1H), 2.49 (s, 3H), 2.48–2.42 (m, 1H) ), 2.39–2.32(m, 2H), 2.23(s, 3H), 2.20–2.07(m, 3H), 2.02–1.87(m, 3H), 1.69–1.52(m, 4H), 1.31–1.19(m, 20H), 0.92(s, 9H).

[0081] Example 13: (2S, 4R)-1-((R)-2-(16-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-16-oxohexadecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V13). Compound V13 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.74 (d, J = 8.3Hz, 1H), 7.52 (d, J = 2.4Hz, 1H), 7.39 (d, J = 2.8Hz, 2H), 7.37–7.28 (m, 5H), 7.26 ( s, 1H), 6.18 (dd, J = 9.2, 3.2Hz, 1H), 4.77 (d, J = 13.2Hz, 1H), 4.70 (t, J = 8.0Hz, 1H), 4.59–4.48 (m, 5H), 4.37–4.28 (m, 3H), 4.06 (d , J=11.2Hz, 2H), 3.63 (s, 3H), 3.62–3.57 (m, 1H), 3.18 (t, J=12.0Hz, 1H), 3.13–3.05 (m, 1H), 2.78–2.65 (m, 1H), 2.50 (s, 3H), 2.3 5(td, J=7.2, 2.0Hz, 2H), 2.23(s, 3H), 2.21–2.07(m, 5H), 2.02–1.89(m, 4H), 1.68–1.51(m, 4H), 1.36–1.20(m, 18H), 0.92(s, 9H).

[0082] Example 14: (2S, 4R)-1-((R)-2-(17-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-17-oxoheptadecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V14). Compound V14 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.67 (d, J=3.6Hz, 1H), 7.76 (dd, J=8.4, 3.6Hz, 1H), 7.52 (s, 1H), 7.43–7.27 (m, 7H), 7.25 (d, J=3.6Hz, 1H), 6.11 (d, J=8.8Hz, 1H), 4.83–4.67 (m, 2H), 4.62–4.46 (m, 5H), 4.38–4.27 (m, 3H), 4.08 (t, J=12.8Hz, 2H), 3.64 (d, J=3.6Hz, 3H), 3. 59 (dt, J=11.2, 3.6Hz, 1H), 3.24–3.07 (m, 2H), 2.73 (s, 1H), 2.59–2.52 (m, 1H), 2.50 (d, J=3.6Hz, 3H), 2.40–2.31 (m, 2H), 2.24 (d .

[0083] Example 15: (2S, 4R)-1-((S)-2-(3-(3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazo-2-yl)piperidin-1-yl)-3-oxopropoxy)propionamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V15). Compound V15 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 7.78–7.51 (m, 1H), 7.68 (dd, J=8.4, 4.0Hz, 1H), 7.50 (s, 1H), 7.40–7.2 6 (m, 7H), 7.09 (d, J=8.5Hz, 1H), 4.80–4.66 (m, 2H), 4.61–4.44 (m, 5H), 4.36–4.22 (m, 3H), 4.08 (t, J=15.6H z, 2H), 3.86–3.66 (m, 4H), 3.63 (s, 3H), 3.60–3.53 (m, 1H), 3.21–3.03 (m, 2H), 2.82–2.61 (m, 1H), 2.58–2.4 8 (m, 4H), 2.46 (d, J = 8.8Hz, 3H), 2.23 (s, 3H), 2.21–2.11 (m, 1H), 2.04–1.79 (m, 5H), 0.94 (d, J = 7.3Hz, 9H).

[0084] Example 16: (2S,4R)-1-((S)-2-(3-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(3-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)propionamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V16). Compound V16 was synthesized by the method of Example 3. 1 H NMR (400MHz, CDCl3) δ8.64 (d, J=4.3Hz, 1H), 7.91 (d, J=6.0Hz, 1H), 7.75–7.67 (m, 1H), 7.54–7.49 (m, 1H), 7. 46–7.40 (m, 3H), 7.38–7.29 (m, 5H), 4.78–4.45 (m, 7H), 4.38–4.26 (m, 3H), 4.08–3.91 (m, 1H), 3.86–3.75 (m, 2 H), 3.74–3.55 (m, 8H), 3.63 (s, 3H), 3.21–3.10 (m, 2H), 2.68 (p, J=7.1Hz, 2H), 2.49 (s, 3H), 2.47 (s, 2H), 2.41 –2.28 (m, 0H), 2.23 (s, 3H), 2.19–2.04 (m, 2H), 1.99–1.80 (m, 2H), 1.67–1.56 (m, 2H), 0.97 (d, J=10.0Hz, 9H).

[0085] Example 17: (2R, 4S)-1-((R)-2-(tert-butyl)-16-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazo-2-yl)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V17). Compound V17 was synthesized by the method of Example 3. 1 H NMR (400MHz, CDCl3) δ8.66 (d, J=1.2Hz, 1H), 7.76–7.68 (m, 1H), 7.78–7.55 (m, 1H), 7.53–7.50 (m , 1H), 7.42–7.27 (m, 7H), 7.14 (dd, J=12.4, 8.4Hz, 1H), 4.79–4.44 (m, 7H), 4.38–4.28 (m, 3H), 4. 12–4.02(m, 2H), 3.86–3.54(m, 16H), 3.22–3.07(m, 2H), 2.79–2.60(m, 3H), 2.50(d, J=2.4Hz, 3H ), 2.48–2.36 (m, 2H), 2.24 (s, 3H), 2.20–2.03 (m, 3H), 2.03–1.86 (m, 4H), 0.95 (d, J=7.6Hz, 9H).

[0086] Example 18: (2R, 4S)-1-((R)-2-(tert-butyl)-19-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V18). Compound V18 was synthesized by the method of Reference Example 3. 1H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.75–7.69 (m, 2H), 7.58–7.50 (m, 3H), 7.39 (d, J=2.8Hz, 2H), 7.35 –7.27 (m, 8H), 7.14–7.06 (m, 1H), 4.74–4.66 (m, 2H), 4.57–4.45 (m, 5H), 4.32 (q, J=5.2, 4.8Hz, 5H), 4 .14–4.03(m, 1H), 3.79(tt, J=7.2, 3.6Hz, 2H), 3.74–3.68(m, 3H), 3.66–3.59(m, 10H), 3.21–3.06(m, 1H), 2.79–2.65(m, 4H), 2.49(s, 3H), 2.23(s, 3H), 2.13–2.05(m, 1H), 2.06–1.90(m, 6H), 0.93(s, 9H).

[0087] Example 19: (2R, 4S)-1-((R)-2-(tert-butyl)-2,2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4,2,2-dioxo-7,10,13,16,19-pentaoxa-3-azadodecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V19). Compound V19 was synthesized by the method of Example 3. 1H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.62–7.55 (m, 1H), 7.51 (dd, J=2.8, 1.2Hz, 1H), 7.39 (d, J=2.8Hz, 1H), 7. 33–7.26 (m, 6H), 7.09 (t, J=8.8Hz, 1H), 4.78–4.63 (m, 2H), 4.58–4.43 (m, 4H), 4.37–4.24 (m, 3H), 4.05 (d, J=13.6Hz, 1H), 4.00 (d, J= 11.2Hz, 1H), 3.85–3.71 (m, 2H), 3.66 (t, J=5.6Hz, 2H), 3.63–3.57 (m, 18H), 3.19–3.06 (m, 2H), 2.78–2.70 (m, 2H), 2.66 (t, J=6.0, 5. 1, 2.9Hz, 1H), 2.47 (d, J=1.1Hz, 3H), 2.46–2.33 (m, 2H), 2.21 (s, 3H), 2.13 (td, J=12.1, 7.6Hz, 2H), 2.03–1.86 (m, 3H), 0.92 (s, 9H).

[0088] Example 20-Synthesis of V20

[0089]

[0090] Step 1: tert-Butyl 4-((R)-1-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamoyl)piperazine-1-carboxylate (Intermediate 15)

[0091] (2R, 4S)-1-(R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (120 mg, 0.278 mmol) and 4-(tert-butyloxycarbonyl)piperazine-1-carboxylic acid (75 mg, 0.31 mmol) were dissolved in DMF (3 mL), HATU (158 mg, 0.42 mmol) and DIPEA (72 mg, 0.556 mmol) were added thereto, and the mixture was stirred overnight at 20°C. Water was added to the mixture, and the mixture was extracted with ethyl acetate for several times. The organic phases were combined, washed once with saturated brine, dried by rotation, and 133 mg (73%) of white solid was obtained by column chromatography. 1H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.40–7.30 (m, 5H), 4.75(t, J=8.0Hz, 1H), 4.61–4.50(m, 2H), 4.41–4.30(m, 2H), 4.15(d, J=11.6 Hz, 1H), 3.58 (dd, J=11.6, 3.6Hz, 1H), 3.46 (s, 4H), 3.03 (s, 2H), 2.62–2.56 ( m, 1H), 2.52 (s, 3H), 2.13 (dd, J=13.6, 8.4Hz, 1H), 1.45 (s, 9H), 0.94 (s, 9H).

[0092] Step 2: (2R,4S)-1-(R)-3,3-dimethyl-2-(2-(piperazin-1-yl)acetylamino)butyryl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 16)

[0093] Dissolve tert-butyl 4-((R)-1-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2-ylcarbamoyl)piperazine-1-carboxylate (130 mg, 0.2 mmol) in dioxane (1.5 mL), add 2N HCl (1.5 mL) under ice bath, and react at 50°C for 2 h. The mixture is concentrated under vacuum, water is added, and washed with dichloromethane several times. The aqueous phase is neutralized by dropwise addition of saturated sodium bicarbonate under ice bath, extracted with dichloromethane several times, the organic phases are combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 108 mg (98%) of white solid. 1 H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.44–7.32 (m, 5H), 4.75 (d, J=8.0Hz, 1H), 4.62–4.47 (m, 2H), 4.40–4.30 (m, 2H), 4. 18 (d, J=2.0Hz, 1H), 3.58 (dd, J=11.6, 3.6Hz, 1H), 2.98 (s, 2H), 2.94–2.87 (m, 4H), 2.62–2.55 (m, 1H), 2.52 (s, 3H), 2.51 (s, 3H), 0.94 (s, 9H).

[0094] Step 3: tert-Butyl 4-(4-(2-(R)-1-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2-amino)-2-oxoethyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Intermediate 17)

[0095] (2R, 4S)-1-(R)-3,3-dimethyl-2-(2-(piperazin-1-yl)acetylamino)butyryl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (105 mg, 0.19 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (160 mg, 0.754 mmol) were dissolved in DCE (4 mL), acetic acid (0.1 mL) was added thereto, and the mixture was stirred at 20° C. for 1 h, followed by the addition of sodium triacetoxyborohydride (160 mg, 0.754 mmol) and stirred overnight at 20° C. The mixture was spin-dried and column chromatography gave 140 mg (97%) of a white solid. 1 H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 7.86 (d, J=8.4Hz, 1H), 7.43–7.30 (m, 5H), 4.72 (t, J=8.0Hz, 1H), 4.6 2–4.48(m, 2H), 4.41–4.30(m, 2H), 4.18–4.00(m, 3H), 3.59(dd, J=11.2, 3.6Hz, 1H), 3.47(s, 8H), 3.00(d , J=2.4Hz, 2H), 2.66 (t, J=12.6Hz, 2H), 2.58–2.54 (m, 5H), 2.51 (s, 3H), 2.49–2.35 (m, 4H), 2.20 (d, J=6 .9Hz, 2H), 2.13 (dd, J=13.6, 8.0Hz, 1H), 2.05 (s, 2H), 1.69 (d, J=13.6Hz, 2H), 1.44 (s, 9H), 0.94 (s, 9H).

[0096] Step 4: (2R,4S)-1-(R)-3,3-dimethyl-2-(2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)acetylamino)butyryl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 18)

[0097] Dissolve tert-butyl 4-(4-(2-(R)-1-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane-2-amino)-2-oxoethyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (140 mg, 0.186 mmol) in dioxane (1.5 mL), add 2N HCl (1.5 mL) under ice bath, and react at 50°C for 2 h. The mixture is concentrated under vacuum, water is added, and washed with dichloromethane several times. The aqueous phase is neutralized by dropwise addition of saturated sodium bicarbonate under ice bath, extracted with dichloromethane several times, the organic phases are combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 45 mg (37%) of white solid. δ8.69 (s, 1H), 7.86 (d, J=8.4Hz, 1H), 7.43–7.30 (m, 5H), 4.72 (t, J=8.0Hz, 1H), 4.62–4.48 (m, 2 H), 4.41–4.30 (m, 2H), 4.18–4.00 (m, 3H), 3.59 (dd, J=11.2, 3.6Hz, 1H), 3.47 (s, 8H), 3.00 (d, J= 2.4Hz, 2H), 2.66 (t, J=12.6Hz, 2H), 2.58–2.54 (m, 5H), 2.51 (s, 3H), 2.49–2.35 (m, 4H), 2.20 (d , J=6.9Hz, 2H), 2.13 (dd, J=13.6, 8.0Hz, 1H), 2.05 (s, 2H), 1.69 (d, J=13.6Hz, 2H), 0.94 (s, 9H).

[0098] Step 5: tert-Butyl 2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzoimidazol-2-yl)piperidin-1-yl)acetate (Intermediate 19)

[0099] 1,3-Dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (100 mg, 0.23 mmol), tert-butyl bromoacetate (45 mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol) were dissolved in acetonitrile (6 mL) and reacted at 80° C. overnight. The mixture was spin-dried and column chromatography was performed to obtain 42 mg (33%) of a colorless oily liquid.

[0100] 1H NMR (400MHz, CDCl3) δ7.76 (d, J=8.4Hz, 1H), 7.53 (dd, J=2.8, 1.6Hz, 1H), 7.38 (d, J=2.8 Hz, 1H), 7.29 (dd, J=8.4, 1.6Hz, 1H), 7.25 (d, J=1.6Hz, 1H), 4.49 (t, J=5.6Hz, 2H), 4.30 (t, J=5.2Hz, 2H), 3.64 (s, 3H), 3.22 (s, 2H), 3.10 (d, J=11.6Hz, 2H), 2.90–2.79 (m, 1H), 2.49 (d, J=12.8Hz, 2H), 2.24 (s, 3H), 2.20–2.14 (m, 1H), 1.98–1.88 (m, 3H), 1.48 (s, 9H).

[0101] Step 6: 2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzoimidazol-2-yl)piperidin-1-yl)acetic acid (Intermediate 20)

[0102] Tert-butyl 2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzoimidazol-2-yl)piperidin-1-yl)acetate (62 mg, 0.113 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added thereto under ice bath, and stirred at 20° C. for 2 h. The mixture was spin dried and used directly in the next step.

[0103] Step 7: (2R,4S)-1-(R)-2-(2-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (V20)

[0104] 2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)acetic acid (37 mg, 0.07 mmol), (2S,4R)-1-(S)-3,3-dimethyl-2-(2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)acetamido)butanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (45 mg, 0.07 mmol), EDCI (16 mg, 0.084 mmol), HOBt (11 mg, 0.084 mmol) and DIPEA (11 mg, 0.084 mmol) were dissolved in DCM (3 mL) and stirred at 20°C overnight. The product was spin-dried and purified by column chromatography to obtain 11 mg (13%) of a white solid.

[0105] 1 H NMR (400MHz, CDCl3) δ8.67 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.53 (dd, J = 2.8, 1.2Hz, 1H), 7.43–7.2 7 (m, 8H), 4.75 (d, J = 8.0Hz, 1H), 4.60–4.47 (m, 5H), 4.45–4.27 (m, 4H), 4.23 (d, J = 13.2Hz, 1H), 4.14 (d, J = 11.6Hz, 1H), 3.64 (s, 3H), 3.59 (dd, J=11.2, 3.6Hz, 1H), 3.31 (d, J=12.8Hz, 1H), 3.22 (s, 10H), 3.05–2.92 (m, 4H), 2.87–2.78 (m, 1H) , 2.59–2.52(m, 7H), 2.45(s, 2H), 2.24(s, 3H), 2.18–2.10(m, 1H), 2.03–1.88(m, 2H), 1.85–1.67(m, 2H), 0.94(s, 10H).

[0106] Example 21: 1-(1-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-N-((R)-1-((2R,4S)-4-hydroxy-2-((4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)piperidine-4-carboxamide (V21). Compound V21 was synthesized by the method of Reference Example 20. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.53 (d, J = 2.4Hz, 1H), 7.41–7.27 (m, 8H), 6.19 (d , J=8.8Hz, 1H), 4.71(t, J=8.0Hz, 1H), 4.60–4.44(m, 6H), 4.39–4.26(m, 3H), 4.20(d, J=12.8Hz, 1H), 4.07(d , J=11.2Hz, 1H), 3.63 (s, 3H), 3.62–3.54 (m, 1H), 3.30 (d, J=12.8Hz, 1H), 3.12 (d, J=12.8Hz, 1H), 3.06–2.7 7(m, 6H), 2.61–2.51(m, 2H), 2.50(s, 3H), 2.23(s, 3H), 2.21–2.05(m, 9H), 1.96–1.63(m, 10H), 0.92(s, 9H).

[0107] Example 22: (2S,4R)-1-((S)-2-(12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-12-oxododecanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (V22). Compound V22 was synthesized by the method of Example 3. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.71 (d, J = 8.8Hz, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.52 (d, J = 2.4Hz, 1H), 7.38 (s, 5H), 7.28 (d, J =6.8Hz, 2H), 6.18 (d, J = 8.4Hz, 1H), 5.10 (p, J = 7.2Hz, 1H), 4.72 (d, J = 13.2Hz, 1H), 4.65 (t, J = 8.0Hz, 1H), 4.51 (q, J = 8.2, 6.8Hz , 4H), 4.32 (t, J=5.2Hz, 2H), 4.05 (t, J=12.8Hz, 2H), 3.61 (s, 4H), 3.22–3.07 (m, 2H), 2.71 (q, J=8.8, 5.6Hz, 1H), 2.50 (s, 3H), 2.40–2.28 (m, 4H), 2.21 (s, 3H), 2.13–1.86 (m, 7H), 1.64–1.51 (m, 5H), 1.48 (d, J=6.8Hz, 3H), 1.33–1.16 (m, 17H), 1.04 (s, 9H).

[0108] Example 23-Synthesis of H1

[0109]

[0110] Step 1: tert-Butyl (2-hydroxyethyl)carbamate (Intermediate 22)

[0111] Ethanolamine (200 mg, 3.28 mmol) and di-tert-butyl dicarbonate (715 mg, 3.28 mmol) were dissolved in THF (5 mL) and reacted at 20° C. for 5 h. The mixture was extracted with EA, washed with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 450 mg (85%) of a colorless oily liquid. 1 H NMR (400MHz, CDCl3) δ3.69 (dd, J=5.5, 4.6Hz, 2H), 3.28 (t, J=5.0Hz, 2H), 1.44 (s, 9H).

[0112] Step 2: 2-((tert-Butyloxycarbonyl)amino)ethyl-4-methylbenzenesulfonate (Intermediate 23)

[0113] Tert-butyl (2-hydroxyethyl)carbamate (500 mg, 3.1 mmol) was dissolved in DCM (5 mL), and trimethylamine hydrochloride (29 mg, 0.31 mmol), triethylamine (784 mg, 7.75 mmol), and TsCl (880 mg, 4.66 mmol) were added thereto under ice bath, and stirred at 20°C for 2 h. DCM was added to the mixture, and the mixture was washed once with 1N HCl, once with saturated sodium bicarbonate solution, and once with saturated brine, and then dried by spin drying, and 800 mg (82%) of colorless oil was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ7.82–7.76 (m, 2H), 7.38–7.32 (m, 2H), 4.06 (t, J=5.1Hz, 2H), 3.38 (q, J=5.4Hz, 2H), 2.45 (s, 3H), 1.41 (s, 9H).

[0114] Step 3: tert-Butyl (2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)carbamate (Intermediate 24)

[0115] 1,3-Dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (300 mg, 0.69 mmol), 2-((tert-butoxycarbonyl)amino)ethyl-4-methylbenzenesulfonate (260 mg, 0.83 mmol), potassium carbonate (290 mg, 2.1 mmol) were dissolved in DMF (5 mL) and reacted at 90° C. overnight. The mixture was then extracted with EA, washed with water, washed once with saturated brine, and dried by spin drying. 45 mg (11%) of a white solid was obtained by column chromatography. 1 HNMR (400MHz, CDCl3) δ7.77 (d, J=8.3Hz, 1H), 7.53 (dd, J=2.6, 1.2Hz, 1H), 7.3 9 (d, J=2.6Hz, 1H), 7.31 (dd, J=8.4, 1.7Hz, 1H), 7.26 (s, 1H), 4.50 (t, J=5.4Hz, 2H), 4.31 (t, J=5.3Hz, 2H), 3.65 (s, 3H), 3.26 (s, 2H), 3.07 (s, 2H), 2.87 (s, 1H) , 2.53(s, 2H), 2.25(s, 3H), 2.22–2.08(m, 4H), 2.05–1.86(m, 2H), 1.47(s, 9H).

[0116] Step 4: 2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)acetamide (H1)

[0117] H1 was synthesized according to the method in Step 9 of Reference Example 1. 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J=2.7Hz, 1H), 7.80 (d, J=2.6Hz, 1H), 7.75 (s, 1H), 7.6 7(t, J=5.6Hz, 1H), 7.57 (d, J=8.3Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 4.66 (t, J=5.1Hz, 2H), 4.43 (t, J=4.9Hz, 2H), 3.53 (s, 3H), 3.22 (q, J=6.3Hz, 1H), 3.08 (d, J=11.2Hz, 2H), 2.99 (s, 0H), 2.23 (s, 1H), 2.11 (s, 3H), 2.04–1.88 (m, 5H), 1.83 (s, 3H), 1.72–1.52 (m, 12H).

[0118] Example 24: Synthesis of H2

[0119]

[0120] Step 1: 2-((3r,5r,7r)-adamantan-1-yl)-N-(3-hydroxypropyl)acetamide (Intermediate 26)

[0121] Adamantaneacetic acid (200 mg, 1.02 mmol) was dissolved in SOCl2 (2.42 g, 20.4 mmol), refluxed at 80°C for 3 h, the mixture was spin-dried, DCM (3 mL), 3-amino-1-propanol (92 mg, 1.23 mmol), and triethylamine (134 mg, 1.33 mmol) were added, and stirred overnight at 20°C. The mixture was spin-dried, and column chromatography gave 145 mg (56%) of a colorless oily liquid. 1 H NMR (400MHz, CDCl3) δ5.89 (t, J=6.4Hz, 1H), 3.63 (t, J=5.6Hz, 2H), 3.40 (m, J=6. 0Hz, 2H), 1.98–1.95 (m, 3H), 1.94 (s, 2H), 1.72–1.66 (m, 3H), 1.65–1.59 (m, 9H).

[0122] Step 2: 3-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)4-methylbenzenesulfonic acid propyl ester (Intermediate 27)

[0123] 2-Adamantane-1-yl-N-hydroxypropylacetamide (140 mg, 0.55 mmol) was dissolved in DCM (5 mL), and trimethylamine hydrochloride (5 mg, 0.055 mmol), triethylamine (140 mg, 1.4 mmol), and TsCl (160 mg, 0.83 mmol) were added thereto under ice bath, and stirred at 20°C for 2 h. DCM was added to the mixture, and the mixture was washed once with 1N HCl, once with saturated sodium bicarbonate solution, and once with saturated brine, and then dried by spin drying, and 51 mg (23%) of colorless oil was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ7.82–7.71(m, 2H), 7.30(d, J=8.0Hz, 2H), 4.94(t, J=6.4Hz, 1H), 4.07(t, J=6.0Hz, 2H), 3.00(q , J=6.8Hz, 2H), 2.42 (s, 3H), 2.01 (s, 2H), 1.93 (s, 3H), 1.79 (p, J=6.4Hz, 2H), 1.73–1.64 (m, 4H), 1.64–1.50 (m, 9H).

[0124] Step 3: 2-((3r,5r,7r)-adamantan-1-yl)-N-(3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)propyl)acetamide (H2)

[0125] 1,3-Dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (110 mg, 0.25 mmol), 3-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)4-methylbenzenesulfonic acid propyl ester (125 mg, 0.31 mmol), potassium carbonate (71 mg, 0.51 mmol) were dissolved in acetonitrile (5 mL) and reacted at 90° C. overnight. The mixture was then spin-dried and column chromatography gave 21 mg (12%) of a white solid. 1H NMR (400MHz, CDCl3) δ7.73 (d, J=8.4Hz, 1H), 7.52 (s, 1H), 7.38 (d, J=2.8Hz, 1H), 7.28 (dd, J= 8.4, 1.6Hz, 1H), 7.25 (s, 0H), 6.23 (s, 1H), 4.49 (t, J=5.2Hz, 2H), 4.30 (t, J=5.2Hz, 2H), 3.63 (s, 3H), 3.28–3.19 (m, 4H), 3.07 (d, J=11.2Hz, 2H), 2.84 (tt, J=11.2, 3.6Hz, 1H), 2.46 (s, 2H ), 2.42–2.36(m, 2H), 2.23(s, 3H), 2.20–2.03(m, 3H), 2.00–1.87(m, 6H), 1.74–1.59(m, 10H).

[0126] Example 25: 2-((3r,5r,7r)-adamantan-1-yl)-N-(4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butyl)acetamide (H3). Compound H3 was synthesized by the method of Example 24. 1 HNMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.53 (d, J=2.8Hz, 1H), 7.39 (s, 1H), 7.29 (dd, J=8 .4, 1.6Hz, 1H), 6.26 (t, J=5.6Hz, 1H), 5.96 (t, J=5.6Hz, 1H), 4.49 (t, J=5.2Hz, 2H), 4.30 (t, J= 5.2Hz, 2H), 3.63 (s, 3H), 3.28–3.19 (m, 4H), 3.07 (d, J=10.6Hz, 2H), 2.84 (tt, J=11.2, 3.6Hz, 1 H), 2.47–2.33(m, 7H), 2.23(s, 3H), 2.20–2.01(m, 3H), 1.99–1.86(m, 5H), 1.72–1.53(m, 12H).

[0127] Example 26: 2-((3r,5r,7r)-adamantan-1-yl)-N-(5-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)pentyl)acetamide (H4). Compound H4 was synthesized by the method of Example 24. 1HNMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.53 (d, J=2.4Hz, 1H), 7.39 (d, J=2.8Hz, 1H ), 7.31–7.25(m, 2H), 5.96(d, J=5.6Hz, 1H), 4.50(d, J=5.2Hz, 2H), 4.30(d, J=5.2Hz, 2H) , 3.63 (s, 3H), 3.29–3.17 (m, 4H), 3.06 (d, J=10.8Hz, 2H), 2.84 (td, J=11.2, 3.6Hz, 1H), 2 .56–2.35(m, 6H), 2.23(s, 3H), 2.19–2.00(m, 2H), 1.98–1.86(m, 7H), 1.73–1.61(m, 9H).

[0128] Example 27: 2-((3r,5r,7r)-adamantan-1-yl)-N-(6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)hexyl)acetamide (H5). Compound H5 was synthesized by the method of Example 24. 1 HNMR (400MHz, CDCl3) δ7.73 (d, J=8.4Hz, 1H), 7.57–7.50 (m, 2H), 7.41 (d, J=2.8Hz, 1H), 7.35–7.28 (m, 2H), 4.53 (s, 2H), 4.33 (d, J=4.8Hz, 2H), 3.65(s, 3H), 3.24(dd, J=12.8, 6.8Hz, 2H), 2.26–2.22(m, 4H), 1.97–1.9 1(m, 7H), 1.72–1.58(m, 16H), 1.53(t, J=6.8Hz, 2H), 1.46–1.35(m, 6H).

[0129] Example 28: Synthesis of H6

[0130]

[0131] Step 1: 2-(7-Hydroxyheptyl)isoindoline-1,3-dione (Intermediate 29)

[0132] 7-Bromoheptane-1-ol (500 mg, 2.6 mmol) and potassium phthalimide (505 mg, 2.73 mmol) were dissolved in DMF (5 mL) and reacted at 120°C for 3 h. The mixture was filtered and extracted with ethyl acetate, and the organic phases were combined, washed once with water and once with saturated brine, and dried by spin drying. 630 mg (92.7%) of white solid was obtained by column chromatography.1 H NMR (400MHz, CDCl3) δ7.86–7.80 (m, 2H), 7.74–7.66 (m, 2H), 3.67 (t, 2H), 3.6 3(t, J=6.8Hz, 2H), 1.74–1.59(m, 2H), 1.59–1.48(m, 2H), 1.39–1.33(m, 6H).

[0133] Step 2: 7-aminoheptane-1-ol (Intermediate 30)

[0134] Dissolve 2-(7-hydroxyheptyl)isoindoline-1,3-dione (820 mg, 2.98 mmol) in ethanol (30 mL), add hydrazine hydrate (597 mg, 11.92 mmol), and reflux at 100°C for 4 h. After cooling, filter and spin-dry the organic phase to obtain 432 mg (100%) of a white solid. 1 H NMR (400MHz, CDCl3) δ3.60 (t, J=6.8Hz, 2H), 2.66 (t, J=6.8Hz, 2H), 1.63–1.49 (m, 2H), 1.46–1.38 (m, 2H), 1.37–1.27 (m, 6H).

[0135] Step 3: 2-((3r,5r,7r)-adamantan-1-yl)-N-(7-hydroxyheptyl)acetamide (Intermediate 31)

[0136] Intermediate 28 was synthesized by the method of Step 1 of Reference Example 24. 1 H NMR (400MHz, CDCl3) δ3.69–3.57 (m, 2H), 3.23 (q, J=7.2, 5.6Hz, 2H), 1.96 (s, 3H), 1.9 0 (s, 2H), 1.74–1.66 (m, 3H), 1.66–1.60 (m, 9H), 1.40–1.30 (m, 7H), 1.29–1.19 (m, 3H).

[0137] Step 4: 7-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)heptyl 4-methylbenzenesulfonate (Intermediate 32)

[0138] Intermediate 29 was synthesized by the method of Step 2 of Reference Example 24. 1H NMR (400MHz, CDCl3) δ7.78 (d, 2H), 7.35 (d, 2H), 4.00 (t, J=6.4Hz, 2H), 3.20 (t, J=7.2, 5.66Hz, 2H), 2.45 (s, 3 H), 1.96 (s, 3H), 1.90 (s, 2H), 1.75–1.66 (m, 3H), 1.65–1.57 (m, 9H), 1.45 (t, J=7.1Hz, 2H), 1.35–1.18 (m, 8H).

[0139] Step 5: 2-((3r,5r,7r)-adamantan-1-yl)-N-(7-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)heptyl)acetamide (H6)

[0140] Compound H6 was synthesized by the method of step 3 of reference example 24. 1 H NMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.53 (d, J=2.8Hz, 1H), 7.42–7.36 (m, 1H), 7.28 (d, J=8.4Hz, 1H), 4.50 (t, J=5.6Hz, 2H), 4.30 (t, J=5.2Hz, 2H), 3.63 (s, 3 H), 3.28–3.16(m, 2H), 2.23(s, 3H), 2.22–1.98(m, 3H), 1.95(s, 4H), 1.90(s, 2H), 1.74–1.65 (m, 4H), 1.65–1.53 (m, 11H), 1.46 (q, J=6.8Hz, 2H), 1.38–1.15 (m, 12H).

[0141] Example 29: 2-((3r,5r,7r)-adamantan-1-yl)-N-(8-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)octyl)acetamide (H7). Compound H7 was synthesized by the method of Example 28. 1HNMR (400MHz, CDCl3) δ7.76 (d, J=8.4Hz, 1H), 7.53 (dd, J=2.8, 1.2Hz, 1H), 7.39 (d, J=2. 8Hz, 1H), 7.29 (dt, J=8.4, 2.4Hz, 2H), 4.50 (t, J=5.6Hz, 2H), 4.31 (dd, J=56.0, 5.6Hz, 2H ), 3.64 (s, 3H), 3.29–3.17 (m, 2H), 2.25 (s, 3H), 2.23–2.01 (m, 3H), 1.96 (q, J=2.8Hz, 4H ), 1.90(s, 2H), 1.78–1.66(m, 4H), 1.66–1.55(m, 11H), 1.48(t, 2H), 1.38–1.18(m, 14H).

[0142] Example 30: 2-((3r, 5r, 7r)-adamantan-1-yl)-N-(9-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)nonyl)acetamide (H8). Compound H8 was synthesized by the method of Example 28. 1 HNMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.53 (dt, J=2.8, 1.2Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.30 (dd, 1H), 7.27 (d, J=1.6Hz, 1H), 4.50 (t, J=5.2Hz, 2H), 4.31 (t, J=5.2Hz, 2H) , 3.64(s, 3H), 3.23(q, J=8.0Hz, 2H), 2.24(s, 3H), 2.23–2.07(m, 3H), 1.95(s, 4H), 1.90( s, 2H), 1.73–1.66 (m, 4H), 1.66–1.56 (m, 11H), 1.49 (t, J=8.0Hz, 2H), 1.40–1.18 (m, 16H).

[0143] Example 31: 2-((3r, 5r, 7r)-adamantan-1-yl)-N-(10-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)decyl)acetamide (H9). Compound H9 was synthesized by the method of Example 28. 1HNMR (400MHz, CDCl3) δ7.75 (d, J=8.4Hz, 1H), 7.53 (t, J=2.4, 1.2Hz, 1H), 7.39 (d, J= 2.4Hz, 1H), 7.29 (dd, J=8.4, 1.6Hz, 1H), 4.50 (t, J=5.2Hz, 2H), 4.30 (t, J=5.2Hz, 2H) , 3.64(s, 3H), 3.22(q, 2H), 2.24(s, 3H), 2.20–2.08(m, 3H), 1.95(s, 4H), 1.90(s, 2H ), 1.72–1.65(m, 4H), 1.65–1.58(m, 11H), 1.48(q, J=6.8Hz, 2H), 1.39–1.14(m, 18H).

[0144] Example 32: 2-((3r,5r,7r)-adamantan-1-yl)-N-(11-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)undecyl)acetamide (H10). Compound H10 was synthesized by the method of Example 28. 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, 1H), 7.81 (d, J=2.4Hz, 1H), 7.77 (s, 1H), 7.64 (t, J=5. 6Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.40 (d, 1H), 4.66 (d, J=5.6Hz, 2H), 4.42 (t, J=4.8Hz, 2H), 3.54(s, 3H), 3.00(q, J=6.4Hz, 2H), 2.11(s, 3H), 2.04–1.94(m, 3H), 1.90(s, 4H), 1.79(s, 2H), 1.70–1.61(m, 4H), 1.60–1.48(m, 11H), 1.35(t, 2H), 1.31–1.17(m, 20H).

[0145] Example 33: 2-((3r, 5r, 7r)-adamantan-1-yl)-N-(12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)dodecyl)acetamide (H11). Compound H11 was synthesized by the method of Example 28. 1H NMR (400MHz, DMSO-d6) δ7.98 (d, 1H), 7.81 (d, J=2.4Hz, 1H), 7.77 (s, 1H), 7.64 (t, J=5. 6Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.40 (d, 1H), 4.66 (d, J=5.6Hz, 2H), 4.42 (t, J=4.8Hz, 2H), 3.54(s, 3H), 3.00(q, J=6.4Hz, 2H), 2.11(s, 3H), 2.04–1.94(m, 3H), 1.90(s, 4H), 1.79(s, 2H), 1.70–1.61(m, 4H), 1.60–1.48(m, 11H), 1.35(t, 2H), 1.31–1.17(m, 20H).

[0146] Example 34: 2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethoxy)ethyl)acetamide (H12). Compound H12 was synthesized by the method of Example 28. 1 H NMR (400MHz, CDCl3) δ7.73 (d, J=8.4Hz, 1H), 7.53 (d, J=2.8Hz, 1H), 7.39 (d, J=2.4Hz, 1H ), 7.31 (dd, J=8.4, 1.6Hz, 1H), 4.51 (t, J=5.2Hz, 2H), 4.31 (t, J=5.2Hz, 2H), 3.68 (s, 2H) , 3.64 (s, 3H), 3.56 (t, J=5.2Hz, 2H), 3.46 (q, J=5.2Hz, 2H), 3.27 (s, 2H), 2.78 (s, 1H), 2. 24(s, 3H), 2.22–2.10(m, 3H), 2.03–1.88(m, 6H), 1.76–1.56(m, 12H), 1.30–1.18(m, 4H).

[0147] Example 35: 2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethoxy(ethoxy)ethyl)acetamide (H13). Compound H13 was synthesized by the method of Example 24. 1H NMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.53 (d, J=2.8Hz, 1H), 7.39 (d, J=2.8 Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 4.51 (t, J=5.6Hz, 2H), 4.31 (t, J=5.2Hz, 2H), 3.64 (s, 5H), 3.63–3.58 (m, 2H), 3.55 (t, J=5.2Hz, 2H), 3.48 (s, 1H), 3.43 (q, J=5.2Hz, 2H), 2.29–2.11(m, 5H), 2.03–1.90(m, 6H), 1.74–1.54(m, 15H), 1.37–1.11(m, 6H).

[0148] Example 36: 2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-(2-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethoxy(ethoxy)ethoxy)ethyl)acetamide (H14). Compound H-14 was synthesized by the method of Example 24. 1 HNMR (400MHz, DMSO-d6) δ7.98 (d, J=2.4Hz, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.75–7.68 (m, 1H), 7.59 (d, J=8.4Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 4.67 (d, J=5.6Hz, 2H), 4.43 (t, J=5.2Hz, 2H), 3.64 (s, 2H), 3.57–3 .52(m, 6H), 3.52–3.47(m, 6H), 3.17(q, J=5.6Hz, 2H), 2.10(s, 3H), 2.03–1.94(m, 2H), 1.94–1.83(m, 5H ), 1.83–1.72 (m, 2H), 1.73–1.59 (m, 4H), 1.59–1.46 (m, 11H), 1.35–1.20 (m, 4H), 1.17 (t, J=7.2Hz, 1H).

[0149] Example 37: Synthesis of C1

[0150]

[0151] Step 1: 5-(2-(1-(3-aminoalanyl)piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,3-dimethylpyridin-2(1H)-one trifluoroacetate (Intermediate 33)

[0152] 1,3-Dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (270 mg, 0.62 mmol), 3-((tert-butyloxycarbonyl)amino)propionic acid (153 mg, 0.8 mmol), HATU (354 mg, 0.93 mmol) were dissolved in DMF (3 mL), DIPEA (160 mg, 1.24 mmol) was added thereto and reacted at 20°C overnight. The mixture was extracted with EA, washed with water several times, washed once with saturated brine, and dried by spin-drying. Column chromatography gave 180 mg. The mixture was dissolved in DCM (2 mL), TFA (1 mL) was added thereto in an ice bath, and stirred at 20°C for 2 h. The mixture was dried by spin-drying to give 184 mg (100%) of trifluoroacetate. 1 H NMR (400MHz, DMSO-d6) δ8.04 (d, J=2.8Hz, 1H), 8.00 (s, 1H), 7.87–7.79 (m, 1H), 7.70 (d, J=8.4Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.26–7.21 (m, 1H), 7.19 –7.13(m, 1H), 4.88(t, J=4.8Hz, 2H), 4.52(t, J=4.9Hz, 2H), 3.98–3.26(m, 9H), 3.09–2.99(m, 2H), 2.77–2.70(m, 1H), 2.12(s, 3H), 2.04–1.73(m, 4H).

[0153] Step 2: 4-((3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C1)

[0154] Tert-butyl (3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropyl)carbamate (180 mg, 0.297 mmol) was dissolved in DCM (4 mL), TFA (0.5 mL) was added thereto, and the mixture was reacted at 20° C. for 3 h, and the trifluoroacetate was obtained by spin drying and directly used in the next step. The above trifluoroacetate (180 mg, 0.29 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (53.4 mg, 0.19 mmol) were dissolved in DMF (3 mL), and DIPEA (73.5 mg, 0.57 mmol) was added thereto and the mixture was reacted at 90° C. overnight. The mixture was extracted with EA, washed with water several times, washed once with saturated brine, dried by spin-drying, and purified by column chromatography to obtain 20 mg (13.8%) of a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.49 (d, J=46.8Hz, 1H), 7.74 (dd, J=8.0, 3.6Hz, 1H), 7.53 (s, 1H), 7.49 (d, J=8.0Hz , 1H), 7.41 (s, 1H), 7.30 (d, J=15.2Hz, 1H), 7.30 (s, 1H), 7.09 (d, J=6.8Hz, 1H), 6.97 (dd, J=8.8, 3.6Hz, 1H ), 6.59 (s, 1H), 4.89 (dd, J=12.4, 5.2Hz, 1H), 4.53 (q, J=4.8Hz, 2H), 4.33 (d, J=4.8Hz, 2H), 3.64 (s, 3H), 3 .48(s, 1H), 3.32–3.07(m, 4H), 2.96(d, J=9.2Hz, 1H), 2.91–2.55(m, 7H), 2.23(s, 3H), 2.00–1.93(m, 4H).

[0155] Example 38: Synthesis of C2

[0156]

[0157] Step 1: tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoate (Intermediate 36)

[0158] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (450 mg, 1.63 mmol) and tert-butyl 4-aminobutyrate hydrochloride (542 mg, 2.77 mmol) were dissolved in DMF (3 mL), and DIPEA (631 mg, 4.89 mmol) was added thereto and reacted overnight at 90° C. The mixture was extracted with EA, washed with water, washed once with saturated brine, and dried by spin drying. 120 mg (18%) of yellow solid was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.50 (dd, J=8.4, 7.2Hz, 1H), 7.10 (dd, J=7.2, 0.8Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.29 (s, 1H), 4.91 (dd, J =12.0, 5.2Hz, 1H), 3.33 (q, J = 6.4Hz, 2H), 2.92–2.68 (m, 3H), 2.35 (t, J = 7.2Hz, 2H), 2.18–2.09 (m, 1H), 1.93 (p, J = 7.2Hz, 2H), 1.45 (s, 9H).

[0159] Step 2: 4-((4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C2)

[0160] Tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoate (80 mg, 0.193 mmol) was dissolved in DCM (3 mL), TFA (0.5 mL) was added thereto, and the mixture was reacted at 20° C. for 3 h. TFA was spin-dried, dissolved in DMF (3 mL), HATU (101 mg, 0.27 mmol), DIPEA (46 mg, 0.35 mmol), 1,3-dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (70 mg, 0.195 mmol) were added thereto, and the mixture was reacted at 20° C. overnight. The mixture was extracted with EA, and the organic phases were combined, washed with water, washed once with saturated brine, and spin-dried. 35 mg (23%) of yellow solid was obtained by column chromatography.

[0161] 1H NMR (400MHz, CDCl3) δ8.55 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.51 (d, J=12.0Hz, 2H), 7. 42 (s, 1H), 7.31 (d, J=8.8Hz, 2H), 7.04 (dd, J=33.2, 8.0Hz, 2H), 6.36 (s, 1H), 4.90 (d, J=11.6Hz, 1H), 4.53 (s, 2H), 4.33 (s, 2H), 3.64 (s, 3H), 3.52–3.30 (m, 2H), 3.29–2.62 (m, 6H), 2.48 (s, 1H), 2.23 (s, 3H), 2.05 (dd, J=54.4, 16.4Hz, 6H), 1.76–1.25 (m, 4H).

[0162] Example 39: Synthesis of C3

[0163]

[0164] Step 1: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (Intermediate 37)

[0165] Intermediate 37 was synthesized by the method of Step 1 of Reference Example 38. 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.49 (t, J=8.4, 7.2Hz, 1H), 7.09 (d, J=7.2Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.25 ( s, 1H), 4.91 (dd, J=12.0, 5.2Hz, 1H), 3.37–3.25 (m, 4H), 2.85–2.68 (m, 2H), 2.43–2.34 (m, 5H), 2.16–2.09 (m, 1H).

[0166] Step 2: 4-((5-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C3)

[0167] 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (40 mg, 0.107 mmol) was dissolved in DMF (2 mL), HATU (56 mg, 0.146 mmol) and DIPEA (25 mg, 0.19 mmol) were added thereto, and the mixture was reacted overnight at 20°C. The mixture was extracted with EA, and the organic phases were combined, washed with water, washed once with saturated brine, and dried by spin drying. 20 mg (26%) of a yellow solid was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.59 (d, J = 2.8Hz, 1H), 7.52–7.47 (m, 2H), 7.41 (d, J = 1.6H z, 1H), 7.31 (dd, J=8.4, 1.6Hz, 1H), 7.07 (d, J=7.2Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 6.27 (t, J=5.6Hz, 1H), 4.94–4.84 (m, 1H), 4.57 (t, J = 4.8Hz, 2H), 4.35 (t, J = 5.2Hz, 2H), 3.70 (q, J = 6.8Hz, 4H), 3.64 (s, 3H), 3.33 (t, J = 6.0Hz, 2H), 2. 91–2.64 (m, 3H), 2.42 (t, J=7.2Hz, 1H), 2.22 (s, 3H), 1.97 (d, J=26.4Hz, 2H), 1.82–1.69 (m, 3H), 1.48–1.43 (m, 6H).

[0168] Example 40: 4-((6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C4). Compound C4 was synthesized by the method of Example 39. 1H NMR (400MHz, CDCl3) δ8.17 (d, J=17.2Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.50 (t, J=8.4Hz, 1H), 7.42 (d, J=2 .4Hz, 1H), 7.36–7.30 (m, 1H), 7.29 (s, 1H), 7.08 (d, J=7.2Hz, 1H), 6.90 (d, J=8.8Hz, 1H), 6.25 (s, 1H), 4.91 (dd, J=12.0, 5.6Hz, 1H), 4.54 (d, J=5.2Hz, 2H), 4.34 (d, J=5.2Hz, 2H), 3.77–3.68 (m, 3H), 3.65 (s, 3H), 3.49 (s, 2H), 3.30 (q, J=6.4Hz, 2H), 3.22–3. 08 (m, 2H), 2.94–2.63 (m, 3H), 2.39 (t, J=7.2Hz, 1H), 2.25 (s, 3H), 2.13 (t, J=6.8Hz, 1H), 1.78–1.67 (m, 4H), 1.53–1.48 (m, 5H).

[0169] Example 41: 4-((7-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C5). Compound C5 was synthesized by the method of Example 39. 1H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 7.96 (s, 1H), 7.77 (d, J = 17.2Hz, 2H), 7.57 (t, J = 8.0Hz, 2H), 7.38 (d, J = 8.4Hz, 1 H), 7.10 (d, J=8.4Hz, 1H), 7.01 (d, J=7.2Hz, 1H), 6.55 (d, J=6.0Hz, 1H), 5.05 (dd, J=12.8, 5.6Hz, 1H), 4.70 (t, J=5.2H z, 2H), 4.44 (d, J = 4.8Hz, 2H), 4.17–3.95 (m, 3H), 3.54 (s, 4H), 3.17 (s, 5H), 2.95–2.81 (m, 1H), 2.71 (t, J = 12.4Hz, 1H) , 2.35 (q, J=7.2Hz, 2H), 2.11 (s, 3H), 2.05–1.99 (m, 1H), 1.93–1.76 (m, 2H), 1.71–1.48 (m, 5H), 1.37 (d, J=6.0Hz, 4H).

[0170] Example 42: 4-((8-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C6). Compound C6 was synthesized by the method of Example 39. 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.54 (d, J = 2.4Hz, 1H), 7.49 (t, J = 7.2Hz, 1H), 7.42 ( d, J=2.4Hz, 1H), 7.36–7.28 (m, 2H), 7.07 (d, J=6.8Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.23 (t, J=5.2Hz, 1H), 4.96– 4.85 (m, 1H), 4.54 (t, J=5.2Hz, 2H), 4.33 (t, J=5.2Hz, 2H), 3.65 (s, 3H), 3.35–3.06 (m, 4H), 2.94–2.61 (m, 3H) , 2.42–2.31(m, 2H), 2.24(s, 3H), 2.18–2.08(m, 2H), 2.03–1.87(m, 3H), 1.80–1.58(m, 7H), 1.52–1.42(m, 6H).

[0171] Example 43: Synthesis of C7

[0172]

[0173] Step 1: 9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonanoic acid (Intermediate 39)

[0174] Intermediate 34 was synthesized by the method of step f2 of reference example 37. 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.49 (dd, J=8.4, 7.2Hz, 1H), 7.08 (d, J=7.2Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.23 (s, 1H), 4.92 (dd, J =12.0, 5.2Hz, 1H), 3.30–3.22(m, 2H), 2.91–2.69(m, 3H), 2.36–2.32(m, 2H), 2.19–2.09(m, 1H), 1.73–1.59(m, 6H), 1.57–1.27(m, 6H).

[0175] Step 2: 4-((9-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-9-oxononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C7)

[0176] Compound C-7 was synthesized by the method of step 2 of reference example 39. 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.74 (d, J = 8.2Hz, 1H), 7.54 (d, J = 2.6Hz, 1H), 7.49 (t, J = 7.2Hz, 1H), 7.42 ( d, J=2.6Hz, 1H), 7.36–7.28 (m, 2H), 7.07 (d, J=7.0Hz, 1H), 6.88 (d, J=8.6Hz, 1H), 6.23 (t, J=5.4Hz, 1H), 4.96– 4.85 (m, 1H), 4.54 (t, J=5.2Hz, 2H), 4.33 (t, J=5.1Hz, 2H), 3.65 (s, 3H), 3.35–3.06 (m, 4H), 2.94–2.61 (m, 3H) , 2.42–2.31(m, 2H), 2.24(s, 3H), 2.18–2.08(m, 2H), 2.03–1.87(m, 3H), 1.80–1.58(m, 7H), 1.52–1.42(m, 6H).

[0177] Example 44: 4-((10-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-10-oxodecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C8). Compound C8 was synthesized by the method of Example 43. 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=19.7Hz, 1H), 7.72 (d, J=8.4Hz, 1H), 7.56 (d, J=2.6Hz, 1H), 7.51–7.44 (m, 2H), 7.36 (s, 1H), 7.33–7.28 (m, 1H), 7.06 (d, J=7.1Hz, 1H), 6.87 (d, J=8.6Hz, 1H), 6.22 (t, J=5.6Hz, 1H), 4.97–4.86 (m, 1H), 4 .56 (t, J=5.0Hz, 2H), 4.34 (t, J=5.0Hz, 2H), 3.77–3.66 (m, 1H), 3.64 (s, 3H), 3.31–3.10 (m, 6H), 2.90–2.63 (m, 4H), 2 .43–2.33(m, 2H), 2.22(s, 3H), 2.17–2.04(m, 1H), 1.95(q, J=4.2Hz, 1H), 1.64(q, J=7.4Hz, 4H), 1.47–1.35(m, 13H).

[0178] Example 45: 4-((11-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-11-oxoundecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C9). Compound C9 was synthesized by the method of Example 43. 1H NMR (400MHz, CDCl3) δ7.72 (d, J=8.4Hz, 1H), 7.56 (s, 1H), 7.49–7.44 (m, 2H), 7.34 (s, 1H), 7.29 (dd, J=8.4, 1.6Hz, 1H), 7.05 (d, J=7.2Hz, 1H), 6.86 (d, J=8.4Hz, 1H), 6.21 (t, J=5.6Hz, 1H), 4.90 (dd, J=11.8, 5.2Hz, 1H), 4.74 (d, J=13.6Hz, 1H), 4.54 (t, J=5.2 Hz, 2H), 4.33 (t, J=5.2Hz, 2H), 4.04 (d, J=13.6Hz, 1H), 3.68–3.59 (m, 4H), 3.24 (q, J=6.4Hz, 2H), 3.20–3.08 (m, 2H), 2.88–2.68 (m, 4H), 2.35 (td, J=7.6, 3.6Hz, 2H), 2.22 (s, 3H), 2.17–2.05 (m, 2H), 2.03–1.84 (m, 2H), 1.68–1.57 (m, 4H), 1.44–1.26 (m, 16H).

[0179] Example 46: 4-((12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-12-oxododecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C10). Compound C10 was synthesized by the method of Example 39. 1H NMR (400MHz, CDCl3) δ8.55 (d, J=14.4Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.50–7.41 (m, 2H), 7.34–7.28 (m, 2H), 7.05 (d, J=7.2Hz, 1H), 6.86 (d, J=8.8Hz, 1H), 6.21 (t, J=5.6Hz, 1H), 4.89 (dd, J=12.0, 5.4Hz, 1H), 4.75 (d, J=13.6Hz, 1H), 4.54 (t, J=5.2Hz, 2H), 4 ... z, 2H), 2.22 (s, 3H), 2.17–2.05 (m, 2H), 2.02–1.86 (m, 2H), 1.63 (p, J=7.2Hz, 4H), 1.44–1.36 (m, 4H), 1.34–1.25 (m, 6H), 0.89–0.81 (m, 2H).

[0180] Example 47: 4-((13-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-13-oxotridecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C11). Compound C11 was synthesized by the method of Example 39. 1H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.51–7.45 (m, 1H), 7.43 (d, J = 2.8Hz, 1H), 7.34 –7.28 (m, 2H), 7.06 (d, J=7.2Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 6.22 (t, J=5.6Hz, 1H), 4.90 (dd, J=12.0, 5.2Hz, 1H), 4.77 (d, J=13. 6Hz, 1H), 4.54 (t, J=5.2Hz, 2H), 4.33 (d, J=5.2Hz, 2H), 4.05 (d, J=12.4Hz, 1H), 3.64 (s, 3H), 3.24 (q, J=6.8Hz, 2H), 3.20–3.06 ( m, 2H), 2.90–2.66 (m, 4H), 2.35 (td, J=7.2, 3.2Hz, 2H), 2.23 (s, 3H), 2.21–1.84 (m, 5H), 1.71–1.58 (m, 4H), 1.43–1.22 (m, 14H).

[0181] Example 48: 4-((14-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-14-oxotetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C12). Compound C12 was synthesized by the method of Example 39. 1 H NMR (400MHz, CDCl3) δ8.13 (s, 1H), 8.00 (s, 0H), 7.73 (d, J=8.4Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.51–7.40 (m, 2H), 7.31 (d, J=8.4Hz, 1H), 7.06 (d, J=7.2Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.21 (d, J=5.6Hz, 1H), 4.90 (dd, J=12.0 , 5.2Hz, 1H), 4.72 (d, J = 13.2Hz, 1H), 4.58 (d, J = 4.8Hz, 2H), 4.36 (d, J = 4.8Hz, 2H), 4.08–3.99 (m, 1H), 3.65 (s, 3H ), 2.90–2.82(m, 1H), 2.40–2.26(m, 4H), 2.22(s, 3H), 2.17–1.88(m, 6H), 1.69–1.56(m, 8H), 1.46–1.37(m, 18H).

[0182] Example 49: 4-((15-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-15-oxopentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C13). Compound C13 was synthesized by the method of Example 39. 1 H NMR (400MHz, CDCl3) δ8.19 (s, 1H), 7.74 (d, J=8.4Hz, 1H), 7.56 (s, 1H), 7.49–7.44 (m, 2H), 7.37–7.30 (m, 2H), 7.07 (d, J= 7.2Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.22 (d, J=5.6Hz, 1H), 4.90 (dd, J=12.0, 5.6Hz, 1H), 4.75 (d, J=13.2Hz, 1H), 4.61–4. 48(m, 2H), 4.37–4.28(m, 2H), 4.05(d, J=13.6Hz, 1H), 3.76–3.66(m, 1H), 3.64(s, 3H), 3.31–3.11(m, 5H), 2.92–2.68(m, 5H), 2.39–2.30(m, 2H), 2.17–2.07(m, 1H), 2.02–1.88(m, 2H), 1.73–1.55(m, 6H), 1.48–1.38(m, 6H), 1.37–1.24(m, 14H).

[0183] Example 50: 4-((2-(3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C14). Compound C14 was synthesized by the method of Example 43. 1HNMR (400MHz, CDCl3) δ9.08 (s, 1H), 7.75–7.68 (m, 1H), 7.57–7.53 (m, 1H), 7.47–7.41 (m, 2H), 7.34–7.28 (m, 2H) ), 7.04 (dd, J=7.2, 5.2Hz, 1H), 6.88 (dd, J=8.4, 2.8Hz, 1H), 6.50 (t, J=5.6Hz, 1H), 4.77 (d, J=13.6Hz, 1H), 4.5 8–4.49 (m, 2H), 4.37–4.30 (m, 2H), 4.16–4.03 (m, 1H), 3.85–3.69 (m, 3H), 3.64 (s, 3H), 3.54 (t, J=5.0Hz, 1H), 3 .31(t, J=5.2Hz, 1H), 3.26–3.09(m, 2H), 2.85–2.56(m, 3H), 2.23(s, 3H), 2.16–2.03(m, 2H), 2.01–1.86(m, 8H).

[0184] Example 51: 4-((2-(2-(3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C15). Compound C15 was synthesized by the method of Example 43. 1 H NMR (400MHz, CDCl3) δ9.13 (d, J=26.8Hz, 1H), 7.73–7.67 (m, 1H), 7.54 (s, 1H), 7.47–7.40 (m, 2H), 7.36–7.27 (m, 2H), 7.04 (d, J=7.2Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.50 (d, J=6.4Hz, 1H), 4.89 (dd, J=12.0, 5.2Hz, 1H), 4.72 (d, J=13.2Hz, 1H), 4.57–4.49 (m, 2H), 4.33 (d, J=5.6Hz, 2H), 4.07–3.98 (m, 1H), 3.85–3.76 (m, 2H), 3.73–3.59 (m, 8 H), 3.47–3.41(m, 2H), 3.19–3.09(m, 2H), 2.87–2.62(m, 4H), 2.22(s, 3H), 2.17–2.06(m, 3H), 1.98–1.86(m, 2H).

[0185] Example 52: 4-((2-(2-(2-(3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazo-2-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C16). Compound C16 was synthesized by the method of Example 38. 1 H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 7.95 (d, J=3.2Hz, 2H), 7.82–7.72 (m, 2H), 7.60–7.53 (m, 2H), 7.42–7.31 (m, 1H), 7.12 (d, J=8.8Hz, 1H), 7.03 (d, J=7.2Hz, 1H), 6.58 (d, J=5.6Hz, 1H), 5.05 (dd, J= 12.8, 5.2Hz, 1H), 4.68 (s, 2H), 4.53–4.41 (m, 3H), 4.20–4.11 (m, 1H), 3.69–3.58 (m, 4H), 3.55–3.32 (m, 18H), 3.31–3.22 (m, 1H), 2.65–2.55 (m, 4H), 2.10 (s, 3H), 2.04–1.99 (m, 1H), 1.87–1.80 (m, 2H).

[0186] Example 53: 4-((15-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-15-oxo-3,6,9,12-tetradecanoyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C17). Compound C17 was synthesized by the method of Example 38. 1H NMR (400MHz, CDCl3) δ7.71 (dd, J=8.8, 3.2Hz, 1H), 7.56–7.41 (m, 3H), 7.32–7.28 (m, 2H), 7 .05–6.99 (m, 1H), 6.93 (dd, J=8.8, 5.6Hz, 1H), 6.50–6.42 (m, 1H), 4.93–4.81 (m, 1H), 4.60 –4.47(m, 3H), 4.39–4.28(m, 2H), 3.94(d, J=13.6Hz, 1H), 3.89–3.81(m, 2H), 3.75–3.58(m , 16H), 3.55(s, 1H), 3.29–3.14(m, 2H), 2.84–2.67(m, 5H), 2.24(s, 3H), 2.16–1.79(m, 6H).

[0187] Example 54: Synthesis of C18

[0188]

[0189] Step 1: tert-Butyl 2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 40)

[0190] 1,3-Dimethyl-5-(2-(piperidin-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)one (80 mg, 0.184 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (176 mg, 0.736 mmol) were dissolved in DCE (3 mL), AcOH (0.1 mL) was added thereto and reacted for 10 min, then sodium triacetoxyborohydride (156 mg, 0.736 mmol) was added and stirred overnight at 20° C. The mixture was dried by rotary evaporation and column chromatography gave 75 mg (62%) of the product. 1H NMR (400MHz, CDCl3) δ7.76 (d, J=8.4Hz, 1H), 7.56–7.52 (m, 1H), 7.39 (d, J=2.8Hz, 1 H), 7.31 (dd, J=8.4, 1.6Hz, 1H), 4.50 (d, J=5.2Hz, 2H), 4.31 (t, J=5.2Hz, 2H), 3.65 (s, 3H), 3.40–3.33 (m, 2H), 3.32–3.26 (m, 2H), 3.27–3.20 (m, 2H), 3.07 (s, 2H), 2.2 5(s, 3H), 2.20–2.12(m, 2H), 2.07(s, 6H), 1.61–1.51(m, 6H), 1.44(d, J=4.8Hz, 9H).

[0191] Step 2: 4-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C-18)

[0192] Compound C18 was synthesized by the method of step f2 of reference example 37.

[0193] 1 H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 7.74 (d, J=8.4Hz, 1H), 7.59–7.51 (m, 2H), 7 .42–7.27(m, 4H), 7.15(d, J=8.4Hz, 1H), 4.95(dd, J=12.0, 5.2Hz, 1H), 4.59–4 .46(m, 2H), 4.31(d, J=5.2Hz, 2H), 3.64(s, 3H), 3.34–3.11(m, 6H), 2.97–2.66 (m, 4H), 2.24 (s, 3H), 2.20–1.98 (m, 8H), 1.95–1.78 (m, 4H), 1.47–1.39 (m, 2H).

[0194] Example 55: Synthesis of C19

[0195]

[0196] Step 1: tert-Butyl 4-(2-(2,6-dioxopiperazin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (Intermediate 41)

[0197] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (350 mg, 1.27 mmol) and tert-butyl piperazine-1-carboxylate (401 mg, 2.15 mmol) were dissolved in DMF (4 mL), and DIPEA (327 mg, 2.54 mmol) was added thereto, and the mixture was reacted overnight at 90° C. The mixture was extracted with EA, washed with water, washed once with saturated brine, and dried by spin drying. 220 mg (39%) of yellow solid was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ8.07 (d, J=6.8Hz, 1H), 7.61 (dd, J=8.4, 7.2Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.21–7.13 (m, 1H), 4.96 (dd .

[0198] Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione (Intermediate 42)

[0199] Dissolve tert-butyl 4-(2-(2,6-dioxopiperazin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carboxylate (220 mg, 0.497 mmol) in DCM (5 mL), add TFA (0.7 mL), and stir overnight at 20°C. Spin dry, add saturated sodium bicarbonate solution under ice bath to adjust pH to about 8, extract with DCM, combine the organic phases, wash once with saturated brine, and spin dry to obtain 124 mg (72%) of the product. 1 H NMR (400MHz, CDCl3) δ7.62–7.57 (m, 1H), 7.40 (d, J=7.2Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 4.96 (dd, J=12.4, 5.2Hz, 1H), 3.39–3.24 (m, 4H), 3.18–3.04 (m, 4H), 2.97–2.66 (m, 3H), 2.15–2.08 (m, 1H).

[0200] Step 3: tert-Butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Intermediate 43)

[0201] Intermediate 43 was synthesized by the method of Step 1 of Reference Example 54. 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.40 (d, J = 7.2Hz, 1H), 7.17 (d, J = 8.4Hz, 1H), 4.96 (dd, J = 12.0, 5.2Hz, 1H), 4.10 (s, 2H) , 3.35(s, 4H), 2.94–2.58(m, 8H), 2.25(d, J=5.6Hz, 2H), 2.15–2.07(m, 1H ), 1.46 (s, 9H), 1.35–1.28 (m, 2H), 1.17–1.05 (m, 2H), 0.94–0.79 (m, 2H).

[0202] Step 4: 4-(4-((1-(2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C19)

[0203] Compound C19 was synthesized by the method of Step 2 in Reference Example 38. 1 H NMR (400MHz, DMSO-d6) δ11.22 (s, 1H), 8.06 (d, J = 2.8Hz, 1H), 7.91 (d, J = 2.8Hz, 1H), 7.85 (d, J = 1.6Hz, 1H), 7.82–7.76 (m, 1H), 7.69 (d, J=8.4Hz, 1H), 7.53–7.40 (m, 3H), 5.19 (dd, J=12.8, 5.6Hz, 1H), 4.76( d, J=5.2Hz, 2H), 4.52 (t, J=4.8Hz, 2H), 4.45 (d, J=12.8Hz, 1H), 4.32–4.17 (m, 1H), 3.63 (s, 3H), 3.48– 3.34(m, 6H), 3.16–2.92(m, 6H), 2.73–2.62(m, 6H), 2.35–2.28(m, 2H), 2.20(s, 3H), 2.16–1.81(m, 8H).

[0204] Example 56: Synthesis of C20

[0205]

[0206] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (Intermediate 44)

[0207] Intermediate 44 was synthesized by the method of step 1 of reference example 55. 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 7.58 (dd, J=8.5, 7.2Hz, 1H), 7.13 (d, J=6.8Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 5.05 (dd, J=12.8 5.3Hz, 1H), 4.44(d, J=6.7Hz, 2H), 4.30(br t, J=8.0Hz, 2H), 4.01-3.95 (m, 2H), 3.23 (s, 3H), 3.13-3.04 (m, 1H), 2.93-2.81 (m, 1H), 2.60-2.52 (m, 2H), 2.03 -1.93 (m, 1H).

[0208] Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidine-3-carbaldehyde (Intermediate 45)

[0209] 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (160 mg, 0.47 mmol) was dissolved in dichloromethane (3 mL), and Dess-Martin periodinane (400 mg, 0.94 mmol) was added thereto and reacted at 20° C. for 1 h. The mixture was spin-dried and column chromatography was performed to obtain 47 mg (30%) of a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.75 (d, J=1.4Hz, 1H), 7.49 (dd, J=8.7, 6.9Hz, 1H), 7.24 (s, 1H), 6.95 (d, J=8.5Hz, 1H), 4.99–4.90 (m, 1H), 4.05–3.96 ( m, 1H), 3.93–3.82 (m, 1H), 3.66–3.55 (m, 2H), 3.22–3.13 (m, 1H), 2.93– 2.65(m, 4H), 2.39–2.31(m, 1H), 2.28–2.23(m, 1H), 2.16–2.08(m, 1H).

[0210] Step 3: tert-Butyl 4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (Intermediate 46)

[0211] Intermediate 46 was synthesized by the method of Step 1 of Reference Example 54. 1H NMR (400MHz, CDCl3) δ7.77 (d, J=8.3Hz, 1H), 7.54 (dd, J=2.6, 1.3Hz, 1H), 7.39 (d, J=2.6Hz, 1H) , 7.31 (dd, J=8.4, 1.7Hz, 1H), 7.25 (s, 1H), 4.50 (t, J=5.4Hz, 2H), 4.31 (t, J=5.3Hz, 2H), 3.65 (s , 3H), 3.28 (d, J=11.1Hz, 2H), 2.99 (s, 1H), 2.75 (d, J=13.5Hz, 4H), 2.61 (s, 2H), 2.25 (d, J=1.0 Hz, 3H), 2.17 (dd, J=23.8, 13.8Hz, 5H), 1.90 (d, J=12.8Hz, 3H), 1.61–1.50 (m, 1H), 1.45 (s, 9H).

[0212] Step 4: 4-(3-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-bipiperidin-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C20)

[0213] Compound C20 was synthesized by the method of steps 2 and 3 of reference example 55. 1 H NMR (400MHz, CDCl3) δ7.71 (d, J=8.4Hz, 1H), 7.53 (d, J=2.4Hz, 1H), 7.45–7.36 (m, 2H), 7.36–7.27 (m , 2H), 7.10(d, J=6.9Hz, 1H), 6.53(d, J=8.6Hz, 1H), 5.01–4.88(m, 1H), 4.55(t, J=5.3Hz, 2H), 4.32( t, J=5.4Hz, 4H), 3.87 (s, 2H), 3.62 (s, 3H), 3.46–3.33 (m, 2H), 3.20 (s, 1H), 3.00 (d, J=10.2Hz, 2H), 2.91 (t, J=6.9Hz, 1H), 2.86–2.63 (m, 8H), 2.29–2.18 (m, 6H), 2.15–1.96 (m, 6H), 1.91–1.73 (m, 2H).

[0214] Example 57: 4-((R)-3-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-dipiperidinyl]-1'-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C21). C21 was synthesized by the method of Example 56. 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 7.93 (d, J=2.5Hz, 1H), 7.80–7.68 (m, 2H), 7.53 (dd, J=13.1, 8.1Hz, 2H), 7.36 (d, J=8.0Hz, 1H), 7.07 (dd, J=11.3, 7.5Hz, 2H), 5.02 (dd, J=12.8, 5.4Hz, 1H), 4.63 (t, J=5.1Hz, 2H), 4.40 (t, J=4.9Hz, 2H), 4.34 (t, J=5.1Hz, 1H), 3.61–3.54 (m, 2H), 3.50 (s, 3H), 3.30–2.96 (m, 10H), 2.84 (ddd, J=17. 4, 14.1, 5.5Hz, 1H), 2.58–2.48(m, 2H), 2.44–2.33(m, 2H), 2.07(s, 3H), 2.04–1.81(m, 10H), 1.70–1.52(m, 3H).

[0215] Example 58: 4-(4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-dipiperidinyl]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C22). C22 was synthesized by the method of Example 56. 1H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 7.93 (d, J=2.9Hz, 1H), 7.74 (dd, J=17.3, 2.2Hz, 2H), 7.68–7.60 (m, 1H), 7.54 (d, J=8.3Hz, 1H), 7.34 (dd, J=8.4, 1.6Hz, 1H), 7.28 (dd, J=7.8, 4.2Hz, 2H), 5.05 (dd, J=12.8, 5.4Hz, 1H), 4.62 (t, J=5.2Hz, 2H), 4.39 (t, J=4.9Hz, 2H), 3.65 (dd, J=12.2, 4.5Hz, 2H), 3.50 (s, 3H), 3.09–2.75 (m, 8H), 2.66–2.51 (m, 1H), 2.41 (s, 2H) ), 2.20 (t, J=9.5Hz, 2H), 2.07 (s, 3H), 2.03–1.81 (m, 9H), 1.77 (d, J=11.9Hz, 4H), 1.60–1.45 (m, 2H), 1.35–1.18 (m, 3H).

[0216] Example 59: Synthesis of C23

[0217]

[0218] Step 1: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine tert-butyl ester (Intermediate 47)

[0219] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (400 mg, 1.45 mmol), glycine tert-butyl ester (247 mg, 1.88 mmol), DIPEA (562 mg, 4.35 mmol) were dissolved in NMP (5 mL) and reacted at 130° C. for 2 h. The mixture was extracted with EA, washed with water several times, washed once with saturated brine, dried by rotation, and subjected to column chromatography to obtain 125 mg (22%) of a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.07 (s, 1H), 7.64 (d, J=8.4Hz, 1H), 6.95 (d, J=2.0Hz, 1H), 6.78 (dd, J=8.4, 2.0Hz, 1H), 5.14 (s, 1H), 5 .05–4.87 (m, 1H), 3.89 (s, 2H), 3.45–3.33 (m, 1H), 2.37 (t, J=8.0Hz, 1H), 2.16–2.09 (m, 1H), 2.07–1.97 (m, 1H), 1.51 (s, 9H).

[0220] Step 2: 5-((2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C23)

[0221] Compound C-23 was synthesized by the method of step 2 of reference example 38. 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 7.96 (d, J=2.8Hz, 1H), 7.83–7.73 (m, 2H), 7.56 (t, J=8.0Hz, 2H), 7.38 (dd, J=8.4, 2.0Hz, 1H), 7 .09 (t, J=5.2Hz, 1H), 6.93 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.4, 2.0Hz, 1H), 5.03 (dd, J=12.8, 5.2Hz, 1H), 4.70 (t, J=4.8Hz, 2H), 4.50 (d, J=13.2Hz, 1H), 4.44 (t, J=4.8Hz, 2H), 4.36 (t, J=5.2Hz, 1H), 4.00 (d, J=13.2Hz, 1H), 3.53 (s, 3H), 3.22–3.08 (m, 3H), 2.87 (td, J=17. 2, 14.0, 5.6Hz, 1H), 2.70 (t, J=12.4Hz, 1H), 2.62–2.51 (m, 2H), 2.42–2.26 (m, 2H), 2.10 (s, 3H), 2.04–1.93 (m, 1H), 1.70–1.43 (m, 2H).

[0222] Example 60: 5-((3-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C24). Compound C24 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 7.96 (d, J=2.6Hz, 1H), 7.85–7.73 (m, 2H), 7.57 (d, J=8.3Hz, 2H), 7.38 (dd, J=8.4, 1.7Hz, 1H), 7.16 (t , J=5.7Hz, 1H), 6.99 (d, J=2.1Hz, 1H), 6.89 (dd, J=8.5, 2.1Hz, 1H), 5.04 (dd, J=12.9, 5.4Hz, 1H), 4.70 (t, J=5.2Hz, 2H), 4.54 (d, J=12.8Hz, 1 H), 4.44 (t, J = 4.9Hz, 2H), 3.99 (d, J = 13.4Hz, 1H), 3.54 (s, 3H), 3.47 (q, J = 6.4Hz, 2H), 3.32–3.24 (m, 1H), 3.17 (t, J = 3.6Hz, 1H), 2.88 (ddd, J=17.3, 14.0, 5.5Hz, 1H), 2.81–2.66 (m, 3H), 2.62–2.52 (m, 2H), 2.11 (s, 3H), 2.04–1.94 (m, 1H), 1.88 (d, J=12.3Hz, 3H), 1.79–1.64 (m, 1H).

[0223] Example 61: 5-((4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C25). Compound C25 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 7.96 (d, J=2.7Hz, 1H), 7.78 (dd, J=15.5, 2.2Hz, 2H), 7.58 (dd, J=8.5, 2.1Hz, 2H), 7.38 (dd, J=8.3, 1.7H z, 1H), 7.20 (t, J=5.5Hz, 1H), 6.98 (d, J=2.1Hz, 1H), 6.88 (dd, J=8.5, 2.1Hz, 1H), 5.03 (dd, J=12.9, 5.4Hz, 1H), 4.70 (t, J=5.1Hz, 2H), 4.53 (d , J=12.9Hz, 1H), 4.45 (t, J=5.0Hz, 2H), 4.02 (d, J=13.4Hz, 1H), 3.54 (s, 3H), 3.33–3.27 (m, 1H), 3.20 (dq, J=12.0, 6.9Hz, 3H), 2.87 (ddd, J=17 .3, 13.9, 5.5Hz, 1H), 2.80–2.70 (m, 1H), 2.62–2.43 (m, 4H), 2.11 (s, 3H ), 2.06–1.93 (m, 1H), 1.92–1.78 (m, 5H), 1.69 (tt, J=12.0, 6.2Hz, 1H).

[0224] Example 62: 5-((5-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C26). Compound C26 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 7.97 (d, J=2.4Hz, 1H), 7.78 (dd, J=15.2, 2.4Hz, 2H), 7.57 (dd, J=8.4, 2.0Hz, 2H), 7.38 (dd, J=8.0, 1.6Hz, 1H), 7.16 (t, J=5.6Hz, 1H), 6.97 (d, J=2.0Hz, 1H), 6.86 (dd, J=8.4, 2.0Hz, 1H), 5.03 (dd, J=12.8, 5.2Hz, 1H), 4.70 (t, J=5.2Hz, 2H), 4.52 (d, J=12.8Hz, 1H) , 4.44(t, J=4.8Hz, 2H), 4.03(d, J=13.6Hz, 1H), 3.65–3.57(m, 1H), 3.54(s , 3H), 3.31–3.24 (m, 1H), 3.25–3.08 (m, 4H), 2.87 (ddd, J=17.2, 13.8, 5.6Hz , 1H), 2.81–2.65(m, 1H), 2.62–2.51(m, 1H), 2.48–2.36(m, 1H), 2.11(s, 3H ), 1.99 (dp, J=12.1, 4.6, 4.1Hz, 1H), 1.94–1.77 (m, 3H), 1.72–1.60 (m, 5H).

[0225] Example 63: 5-((6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C27). Compound C-27 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 7.97 (d, J=2.8Hz, 1H), 7.83–7.76 (m, 2H), 7.56 (t, J=8.4Hz, 2H), 7.40 (dd, J=8.0, 1.6Hz, 1H), 7.14 (t, J =5.6Hz, 1H), 6.95 (d, J = 2.0Hz, 1H), 6.85 (dd, J = 8.8, 2.4Hz, 1H), 5.03 (dd, J = 12.8, 5.2Hz, 1H), 4.71 (t, J = 5.2Hz, 2H), 4.52 (d, J = 13.2Hz, 1H), 4.45 (t, J=4.9Hz, 2H), 4.01 (d, J=13.4Hz, 1H), 3.65–3.57 (m, 1H), 3.54 (s, 3H), 3.42–3.26 (m, 4H), 2.87 (ddd, J=17.2, 13.8, 5.6Hz, 1H), 2.75– 2.66(m, 1H), 2.62–2.51(m, 2H), 2.44–2.34(m, 2H), 2.11(s, 3H), 2.03– 1.95 (m, 1H), 1.94–1.76 (m, 2H), 1.73–1.53 (m, 5H), 1.47–1.36 (m, 2H).

[0226] Example 64: 5-((7-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C28). Compound C28 was synthesized by the method of Example 59. 1H NMR (400MHz, CDCl3) δ8.86 (s, 1H), 8.07 (d, J=8.4Hz, 1H), 7.92–7.83 (m, 2H), 7.74 (d, J=2.8Hz, 1H), 7.65 (dd, J=8.4, 1.6Hz, 1H ), 7.61 (d, J=1.6Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 7.04 (dd, J=8.4, 2.4Hz, 1H), 5.38–5.28 (m, 1H), 5.28–5.20 (m, 1H), 5.12 (d, J= 13.4Hz, 1H), 4.87 (t, J=5.6Hz, 2H), 4.67 (t, J=5.2Hz, 2H), 4.39 (d, J=13.6Hz, 1H), 3.97 (s, 3H), 3.62–3.42 (m, 4H), 3.24–2.98 (m, 4H), 2.80–2.64 (m, 2H), 2.57 (t, J=0.9Hz, 3H), 2.54–2.39 (m, 2H), 2.38–2.20 (m, 3H), 2.10–1.91 (m, 5H), 1.83–1.71 (m, 3H).

[0227] Example 65: 5-((8-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C29). Compound C29 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 7.96 (d, J=2.8Hz, 1H), 7.80 (dd, J=2.8, 1.2Hz, 1H), 7.76–7.73 (m, 1H), 7.58–7.53 (m, 2H), 7.38 (dd, J =8.4, 1.6Hz, 1H), 7.11 (t, J = 5.6Hz, 1H), 6.94 (d, J = 2.0Hz, 1H), 6.84 (dd, J = 8.4, 2.1Hz, 1H), 5.02 (dd, J = 12.8, 5.6Hz, 1H), 4.69 (t, 2H), 4.50 (d, J=13.2Hz, 1H), 4.44 (t, J=4.8Hz, 2H), 4.07–3.94 (m, 2H), 3.53 (s, 3H), 3.16 (q, J=6.8Hz, 3H), 2.94–2.78 (m, 1H), 2.76–2.64 (m, 1H), 2.35 (q, J=7.4Hz, 2H), 2.11 (s, 3H), 1.99 (s, 2H), 1.92–1.74 (m, 1H), 1.67–1.45 (m, 3H), 1.43–1.30 (m, 6H), 1.30–1.20 (m, 4H), 1.20–1.13 (m, 1H).

[0228] Example 66: 5-((9-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-9-oxononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C30). Compound C30 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 7.98 (s, 1H), 7.79 (d, J = 9.6Hz, 2H), 7.64–7.50 (m, 2H), 7.40 (d, J = 8.4Hz, 1 H), 7.12 (t, 1H), 6.93 (s, 1H), 6.83 (d, J = 8.4Hz, 1H), 5.10–4.93 (m, 1H), 4.71 (s, 2H), 4.51 (d, J = 12.0Hz, 1H), 4.45 (t, J=4.8Hz, 2H), 4.01 (d, J=13.6Hz, 1H), 3.53 (s, 3H), 3.15 (d, J=7.8Hz, 3H), 2.93–2.77 (m, 1H), 2.75–2.62 (m, 1 H), 2.38–2.25(m, 2H), 2.11(s, 3H), 2.05–1.93(m, 2H), 1.93–1.71(m, 3H), 1.62–1.46(m, 4H), 1.43–1.16(m, 11H).

[0229] Example 67: 5-((10-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-10-oxodecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C31). Compound C31 was synthesized by the method of Example 59. 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.59–7.47 (m, 2H), 7.38 (s, 1H), 7.33–7.22 (m, 2H), 6 .87 (s, 1H), 6.67 (d, J = 8.4Hz, 1H), 5.02–4.82 (m, 2H), 4.74 (d, J = 13.2Hz, 1H), 4.50 (d, J = 5.9Hz, 2H), 4.30 (t, J = 5.6Hz, 2H), 4.03 (d, J=13.6Hz, 1H), 3.60 (s, 3H), 3.30–3.01 (m, 4H), 2.87–2.75 (m, 1H), 2.68 (t, J=13.2Hz, 3H) , 2.45–2.25(m, 2H), 2.20(s, 3H), 2.15–2.01(m, 2H), 2.01–1.84(m, 2H), 1.68–1.52(m, 5H), 1.41–1.24(m, 10H).

[0230] Example 68: 5-((11-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-11-oxoundecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C32). Compound C32 was synthesized by the method of Example 59. 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.96 (d, J=2.8Hz, 1H), 7.80 (t, J=2.8, 1. 2Hz, 1H), 7.76 (d, J=1.6Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4, 1.6Hz, 1 H), 7.27 (t, J=7.8Hz, 1H), 6.94–6.89 (m, 1H), 6.72 (d, J=8.0Hz, 1H), 5.55 (t, J= 5.6Hz, 1H), 5.11 (dd, J=13.2, 5.1Hz, 1H), 4.70 (t, J=5.2Hz, 2H), 4.50 (d, J=13.2 Hz, 1H), 4.44 (t, J=4.8Hz, 2H), 4.25–4.09 (m, 2H), 4.00 (d, J=14.2Hz, 1H), 3.53 (s, 3H), 3.32–3.22 (m, 1H), 3.18 (d, J=12.6Hz, 1H), 3.10 (q, J=6.8Hz, 2H), 2.92( ddd, J=17.2, 13.6, 5.2Hz, 1H), 2.76–2.57 (m, 2H), 2.40–2.23 (m, 3H), 2.11 (s, 3H) ), 2.08–1.98(m, 1H), 1.91–1.74(m, 2H), 1.72–1.45(m, 2H), 1.41–1.27(m, 14H).

[0231] Example 69: 5-((12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-12-oxododecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C33). Compound C33 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 7.96 (d, J=2.6Hz, 1H), 7.82–7.73 (m, 2H), 7. 56 (t, J=8.2Hz, 2H), 7.38 (dd, J=8.5, 1.7Hz, 1H), 7.09 (t, J=5.4Hz, 1H), 6.93 (d, J=2 .1Hz, 1H), 6.83 (dd, J=8.4, 2.1Hz, 1H), 5.03 (dd, J=12.9, 5.4Hz, 1H), 4.70 (t, J=5. 0Hz, 2H), 4.50 (d, J=13.1Hz, 1H), 4.44 (t, J=4.9Hz, 2H), 4.36 (t, J=5.1Hz, 1H), 4.00 (d, J=13.5Hz, 1H), 3.53 (s, 3H), 3.44 (qd, J=7.1, 5.2Hz, 1H), 3.31–3.24 (m, 1H), 3. 23–3.06 (m, 3H), 2.87 (ddd, J=17.5, 14.0, 5.5Hz, 1H), 2.77–2.64 (m, 1H), 2.62–2.52 (m, 2H), 2.32 (hept, J=7.8Hz, 2H), 2.10 (s, 3H), 2.03–1.93 (m, 1H), 1.93–1.76 (m, 2H ), 1.63 (dd, J=16.0, 12.5Hz, 1H), 1.53 (dq, J=11.2, 6.9Hz, 4H), 1.40–1.20 (m, 13H).

[0232] Example 70: 5-((13-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-13-oxotridecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C34). Compound C34 was synthesized by the method of Example 59. 1H NMR (400MHz, CDCl3) δ8.37 (d, J=8.8Hz, 1H), 7.73 (d, J=8.3Hz, 1H), 7.59–7.51 (m, 2H), 7.40 (d, J=2.6Hz, 1H), 7.35–7.27 (m, 2H), 6.92 (d, J=2.2Hz, 1H), 6.71 (dd, J=8.5, 2.2Hz, 1H), 4.94–4.85 (m, 1H), 4.77 (dd, J=10.8, 4.8Hz, 2H), 4.53 (t, J=5 .1Hz, 2H), 4.32 (t, J=5.0Hz, 2H), 4.09–3.99 (m, 1H), 3.63 (s, 3H), 3.22–3.04 (m, 5H), 2.90–2.63 (m, 4H), 2.35 (td, J=7.4, 3.6Hz, 2H), 2.23(s, 3H), 2.19–2.06(m, 2H), 2.03–1.86(m, 6H), 1.68–1.55(m, 6H), 1.53–1.45(m, 4H), 1.43–1.19(m, 5H).

[0233] Example 71: 5-((14-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-14-oxotetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C35). Compound C35 was synthesized by the method of Example 59. 1H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 7.98 (d, J = 2.8Hz, 1H), 7.80 (d, J = 2.8Hz, 2H), 7.57 (dd, J = 19.6, 8.4Hz, 2H), 7.43 (d, J = 8.8Hz, 1H), 7.10 (t, J=5.6Hz, 1H), 6.93 (s, 1H), 6.83 (dd, J=8.4, 2.0Hz, 1H), 5.03 (dd, J=12.8, 5.6Hz, 1H), 4.73 (t, J=5.2Hz, 2H), 4.51 (d, J=13.2Hz, 1H), 4.46 (t, J=4 .8Hz, 2H), 4.09–3.93(m, 1H), 3.68–3.56(m, 1H), 3.54(s, 2H), 3.21–3.0 7 (m, 3H), 2.87 (ddd, J=18.0, 14.0, 5.6Hz, 1H), 2.70 (t, J=12.0Hz, 1H), 2. 65–2.52(m, 1H), 2.39–2.29(m, 2H), 2.10(s, 3H), 2.03–1.94(m, 1H), 1.94 –1.75(m, 2H), 1.73–1.60(m, 1H), 1.60–1.44(m, 4H), 1.41–1.23(m, 21H).

[0234] Example 72: 3-(4-((2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C36)

[0235]

[0236] Step 1: (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycine tert-butyl ester (Intermediate 49)

[0237] 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 1.16 mmol) and tert-butyl bromoacetate (271 mg, 1.39 mmol) were dissolved in NMP (5 mL), and DIPEA (449 mg, 3.48 mmol) was added thereto and reacted at 130° C. overnight. The mixture was extracted with EA, and the organic phases were combined, washed with water several times, washed once with saturated brine, and dried by spin drying. 132 mg (30%) of white solid was obtained by column chromatography. 1H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.36 (t, J=7.7Hz, 1H), 7.30 (d, J=7.1Hz, 1H), 6.68 (d, J=7.6Hz, 1H), 5.23 (dd, J=13.2, 5.2Hz, 1H), 4. 35 (d, J=15.5Hz, 1H), 4.20 (d, J=15.5Hz, 1H), 3.92–3.86 (m, 2H), 2.89–2.77 (m, 2H), 2.33–2.25 (m, 1H), 2.23–2.14 (m, 1H), 1.50 (s, 9H).

[0238] Step 2: 3-(4-((2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C36)

[0239] Compound C36 was synthesized by the method of Step 2 of Reference Example 38. 1 H NMR (400MHz, DMSO-d6) δ11.02 (d, J=7.9Hz, 1H), 7.97 (d, J=2.7Hz, 1H), 7.85–7.75 (m, 2H), 7.58 (d, J=8.4Hz, 1H), 7.40 (dd , J=8.4, 1.7Hz, 1H), 7.31 (t, J=7.7Hz, 1H), 7.00 (dd, J=7.5, 0.8Hz, 1H), 6.82 (dd, J=8.1, 0.8Hz, 1H), 5.61 (s, 1H), 5.13 (dd . 03–2.79 (m, 2H), 2.62 (d, J=17.1Hz, 1H), 2.39 (qd, J=13.4, 4.6Hz, 1H), 2.11 (s, 3H), 2.06–1.86 (m, 4H), 1.78–1.67 (m, 1H).

[0240] Example 73: 3-(4-((4-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C37). Compound C37 was synthesized by the method of Example 72. 1 H NMR (400MHz, DMSO-d6) δ11.04–10.99 (m, 1H), 7.97 (d, J=2.7Hz, 1H), 7.80 (dd, J=2.7, 1.2Hz, 1H), 7.76 (d, J=1.7Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.39 (dd, J=8 .4, 1.7Hz, 1H), 7.30 (t, J=7.7Hz, 1H), 6.93 (dd, J=7.4, 0.8Hz, 1H), 6.81 (dd, J =8.1, 0.8Hz, 1H), 5.70 (t, J = 5.6Hz, 1H), 5.11 (dd, J = 13.2, 5.1Hz, 1H), 4.70 (t, J=5.0Hz, 2H), 4.54(d, J=13.0Hz, 1H), 4.44(t, J=4.9Hz, 2H), 4.33–4.09(m, 2H ), 3.54(s, 3H), 3.37–3.24(m, 1H), 3.24–3.09(m, 3H), 2.97–2.85(m, 1H), 2.73( t, J=12.3Hz, 1H), 2.64–2.55 (m, 1H), 2.52–2.43 (m, 1H), 2.30 (qd, J=13.2, 4.5 Hz, 2H), 2.11 (s, 3H), 2.08–1.99 (m, 2H), 1.94–1.75 (m, 5H), 1.75–1.60 (m, 1H).

[0241] Example 74: 3-(4-((5-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C38). Compound C38 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.93 (d, J=2.7Hz, 1H), 7.74 (dd, J=16.1, 2 .2Hz, 2H), 7.53 (d, J=8.5Hz, 1H), 7.35 (dd, J=8.5, 1.8Hz, 1H), 7.25 (t, J=7.7Hz, 1 H), 6.89 (d, J=7.4Hz, 1H), 6.74 (d, J=8.1Hz, 1H), 5.58 (t, J=5.5Hz, 1H), 5.07 (dd, J=13.3, 5.1Hz, 1H), 4.66 (t, J=5.0Hz, 2H), 4.47 (d, J=13.1Hz, 1H), 4.40 (t, J=5.0 Hz, 2H), 4.27–4.06 (m, 2H), 3.96 (dd, J=15.6, 10.1Hz, 1H), 3.50 (s, 3H), 3.27–3.2 0 (m, 1H), 3.19–3.05 (m, 3H), 2.87 (ddd, J=18.6, 13.7, 5.4Hz, 1H), 2.67 (td, J=12. 4, 11.8, 5.3Hz, 1H), 2.61–2.50 (m, 1H), 2.37 (d, J=7.3Hz, 2H), 2.25 (qd, J=13.3, 4 .5Hz, 1H), 2.07(s, 3H), 2.03–1.91(m, 1H), 1.88–1.70(m, 3H), 1.68–1.53(m, 5H).

[0242] Example 75: 3-(4-((6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C39). Compound C39 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.96 (d, J=2.9Hz, 1H), 7.78 (dd, J=16.5, 2.1Hz, 2H), 7.57 (d, J=8.4Hz, 1H), 7.39 (dd, J=8.4, 1.7Hz, 1H), 7.28 (t, J=7.7Hz , 1H), 6.92 (d, J=7.3Hz, 1H), 6.75 (d, J=8.2Hz, 1H), 5.59 (s, 1H), 5.10 (dd, J=13. 3, 5.1Hz, 1H), 4.70 (t, J=5.1Hz, 2H), 4.51 (d, J=13.0Hz, 1H), 4.44 (t, J=5.0Hz, 2 H), 4.30–4.09 (m, 2H), 4.00 (d, J=13.6Hz, 1H), 3.53 (s, 3H), 3.29 (td, J=11.0, 5. 5Hz, 1H), 3.22–3.08 (m, 4H), 2.91 (ddd, J=17.8, 13.6, 5.4Hz, 1H), 2.71 (t, J=11. 7Hz, 1H), 2.65–2.56 (m, 1H), 2.37 (q, J=7.0Hz, 1H), 2.33–2.20 (m, 1H), 2.11 (s, 3 H), 2.08–1.97(m, 1H), 1.94–1.75(m, 3H), 1.73–1.50(m, 5H), 1.47–1.37(m, 2H).

[0243] Example 76: 3-(4-((7-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-oxoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C40). Compound C40 was synthesized by the method of Example 72. 1H NMR (400MHz, CDCl3) δ9.40 (d, J=48.8Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 7.52 (d, J=2.6Hz, 1H), 7.41 (d, J=2.6Hz, 1H), 7.29 (d, J=3.5Hz , 2H), 7.27 (s, 2H), 7.13 (dd, J=7.4, 2.2Hz, 1H), 6.72 (d, J=8.1Hz, 1H), 5.12–5.02 (m, 1H), 4.71 (d, J=13.2Hz, 1H), 4.52 (t, J=5.6Hz , 2H), 4.30 (t, J=5.2Hz, 2H), 4.23 (d, J=16.0Hz, 1H), 4.12 (d, J=16.0Hz, 1H), 4.00 (d, J=13.6Hz, 1H), 3.59 (s, 3H), 3.20–3.06 (m, 4H ), 2.75–2.62(m, 3H), 2.42–2.27(m, 2H), 2.20(s, 3H), 2.15–2.03(m, 1H), 1.98–1.84(m, 3H), 1.71–1.56(m, 4H), 1.49–1.33(m, 6H).

[0244] Example 77: 3-(4-((8-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-8-oxooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C41). Compound C41 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.96 (d, J=2.4Hz, 1H), 7.80 (t, J=2.8, 1.2Hz, 1H), 7.76 (d, J=1.6Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4, 1. 6Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 6.95–6.88 (m, 1H), 6.74 (dd, J=8.4, 0.8Hz, 1 H), 5.57 (t, J=5.6Hz, 1H), 5.11 (dd, J=13.2, 5.2Hz, 1H), 4.70 (t, J=4.8Hz, 2H) , 4.50 (d, J = 13.2Hz, 1H), 4.44 (t, J = 4.8Hz, 2H), 4.27–4.09 (m, 2H), 4.00 (d, J =13.6Hz, 1H), 3.54(s, 3H), 3.32–3.23(m, 1H), 3.21–3.07(m, 3H), 2.92(ddd, J=17.2, 13.6, 5.2Hz, 1H), 2.74–2.57 (m, 2H), 2.41–2.24 (m, 3H), 2.11 (s, 3H) , 2.07–1.98(m, 1H), 1.87-1.77(m, 3H), 1.72–1.47(m, 5H), 1.44–1.28(m, 6H).

[0245] Example 78: 3-(4-((9-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-9-oxononyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C42). Compound C42 was synthesized by the method of Example 72. 1H NMR (400MHz, CDCl3) δ8.80 (d, J=25.6Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.53 (d, J=2.4Hz, 1H), 7.40 (d, J=2.4Hz, 1H), 7.36–7.29 (m, 2H), 7.28 (s, 1H), 7.21 (d, J=7.6Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 5.18 (dt, J=13.2, 5.2, 2.8Hz, 1H), 4.76 (d, J=13.6Hz, 1H), 4.53 (t, J=5.6Hz , 2H), 4.32 (t, J = 5.2Hz, 2H), 4.26 (d, J = 2.4Hz, 1H), 4.13 (d, J = 15.6Hz, 1H), 4.08–4.01 (m, 1H), 3.71 (s, 1H), 3.63 (s, 3H), 3.25–3.07 (m , 4H), 2.88–2.66(m, 3H), 2.40–2.25(m, 2H), 2.23(s, 3H), 2.19–2.05(m, 2H), 2.03–1.87(m, 4H), 1.71–1.57(m, 4H), 1.45–1.31(m, 8H).

[0246] Example 79: 3-(4-((10-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-10-oxodecanyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C43). Compound C43 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ 11.01 (s, 1H), 7.96 (d, J = 2.7Hz, 1H), 7.77 (d, J = 16.1Hz, 2H), 7.56 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.7Hz, 1H), 7.27 (t , J=7.8Hz, 1H), 6.91 (d, J=7.7Hz, 1H), 6.72 (d, J=8.2Hz, 1H), 5.56 (d, J=6.0Hz, 1H), 5.11 (dd, J=13.5, 5.4Hz, 1H), 4.90–4.65 (m, 2H), 4.61 –4.42 (m, 4H), 4.36–4.10 (m, 3H), 4.00 (d, J=12.4Hz, 1H), 3.54 (d, J=4.7Hz, 3H), 3.22–3.04 (m, 2H), 2.92 (ddd, J=18.0, 13.7, 5.7Hz, 1H), 2 .77–2.56 (m, 2H), 2.48–2.21 (m, 3H), 2.11 (s, 3H), 2.02 (d, J = 13.5Hz, 1H), 1.85 (d, J = 13.8Hz, 1H), 1.70–1.46 (m, 3H), 1.46–1.18 (m, 13H).

[0247] Example 80: 3-(4-((11-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-11-oxoundecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C44). Compound C44 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.96 (d, J=2.8Hz, 1H), 7.81–7.73 (m, 2H ), 7.56 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.0, 1.6Hz, 1H), 7.27 (t, J=7.6Hz, 1H), 6. 92 (d, J=7.6Hz, 1H), 6.73 (d, J=8.0Hz, 1H), 5.56 (t, J=5.6Hz, 1H), 5.11 (dd, J=1 3.2, 5.2Hz, 1H), 4.70 (t, J=5.2Hz, 2H), 4.50 (d, J=12.8Hz, 1H), 4.44 (t, J=4.8H z, 2H), 4.31–4.06 (m, 2H), 4.00 (d, J=13.6Hz, 1H), 3.53 (s, 3H), 3.32–3.23 (m, 1H), 3.22–3.14(m, 1H), 3.10(q, J=6.8Hz, 2H), 2.92(ddd, J=17.2, 13.6, 5.6Hz, 1H), 2.69 (t, J=12.8Hz, 1H), 2.65–2.56 (m, 1H), 2.41–2.22 (m, 3H), 2.11 (s, 3H) , 2.08–1.97(m, 1H), 1.94–1.73(m, 3H), 1.71–1.45(m, 4H), 1.41–1.24(m, 13H).

[0248] Example 81: 3-(4-((12-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-12-oxododecanyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C45). Compound C45 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.96 (d, J = 2.6Hz, 1H), 7.83–7.73 (m, 2H), 7.57 (d, J = 8.4Hz, 1H), 7.38 (dd, J = 8.4, 1.7Hz, 1H), 7.27 (t, J = 7.7Hz, 1 H), 6.92 (d, J=7.7Hz, 1H), 6.72 (d, J=8.0Hz, 1H), 5.55 (t, J=5.5Hz, 1H), 5.1 1(dd, J=13.2, 5.1Hz, 1H), 4.70 (t, J=5.2Hz, 2H), 4.50 (d, J=13.1Hz, 1H), 4.4 4(t, J=4.9Hz, 2H), 4.30–4.08(m, 2H), 4.00(d, J=14.2Hz, 1H), 3.53(s, 3H), 3.33–3.23 (m, 0H), 3.21–3.05 (m, 3H), 2.92 (ddd, J=17.2, 13.5, 5.4Hz, 1H), 2 .70(t, J=12.5Hz, 1H), 2.66–2.57(m, 1H), 2.42–2.22(m, 3H), 2.11(s, 3H), 2 .06–1.96(m,1H), 1.95–1.73(m,3H), 1.72–1.40(m,4H), 1.39–1.25(m,16H).

[0249] Example 82: 3-(4-((13-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-13-oxotridecanyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C46). Compound C46 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 9.29 (s, 1H), 7.98 (d, J=2.6Hz, 1H), 7.80 (dd , J=2.7, 1.3Hz, 1H), 7.77 (d, J=1.7Hz, 1H), 7.56 (d, J=8.3Hz, 1H), 7.38 (dd, J=8.4, 1.7Hz, 1H), 7.27 (t, J=7.7Hz, 1H), 6.91 (d, J=7.1Hz, 1H), 6.72 (d, J=8.0Hz, 1H), 5. 57 (t, J=5.5Hz, 1H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.70 (t, J=5.1Hz, 2H), 4.50 (d, J =13.1Hz, 1H), 4.44 (t, J = 4.9Hz, 2H), 4.30–4.08 (m, 2H), 4.02–3.89 (m, 2H), 3.68–3 .56(m, 2H), 3.53(s, 3H), 3.32–3.22(m, 1H), 3.21–3.02(m, 6H), 2.92(ddd, J=17.3, 13.5, 5.3Hz, 1H), 2.77–2.66(m, 1H), 2.65–2.57(m, 1H), 2.39–2.22(m, 3H), 2.10(s , 3H), 2.07–1.99(m, 1H), 1.92–1.73(m, 2H), 1.69–1.45(m, 4H), 1.39–1.20(m, 11H).

[0250] Example 83: 3-(4-((14-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-14-oxotetradecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C47). Compound C47 was synthesized by the method of Example 72. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.96 (d, J=2.6Hz, 1H), 7.80 (dd, J=2.7, 1.3H z, 1H), 7.76 (d, J=1.7Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4, 1.7Hz, 1H), 7 .27(t, J=7.7Hz, 1H), 6.97–6.89(m, 1H), 6.72(d, J=8.0Hz, 1H), 5.55(t, J=5.5Hz, 1 H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.70 (t, J=4.9Hz, 2H), 4.50 (d, J=13.1Hz, 1H), 4.4 4(t, J=4.9Hz, 2H), 4.26–4.08(m, 2H), 3.99(d, J=13.6Hz, 1H), 3.53(s, 3H), 3.32–3 .23 (m, 1H), 3.18 (d, J=12.8Hz, 1H), 3.09 (q, J=6.7Hz, 2H), 2.92 (ddd, J=17.3, 13.6 , 5.4Hz, 1H), 2.70 (t, J=12.6Hz, 1H), 2.64–2.57 (m, 1H), 2.40–2.21 (m, 3H), 2.10 (s , 3H), 2.07–1.96 (m, 1H), 1.93–1.74 (m, 2H), 1.72–1.42 (m, 3H), 1.39–1.20 (m, 21H).

[0251] Example 84: 4-(3-((4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C48). C48 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ8.14 (s, 1H), 7.76 (d, J=8.4Hz, 1H), 7.53 (dd, J=2.7, 1.3Hz, 1H), 7.45 (dd, J=8.5, 7. 1Hz, 1H), 7.39 (d, J=2.6Hz, 1H), 7.31 (dd, J=8.4, 1.7Hz, 1H), 7.17 (d, J=7.0Hz, 1H), 6.59 (d, J=8.5Hz, 1H) , 4.92 (dd, J=12.1, 5.3Hz, 1H), 4.50 (t, J=5.4Hz, 2H), 4.43 (t, J=8.4Hz, 2H), 4.31 (t, J=5.3Hz, 2H), 3.96 ( s, 2H), 3.65 (s, 3H), 3.10 (s, 4H), 2.93–2.69 (m, 4H), 2.25 (s, 3H), 2.22–2.03 (m, 15H), 2.01–1.79 (m, 4H).

[0252] Example 85: 4-(4-((4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C49). C49 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 8.15 (t, J=1.2Hz, 1H), 7.84 (dd, J=7.2, 1.2Hz, 1H), 7.67–7.62 (m, 1H), 7.58 (p, J=1.3Hz, 1H), 7.50 (s, 1 H), 7.41–7.36 (m, 2H), 7.20 (dd, J=7.3, 1.1Hz, 1H), 5.49 (t, J=3.6Hz, 1H), 4.49 (t, J=7.0Hz, 2H), 3.92 (t, J=7.1Hz, 2H), 3.40 (ddd, J=12.3, 8.4, 6.2Hz, 2H), 3.33 (d, J=1.1Hz, 3H), 3.18 (p, J=5.1Hz, 1H), 3.12 (ddd, J=12.4, 8.3, 6.2Hz, 2H), 2.87–2.74 (m, 4H), 2.69 (ddd, J=12.4, 7 .8, 6.1Hz, 2H), 2.65–2.48 (m, 9H), 2.21 (dddd, J=12.5, 7.0, 4.5, 3.7Hz, 1H), 2.08 (d, J=1.3Hz, 3H), 2.06–1.91 (m, 3H), 1.91–1.61 (m, 10H).

[0253] Example 86: 3-(4-(4-(2-(4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C50). C50 was synthesized according to the method of Example 56. 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 8.15 (p, J = 0.9Hz, 1H), 7.84 (dd, J = 7.2, 1.2Hz, 1H), 7.67–7.62 (m, 1H), 7.58 (p, J = 1.3Hz, 1H), 7. 41–7.36 (m, 2H), 7.20 (dd, J=7.3, 1.1Hz, 1H), 5.49 (t, J=3.6Hz, 1H), 4.49 (t, J=7.0Hz, 2H), 3.92 (t, J=7.1Hz, 2H), 3.43 (ddd, J=12. 5, 8.2, 5.7Hz, 2H), 3.33 (d, J = 1.1Hz, 3H), 3.24–3.15 (m, 3H), 2.87–2.74 (m, 6H), 2.66–2.42 (m, 7H), 2.31 (dt, J = 12.2, 8.3Hz, 1H), 2 .21 (dddd, J=12.5, 7.0, 4.5, 3.7Hz, 1H), 2.08 (d, J=1.3Hz, 3H), 2.06–1.91 (m, 4H), 1.82–1.55 (m, 11H), 1.47 (td, J=8.2, 5.9Hz, 2H).

[0254] Example 87: 4-(4-((2-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C51). C51 was synthesized by the method of Reference Example 56. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=8.3Hz, 1H), 7.57–7.50 (m, 2H), 7.41–7.27 (m, 4 H), 7.16 (d, J=8.5Hz, 1H), 4.99–4.90 (m, 1H), 4.50 (d, J=5.4Hz, 2H), 4.31 (t, J=5 .2Hz, 2H), 3.79–3.69(m, 2H), 3.64(s, 3H), 3.22(s, 2H), 3.05(s, 2H), 2.97–2.67 (m, 5H), 2.62–2.29 (m, 7H), 2.24 (s, 3H), 2.19–1.90 (m, 11H), 1.83–1.44 (m, 6H).

[0255] Example 88: 5-(3-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C52). C52 was synthesized by the method of Reference Example 56. 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.77 (dd, J=8.3, 3.9Hz, 1H), 7.65 (dd, J=8.2, 3.9Hz, 1H), 7.5 3(s, 1H), 7.39(s, 1H), 7.34–7.29(m, 1H), 6.78(d, J=3.7Hz, 1H), 6.52(d, J=8.3Hz, 1H), 4.93(t, J=6.2Hz, 1H), 4.50 (s, 0H), 4.31 (d, J=5.0Hz, 2H), 4.17 (s, 2H), 3.76 (s, 2H), 3.65 (d, J=4.1Hz, 3 H), 2.82 (dt, J=46.7, 17.6Hz, 4H), 2.25 (d, J=3.9Hz, 3H), 2.20–2.09 (m, 2H), 1.98–1.67 (m, 12H).

[0256] Example 89: 5-((R)-3-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C53). C53 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ7.77 (d, J=8.3Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.53 (d, J=2.6Hz, 1H), 7.40 (d, J=2.9Hz, 1H), 7.31 (dd, J=8.6, 1.7Hz, 1H), 7.27 (s, 1H), 6.91 (d, J=2.2Hz, 1H), 6.66 (dd, J=8.3, 2.2Hz, 1H), 4.92 (dd, J=12.1, 5.5Hz, 1H), 4.51 (t, J =5.3Hz, 2H), 4.31 (t, J = 5.2Hz, 2H), 3.72 (s, 2H), 3.64 (s, 3H), 3.39 (dt, J = 9.9, 7.6Hz, 1H), 3.31–3.17 (m, 3H), 2.99 (dq, J = 10.6, 4.9, 3.8Hz, 1H), 2.90–2.59 (m, 6H), 2.46 (q, J=12.6Hz, 2H), 2.27–2.20 (m, 5H), 2.12–2.00 (m, 4H), 1.91–1.81 (m, 1H).

[0257] Example 90: 5-(4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C54). C54 was synthesized by the method of Reference Example 56. 1 H NMR (400MHz, CDCl3) δ8.15 (t, J=1.2Hz, 1H), 7.67–7.60 (m, 2H), 7.58 (p, J=1.3Hz, 1H), 7.41–7.36 (m, 2H), 7.34 (d, J= 2.2Hz, 1H), 7.08 (dd, J=7.2, 2.3Hz, 1H), 5.39 (t, J=3.7Hz, 1H), 4.49 (t, J=7.0Hz, 2H), 3.92 (t, J=7.1Hz, 2H), 3.46 (d dd, J=12.4, 8.3, 6.3Hz, 2H), 3.33 (d, J=1.1Hz, 3H), 3.18 (p, J=5.1Hz, 1H), 3.07 (ddd, J=12.4, 8.2, 6.4Hz, 2H), 2.87– 2.74 (m, 4H), 2.66–2.49 (m, 4H), 2.17 (dddd, J=12.4, 7.0, 4.4, 3.6Hz, 1H), 2.08 (d, J=1.3Hz, 3H), 2.06–1.69 (m, 10H).

[0258] Example 91: 5-(3-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-dipiperidin-1'-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C55). C55 was synthesized by the method of Reference Example 56. 1 HNMR (400MHz, CDCl3) δ7.75 (d, J=8.4Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.52 (d, J=8.3Hz, 1H), 7.40 (d, J=2.6Hz, 1H), 7.3 5–7.26 (m, 2H), 6.83 (s, 1H), 6.48 (dd, J=8.2, 2.1Hz, 1H), 4.93 (dd, J=12.0, 5.7Hz, 1H), 4.50 (d, J=5.3Hz, 2H), 4.31 (t , J=5.2Hz, 2H), 4.14 (td, J=8.0, 2.6Hz, 2H), 3.68 (dd, J=8.9, 4.8Hz, 2H), 3.64 (s, 3H), 3.35 (s, 1H), 3.06 (d, J=9.1Hz, 4H), 2.88–2.60 (m, 6H), 2.24 (s, 3H), 2.21–2.08 (m, 7H), 2.05 (s, 2H), 1.98 (d, J=12.9Hz, 3H), 1.78 (d, J=12.0Hz, 2H).

[0259] Example 92: 5-(4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)-[1,4'-dipiperidinyl]-1'-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C56). C56 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ8.15 (t, J=1.2Hz, 1H), 7.67–7.60 (m, 2H), 7.58 (p, J=1.3Hz, 1H), 7.41–7.36 (m, 2H), 7.34 (d, J=2.2Hz, 1H), 7.0 8 (dd, J=7.2, 2.3Hz, 1H), 5.39 (t, J=3.7Hz, 1H), 4.49 (t, J=7.0Hz, 2H), 3.92 (t, J=7.1Hz, 2H), 3.46 (ddd, J=12.4, 8.3, 6.3Hz, 2H), 3. 33 (d, J=1.1Hz, 3H), 3.18 (p, J=5.5Hz, 1H), 3.07 (ddd, J=12.4, 8.2, 6.4Hz, 2H), 2.81–2.71 (m, 4H), 2.71–2.47 (m, 8H), 2.34 (p, J=5.4 Hz, 1H), 2.17 (dddd, J=12.5, 7.0, 4.4, 3.7Hz, 1H), 2.08 (d, J=1.3Hz, 3H), 2.03–1.93 (m, 2H), 1.87–1.71 (m, 10H), 1.61–1.51 (m, 2H).

[0260] Example 93: 5-(3-((4-((4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C57). C57 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ7.76 (dd, J=8.8, 4.7Hz, 1H), 7.62 (dd, J=8.5, 4.6Hz, 1H), 7.54 (d, J=5.7Hz, 1H), 7.39 (d, J=2.7Hz, 1H), 7.30 (d, J=8. 6Hz, 1H), 7.27 (s, 1H), 6.79 (t, J=3.3Hz, 1H), 6.47 (dd, J=8.2, 2.3Hz, 1H), 4.92 (dt, J=12.4, 6.7Hz, 1H), 4.57–4.45 (m, 2H), 4.38–4.26 (m, 2 H), 4.16 (t, J = 7.8Hz, 2H), 3.70 (t, J = 6.5Hz, 2H), 3.64 (d, J = 4.9Hz, 3H), 3.48 (d, J = 4.7Hz, 1H), 3.13 (dt, J = 30.5, 15.1Hz, 5H), 2.99–2.68 ( m, 5H), 2.47–2.27 (m, 3H), 2.24 (s, 3H), 2.22–2.11 (m, 6H), 2.05 (d, J=4.3Hz, 3H), 2.03–1.91 (m, 1H), 1.91–1.77 (m, 2H), 1.75–1.54 (m, 1H).

[0261] Example 94: 5-(3-((6-(4-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)methyl)azetidin-1-yl)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (C58). C58 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ7.76 (d, J=8.3Hz, 1H), 7.62 (d, J=8.2Hz, 1H), 7.53 (s, 1H), 7.39 (d, J=2.6Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 6.86 (t, J=2.4Hz, 1H), 6.47 (d, J=8.3Hz, 1H), 4.92 (dd, J=12.1, 4.9Hz, 1H), 4.49 (t, J=5.2Hz, 2H), 4.30 (t, J=5.2H z, 2H), 4.09 (t, J=7.7Hz, 2H), 3.69 (d, J=5.2Hz, 2H), 3.65 (s, 3H), 3.49 (d, J=1.3Hz, 1H), 3.38 (q, J=7.4Hz, 2H), 3.28 (t, J=8.1H z, 2H), 3.04 (d, J=10.6Hz, 2H), 2.93–2.64 (m, 9H), 2.28 (s, 4H), 2.25 (s, 3H), 2.18–2.07 (m, 4H), 1.64 (dd, J=34.9, 15.5Hz, 1H).

[0262] Example 95: 5-(4-((6-(6-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-azaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (C59). C59 was synthesized by the method of Reference Example 56. 1H NMR (400MHz, CDCl3) δ7.74 (d, J=8.4Hz, 1H), 7.63 (d, J=8.6Hz, 1H), 7.52 (d, J=2.3Hz, 1H), 7.38 (d, J=2.6Hz, 1H), 7.28 (d, J=9.1Hz, 2H), 7. 24 (d, J=1.7Hz, 1H), 7.00 (dd, J=8.6, 2.4Hz, 1H), 4.95–4.87 (m, 1H), 4.47 (d, J=5.4Hz, 2H), 4.29 (t, J=5.4Hz, 2H), 3.92 (t, J=12.4Hz, 2H), 3.62 (s, 3H), 3.33 (s, 2H), 3.24 (s, 2H), 3.05–2.97 (m, 2H), 2.96–2.55 (m, 7H), 2.38 (dd, J=7.1, 2.5Hz, 2H), 2.26 (dd, J=12.2, 7.8Hz, 2H), 2 .23 (s, 3H), 2.14–1.98 (m, 5H), 1.91 (d, J = 11.4Hz, 3H), 1.80 (d, J = 10.5Hz, 2H), 1.62 (tdd, J = 21.2, 12.1, 6.3Hz, 2H), 1.30 (d, J = 9.9Hz, 2H).

[0263] Effect test:

[0264] Establishment of CCK8 method for determining tumor cell proliferation inhibitory activity and compound activity determination

[0265] Tumor cells (THP-1) in the logarithmic growth phase were inoculated into a 96-well plate at a certain cell amount and cultured for 12 hours. Different concentrations of inhibitors were added and the cells were cultured for 96 hours at 37°C and 5% CO2. 10 μL of CCK8 solution was added to each well and cultured for 4 hours. The OD value was measured at a wavelength of 520 nm using an enzyme marker to calculate the antiproliferative activity IC 50 The comparative example is the existing p300 / CBP, BET bromodomain selective inhibitor NEO2734, and the CCK8 detection technology is used to verify the results. The verification results are shown in Table 2:

[0266] Table 2 Antiproliferative activity of compounds on THP-1 cells

[0267]

[0268] It can be found that compared with the positive control NEO2734, it can be found that the compound provided by the present invention has an excellent inhibitory effect on tumor cells.

[0269] Western-blot assay for BET and CBP protein degradation

[0270] The drug-intervention MV4;11 cells were collected, washed twice with pre-cooled PBS, and the protease inhibitors were mixed with RIPA lysis buffer at a ratio of 1:100, and the cells were lysed on ice for 30 minutes. After centrifugation at 4°C, 13000rpm / min×20min, the supernatant was taken, and the protein amount was quantitatively detected by the BCA method. Next, 5×loading was added to the protein and heated at 100°C for 10min. The protein was separated by SDS-PAGE electrophoresis, transferred to the membrane, blocked for 2h, and incubated with the primary antibody at 4°C overnight. The membrane was washed with TBST, incubated with the secondary antibody at 1:1000 for 1.5h, and developed with the gel display system after adding ECL chemiluminescence. The gray value of each band was analyzed with Image J software, and the degradation ratio was obtained by normalization. The inhibitor concentration DC when the protein was degraded by 50% was calculated. 50 and D max The degradation effects of some compounds of the present application on BET and CBP in MV4;11 cells are shown in Table 3. The degradation results of some compounds in Table 3 on BET and CBP targets in MV4;11 cells are shown in Figure 1 .

[0271] Table 3 Degradation activity of compounds on BET and CBP proteins in MV4;11 cells

[0272]

[0273]

[0274] The above results show that the compounds provided by the present invention have excellent BET and CBP / p300 dual-target inhibitory effects.

[0275] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the degradation agent targeting BET and / or CBP / p300 protein and its application, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0276] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0277] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A degradation agent targeting BET and / or CBP / p300 protein, characterized in that: The structure of the degradation agent is selected from Formula I or Formula II: wherein the linking group is selected from Any one of, n is selected from an integer of 1-15; E3 ubiquitin ligase ligands are selected from Any one of; The hydrophobic tag is selected from Any one of; Indicates the group attachment site.

2. The degradation agent according to claim 1, characterized in that The linking group is selected from n is selected from integers of 1-15.

3. The degradation agent according to claim 1 or 2, characterized in that Said n is an integer of 2-12.

4. The degradation agent according to any one of claims 1 to 3, characterized in that The E3 ubiquitin ligase ligand is selected from 5. The degradation agent according to any one of claims 1 to 4, characterized in that The hydrophobic tag is selected from 6. The degradation agent according to any one of claims 1 to 5, characterized in that The degradation agent is selected from any one of the following structural compounds:

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one degrading agent according to any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further comprises any one of a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener or a flavoring agent, or a combination of at least two of them.

9. Use of the degrading agent according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 or 8 in the preparation of a medicament for preventing and / or treating diseases related to BET and / or CBP / p300 overexpression.

10. Use of the degradation agent according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 or 8 in the preparation of a medicament for preventing and / or treating cancer, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.

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