Degrading agent for degrading BRD protein and pharmaceutical composition containing same

Abstract

The present invention relates to a PROTAC compound that binds to BRD4 protein, and the PROTAC compound can bind to and degrade BRD4 protein, making it useful for treating or preventing diseases related to BRD4 protein. The compound of the present invention has excellent anti-cancer effects and can also induce degradation of BRD4 protein, which can show therapeutic effects against BRD4 and related diseases.

Description

[Technical Field]

[0001] The present invention relates to novel PROTAC compounds that bind to the cMET protein and pharmaceutical compositions comprising the same. [Background technology]

[0002] PROTACs are heterodimeric molecules in which a ligand for a target protein and a ligand that binds to an E3 ligase are linked via a linker. PROTACs simultaneously bind to both proteins, bringing the target protein in close proximity to the E3 ligase, which recognizes the target protein as a substrate and triggers polyubiquitination and subsequent proteasomal degradation. Because this principle can effectively remove specific proteins from cells, PROTACs can be used as chemical probes to study the function of target proteins and may also have potential as therapeutic agents for disease. The term TPD (targeted protein degradation) is sometimes used instead of the term PROTAC.

[0003] In the present invention, a target protein binding moiety and an E3 ligase binding moiety that bind to cMET protein were prepared, and a novel PROTAC compound was completed by linking the E3 ligase binding moiety and the cMET protein target binding moiety via a linker. Summary of the Invention [Problem to be solved by the invention]

[0004] The technical problem intended to be solved by the present invention relates to a PROTAC linked to a novel E3 ligase binding moiety and a cMET protein target binding moiety via a linker, as well as pharmaceutical compositions comprising the same. [Means for solving the problem]

[0005] In order to achieve the technical task, the present invention provides a TPD compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] BRD4 target protein binding domain (P)-{linker (L)}p-E3 ligase binding domain (E) During the ceremony, The E3 ligase binding moiety (E) has a structure represented by the following chemical formula 2 or 3: The BRD4 target protein binding moiety (P) has the structure shown in Formula 4 or 5 below: p is an integer of 0 or 1, [ka] During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 linear or branched alkyloxy, or a heterocycle containing 4 to 8 rings and containing oxygen or nitrogen; Q1 to Q4 are each independently CF, C—Cl, CH, CX, or N, and at least one of Q1 to Q4 is CX; Y is H, halogen, or C1-C6 straight or branched chain alkyl unsubstituted or optionally substituted with halogen or cyclic alkyloxy; Z is the moiety to which one end of the linker is attached, R 1 is hydrogen, nitro, amino, carbonyl, C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain alkyl substituted with halogen, or cycloalkyl.

[0006] In the present invention, the other end of the linker (L) is (i) replacing X in the structure of chemical formula 2 and connecting to the structure of chemical formula 1; or (ii) It is bonded to the nitrogen atom or oxygen atom of X in the structure of Chemical Formula 2.

[0007] In the present invention, the linker (L) is [ka] or a structure selected from the group of formulas: [ka] In the formula, R2 and R3 each independently represent unsubstituted or substituted C1-C4 alkyl, piperidine, piperazine, -(CH2) s -, -(CH2) q -[O(C2H4)] r -, -O-(CH2)-, benzene or morpholine; Q5 and Q6 are independently a carbon atom or a nitrogen atom; m, n, q, r, s, t, and u are each independently an integer selected from 0 to 7.

[0008] Additionally, the present invention relates to an anticancer composition comprising the above compound. [Effects of the Invention]

[0009] The present invention relates to a PROTAC compound that binds to cMET protein and can degrade it, making it useful for treating or preventing diseases associated with cMET protein. The compound of the present invention has excellent anti-cancer effects and can also induce degradation of cMET protein, which can exhibit therapeutic effects against cMET and related diseases. [Brief explanation of the drawings]

[0010] [Figure 1] Schematic of a PROTAC compound consisting of an E3 ligase binding moiety, a linker, and a target protein binding moiety. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0012] The terms used in this specification are used only to describe specific embodiments and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. The "including" of an element in the present specification means that it may include more of the other elements rather than excluding other elements, unless otherwise specified.

[0013] The PROTAC according to the present invention may be a compound of formula 1:

[0014] [Chemical formula 1] cMET target protein binding matrix (P)-[linker (L)]p-E3 ligase binding matrix (E) The basic framework of the E3 ligase binding portion according to the present invention can be prepared through the reaction steps of the following formula 1 or formula 2.

[0015] The basic framework of the E3 ligase binding portion according to the present invention can be prepared through the reaction steps of the following formula 1 or formula 2. [Reaction Scheme 1] [ka] [Reaction Scheme 2] [ka]

[0016] In Reaction Scheme 1 or 2, X is hydrogen, halogen, amino, nitro, hydroxy, piperazine group, or C1-C4 alkoxy. However, for convenience of explanation, in the above formula, the substituents that can be bonded to carbons at Q1-Q4 of the compound of Formula 1 are omitted, and R 1 Among the substituents, only simple substituents such as hydrogen or methyl are represented.

[0017] Below, embodiments are used to prepare specific examples of E3 ligase binding moiety compounds.

[0018] Example A: Preparation of E3 Ligase Ligating Moiety Compounds Example A-1: ​​Compound [ka] Preparation of (prepared according to reaction scheme 1) 1-1) Preparation of methyl 2-methyl-6-nitrobenzoate [ka] At room temperature, K2CO3 (19.1 g, 138 mmol) was added to a solution of 2-methyl-6-nitrobenzoic acid (5 g, 27.6 mmol) in acetone (100 ml). After stirring for 30 minutes, iodomethane (19.6 g, 138 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product was used in the next reaction without further purification. (5.45 g, 98%) MS (ESI, m / z): [M+1] + =[195.2].

[0019] 1-2) Preparation of methyl 2-(bromomethyl)-6-nitrobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carboroxoate (0.67 g, 7.26 mmol) were added sequentially to a solution of methyl 2-methyl-6-nitrobenzoate (5.39 g, 27.6 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0020] 1-3) Preparation of methyl 2-formyl-6-nitrobenzoate [ka] At room temperature, NMO (N-methylmorpholine N-oxide) (561 mg, 4.87 mmol) and molecular sieves at 4°C were added sequentially to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (10 ml). The DCM layer was washed with water (50 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0021] 1-4) Preparation of 2-formyl-6-nitrobenzoic acid [ka] At room temperature, a solution (10 ml) of lithium (+1) hydroxylate (1.15 g, 47.8 mmol) in water was added to a solution of methyl 2-formyl-6-nitrobenzoate (2 g, 9.56 mmol) in THF (10 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0022] 1-5) Formulated with 8-nitroptalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (417 mg, 8.33 mmol) was added to a solution of 2-formyl-6-nitrobenzoic acid (1.2 g, 6.15 mmol) in methanol (10 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0023] 1-6) 3-(8-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione Preparation [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 8-nitro-1,2-dihydrodroprazine-1-one (60 mg, 0.314 mmol) in DMF (1 ml). The reaction was heated to 85 °C for 5 h. After cold soaking, the reaction was poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (68 mg, 71.7%). MS (ESI, m / z): [M+1] + =[302.6].

[0024] 1-7) 3-(8-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione Preparation [ka] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(8-nitro-1-oxo-1,2-dihydropoptarazin-2-yl)piperidine-2,6-dione (25 mg, 0.82 mmol) in methanol (5 ml) and stirred under hydrogen in a balloon for 1 hour. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound in 99% yield. MS (ESI, m / z): [M+1] + =[272.3].

number

[0025] Example A-2: Compound [ka] Preparation of 2-1) Preparation of methyl 2-methyl-3-nitrobenzoate [ka] At room temperature, K2CO3 (19.1 g, 138 mmol) was added to a solution of 2-methyl-3-nitrobenzoic acid (5 g, 27.6 mmol) in acetone (100 ml). After stirring for 30 minutes, iodomethane (19.6 g, 138 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product was used in the next reaction without further purification. (5.45 g, 98%) MS (ESI, m / z): [M+1] + =[195.3].

[0026] 2-2) Preparation of methyl 2-(bromomethyl)-3-nitrobenzoate [ka] At room temperature, 1-bromophilidine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carbophoroxoate (0.67 g, 7.26 mmol) were added sequentially to a solution of methyl 2-methyl-3-nitrobenzoate (5.39 g, 27.6 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0027] 2-3) Preparation of methyl 2-formyl-3-nitrobenzoate [ka] At room temperature, NMO (561 mg, 4.87 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-3-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (10 ml). The DCM layer was washed with water (50 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0028] 2-4) Preparation of 2-formyl-3-nitrobenzoic acid [ka] At room temperature, an aqueous solution of lithium hydroxide (+1) (1.15 g, 47.8 mmol) was added to a solution of methyl 2-formyl-3-nitrobenzoate (2 g, 9.56 mmol) in THF (10 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0029] 2-5) Preparation of 5-nitrobutalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (417 mg, 8.33 mmol) was added to a solution of 2-formyl-3-nitrobenzoic acid (1.2 g, 6.15 mmol) in methanol (10 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0030] 2-6) Preparation of 3-(5-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 5-nitrophthalazin-1(2H)-one (60 mg, 0.314 mmol) in DMF (1 ml). The reaction was heated to 85 °C for 5 h. After cooling, the reaction was poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (68 mg, 71.7%). MS (ESI, m / z): [M+1] + =[302.4].

[0031] 2-7) Preparation of 3-(5-amino-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 20 mg of 10% Pd / C (wet) (5 mg) (5 mg) was added to a solution of 3-(5-nitro-1-oxoptalazin-2(1H)-yl) in methanol (5 ml) and stirred under hydrogen in a balloon for 1 hour. The solid was filtered and the filtrate was concentrated under reduced pressure to give the title compound in 99% yield. MS (ESI, m / z): [M+1] + =[272.3].

number

[0032] Example A-3: Compound [ka] Preparation of 3-1) Preparation of methyl 2-fluoro-6-methylbenzoate [ka] At room temperature, K2CO3 (44.8 g, 324 mmol) was added to a solution of 2-fluoro-6-methylbenzoic acid (10 g, 64.9 mmol) in acetone (200 ml). After stirring for 30 minutes, iodomethane (46 g, 324 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under gunk. The product was used in the next reaction without further purification. (11.2 g, 103%) MS (ESI, m / z): [M+1] + =[168.3].

[0033] 3-2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (24.7 g, 139 mmol) and benzoyl benzoperoxoate (1.53 g, 6.30 mmol) were added sequentially to a solution of methyl 2-fluoro-6-methylbenzoate (21.2 g, 126 mmol) in ClCH2CHCl (250 ml). The reaction was heated to reflux for 16 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (35 g, 112% yield) MS (ESI, m / z): [M+1] + =[245.9].

[0034] 3-3) Preparation of methyl 2-fluoro-6-formylbenzoate [ka] At room temperature, NMO (24.9 g, 212 mmol) was added to a solution of methyl 2-(bromomethyl)-6-fluorobenzoate (35 g, 142 mmol) in DCM (280 ml). The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (11.52 g, 45%) MS (ESI, m / z): [M+1] + =[183.1].

[0035] 3-4) Preparation of 2-fluoro-6-formylbenzoic acid [ka] At room temperature, an aqueous solution (41 ml) of lithium hydroxide (+1) (7.57 g, 180 mmol) was added to a solution of methyl 2-fluoro-6-formylbenzoate (11.5 g, 63.2 mmol) in THF (82 ml). After stirring for 4 hours, the reaction was concentrated under reduced pressure and the THF was dried. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (100 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (10.4 g, 97.8%). MS (ESI, m / z): [M+1] + =[168.8].

[0036] 3-5) Preparation of 8-fluorothalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (3.72 mg, 61.9 mmol) was added to a solution of 2-fluoro-6-formylbenzoic acid (10.4 g, 61.9 mmol) in methanol (120 ml) and stirred at room temperature for 16 hours. The white precipitate was filtered and washed with methanol. The resulting white crystals were slurried in 100 ml of ethyl acetate (EA) and filtered to give white crystals (3.05 g, 30%). MS (ESI, m / z): [M+1] + =[164.8].

[0037] 3-6) Preparation of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] NaH (60%, 53.6 mg, 1.34 mmol) was added to a solution of 8-fluorotalazine-1(2H)-one (200 mg, 1.22 mmol) in DMF (5 ml) at 0° C. and stirred for 30 minutes. 3-Bromoperidine-2,6-dione (468 mg, 2.44 mmol) was added to the solution and stirred for 6 hours. The reaction was quenched with water and extracted twice with ethyl acetate (20 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (70 mg, 20.8%). MS (ESI, m / z): [M+1] + =[276.1].

number

[0038] Example A-4: Preparation of Compound [ka] 4-1) Preparation of methyl 5-fluoro-6-methylbenzoate [ka] At room temperature, sulfuric acid (2 ml) was added to a solution of 3-fluoro-2-methylbenzoic acid (10 g, 64.9 mmol) in methanol (60 ml). The mixture was heated to 80° C. and stirred overnight. After cooling to room temperature, the reaction mixture was evaporated, extracted with NaHCO and ethyl acetate (EA), and dried over MgSO. The crude product was used in the next reaction without further purification. (10.1 g, 92% yield) MS (ESI, m / z): [M+1] + =[168.3].

[0039] 4-2) Preparation of methyl 2-(bromomethyl)-3-fluorobenzoate [ka] At room temperature, 1-bromomorpholidine-2,5-dione (15.9 g, 89.2 mmol) and benzoylbenzebolosodium (0.72 g, 2.97 mmol) were added sequentially to a solution of methyl 3-fluoro-2-methylbenzoate (10 g, 59.5 mmol) in ClCH2CHCl (250 ml). The reaction was heated to reflux for 16 hours. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (10.5 g, 71% yield) MS (ESI, m / z): [M+1] + =[245.9].

[0040] 4-3) Preparation of methyl 3-fluoro-2-formylbenzoate [ka] At room temperature, NMO (10.4 g, 89 mmol), 4 Å molecular sieves were added to a solution of methyl 2-(bromomethyl)-3-fluorobenzoate (10 g, 40.5 mmol) in DCM (200 ml). The reaction mixture was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound. (5.5 g, 75%) MS (ESI, m / z): [M+1] + =[183.1].

[0041] 4-4) Preparation of 3-fluoro-2-formylbenzoic acid [ka] To a solution of methyl 3-fluoro-2-formylbenzoate (2.5 g, 13.7 mmol) in THF (68 mL) at room temperature was added a solution of lithium(+1) hydroxide monohydrate (2.88 g, 68.6 mmol) in water (41 mL). After stirring for 4 hours, the reaction was concentrated under reduced pressure to remove the THF, cooled to 0°C, and acidified with 1N HCl to adjust the pH to 4. The semi-solidified water was extracted twice with ethyl acetate (100 mL). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (2.5 g, 108%). MS (ESI, m / z): [M+1] + =[168.8].

[0042] 4-5) Preparation of 5-fluoro-1,2-dihydrophthalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (1.22 mg, 16.4 mmol) was added to a solution of 3-fluoro-2-formylbenzoic acid (2.5 g, 14.9 mmol) in 1:1 THF:water (70 ml) and stirred for 16 hours. The mixture was acidified to pH 4, and the solid was filtered with hexane. Vacuum drying afforded the title compound (1.3 g, 53%). MS (ESI, m / z): [M+1] + =[165.3]

[0043] 4-6) Preparation of 3-(5-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione [ka] LDA (lithium diisopropylamide, 2.19 mmol) was added to a solution of 5-fluorine-1,2-dihydrohoptalazine (300 mg, 1.83 mmol) in DMF (10 ml) at 0°C and stirred for 30 minutes. 3-Bromoperidine-2,6-dione (526 mg, 2.74 mmol) was added to the solution and stirred at 80°C for 6 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (100 ml), and the pH was adjusted to 3-4 with 6N HCl. The mixture was then extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The product was recrystallized in hexane and dried under vacuum to give the title compound. MS (ESI, m / z): [M+1] + =[276.1].

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[0044] Example A-5: [ka] Preparation of compounds 5-1) Preparation of methyl 4-fluoro-6-methylbenzoate [ka] Methyl 4-fluoro-2-methylbenzoate was prepared from 4-fluoro-2-methylbenzoic acid according to the preparation method of Example 4-1.

[0045] 5-2) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate [ka] At room temperature, 1-bromophillolidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzebolocarbon (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 4-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The product was purified by MPLC (HX / EA EA 0->5%) (22 g, 75% yield). MS (ESI, m / z): [M+1] + =[248.4].

[0046] 5-3) Preparation of methyl 3-fluoro-2-formylbenzoate [ka] At room temperature, NMO (15.6 mg, 134 mmol) and 4 Å molecular sieves were applied sequentially to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22 g, 89 mmol) in DCM (100 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (50 ml). The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (12 g, 73.98%) MS (ESI, m / z): [M+1] + =[183.2].

[0047] 5-4) Preparation of 4-fluoro-2-formylbenzoic acid [ka] At room temperature, an aqueous solution of lithium (+1) hydroxylate (13.8 g, 329 mmol) was added to a solution of methyl 4-fluoro-6-formylbenzoate (12 g, 65.9 mmol) in THF (50 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (10 g, 90.3%). MS (ESI, m / z): [M+1] + =[169.2].

[0048] 5-5) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (2.02 g, 40.3 mmol) was added to a solution of 4-fluoro-2-formylbenzoic acid (6.78 g, 40.3 mmol) in methanol (50 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150 ml) and extracted twice with ethyl acetate (150 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (5.5 g, 83.07%). MS (ESI, m / z): [M+1] + =[165.3].

[0049] 5-6) 3-(6-Fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione Preparation [ka] Sodium 2-methylpropane-2-oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluorine-1,2-dihydrohoptalazin-1-one (100 mg, 0.609 mmol) in DMF (2 ml) at 0° C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione (90 mg, 0.471 mmol) was added to the reaction mixture, which was then stirred at room temperature for 6 hours. Water (20 ml) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 ml). The combined ethyl acetate was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography. The title compound was obtained as white crystals (110 mg, 65.5%). MS (ESI, m / z): [M+1] + =[276.6].

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[0050] Example A-6: Compound [ka] Preparation of 6-1) Preparation of methyl 4-fluoro-6-methylbenzoate [ka] Methyl 5-fluoro-2-methylbenzoate was prepared from 5-fluoro-2-methylbenzoic acid according to the preparation method of Example 4-1.

[0051] 6-2) Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate [ka] At room temperature, 1-bromophillolidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzene carboroxoate (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 5-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The purified product was purified by MPLC (HX / EA EA 0->5%) (29 g, 98.8% yield). MS (ESI, m / z): [M+1] + =[248.4].

[0052] 6-3) Preparation of methyl 5-fluoro-2-formylbenzoate [ka] At room temperature, NMO (20.6 mg, 176 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-5-fluorobenzoate (29 g, 117 mmol) in DCM (100 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (50 ml). The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (15 g, 70.16% yield) MS (ESI, m / z): [M+1] + =[183.2].

[0053] 6-4) Preparation of 5-fluoro-2-formylbenzoic acid [ka] At room temperature, an aqueous solution of lithium hydroxide (+1) (17.3 g, 412 mmol) was added to a solution of methyl 5-fluoro-2-formylbenzoate (15 g, 82.3 mmol) in THF (50 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0 °C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (12 g, 86.67%). MS (ESI, m / z): [M+1] + =[169.2].

[0054] 6-5) Preparation of 7-fluoro-1,2-dihydrobutalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (3.74 g, 74.8 mmol) was added to a solution of 5-fluoro-2-formylbenzoic acid (8.16 g, 48.5 mmol) in methanol (50 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150 ml) and extracted twice with ethyl acetate (150 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (6.5 g, 81.59%). MS (ESI, m / z): [M+1] + =[165.3].

[0055] 6-6) Preparation of 3-(7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (586 mg, 6.09 mmol) was added to a solution of 7-fluorone-1,2-dihydrohoptalazin-1-one (500 mg, 3.05 mmol) in DMF (5 ml) at 0° C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione (1.05 mg, 5.48 mmol) was added to the reaction mixture, which was stirred at room temperature for 6 hours. The reaction mixture was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography. The title compound was obtained as white crystals (300 mg, 35.78%). MS (ESI, m / z): [M+1] + =[276.6].

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[0056] Example A-7: Compound [ka] Preparation of (prepared according to Equation 2) 7-1) Preparation of methyl 2-acetyl-6-fluorobenzoate [ka] Tetrakis(triphenylphosphine)-palladium(0) (557 mg, 0.48 mmol) was added to a solution of methyl 2-acetyl-6-fluorobenzoate (1.12 g, 4.81 mmol) and tributyl(1-ethoxyvinyl)tin (1.91 g, 5.29 mmol) in toluene (20 ml) and stirred at 100°C for 16 hours. After cooling, 5 ml of 1N HCl was added and stirred for 1 hour. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica column chromatography to give the title compound as a yellow oil (820 mg, 87% yield). MS (ESI, m / z): [M+1]+ = [196.8].

[0057] 7-2) Preparation of 2-acetyl-6-fluorobenzoic acid [ka] LiOH (494 mg, 20.6 mmol) was added to a solution of methyl 2-acetyl-6-fluorobenzoate (810 mg, 4.13 mmol) in THF (20 ml) and water (10 ml) and stirred at room temperature for 20 hours. The solution was acidified with 1N HCl to a pH of approximately 3. 100 mL of EA was added, and the organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound. (810 mg, 108% yield) MS (ESI, m / z): [M+1] + =[183.1].

[0058] 7-3) Preparation of 8-fluoro-4-methylphthalazin-1(2H)-one [ka] Hydrazine monohydrate (261 mg, 5.20 mmol) was added to a solution of 2-acetyl-6-fluorobenzoic acid (790 mg, 4.34 mmol) in methanol (23 ml) and stirred at room temperature for 16 hours. The precipitate was filtered and washed with ACN (acetonitrile) to give the title compound as a white solid (612 mg, 79.2% yield). MS (ESI, m / z): [M+1] + =[179.1].

[0059] 7-4) Preparation of 3-(8-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1M-Lithium diisopropylamide (3.6 ml, 3.6 mmol) was added to a solution of 8-fluoro-4-methylphthalazin-1(2H)-one (534 mg, 3 mmol) in THF (30 ml) at 0° C. and stirred for 20 minutes. 3-Bromopiperidine-2,6-dione (863 mg, 4.5 mmol) was added to the solution and stirred at 80° C. for 2 hours. The reaction was concentrated under reduced pressure and dried. Water (10 mL) was added, stirred for 1 hour, and then acidified with 1N HCl to adjust the pH to 4. The precipitate was filtered and washed with water to give the title compound as a white solid (760 mg, yield: 86.5%). MS (ESI, m / z): [M+1] + =[289.8].

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[0060] Example A-8: Compound [ka] Preparation of 8-1) Preparation of 3-(8-((2,4-dimethoxybenzyl)amino)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (0.104 mmol), 2,4-dimethoxybenzylamine (0.207 mmol), and DIPEA (N,N-diisopropylethylamine) (0.312 mmol) in NMP (N-methyl-pyrrolidone) (1 mL) was heated in a microwave oven for 2 hours at 120 °C. The reaction mixture was purified by reverse-phase chromatography (C18, water (0.1% FA) / ACN (0.1% FA), gradient) to give 33 mg of a white solid (33 mg, 72% yield). MS (ESI, m / z): [M+1] +=[437.0]

[0061] 8-2) Preparation of 3-(8-amino-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 0.3 ml of TFA (trifluoroacetic acid) was added to 3-(8-((2,4-dimethoxybenzyl)amino)4-methyl-1-oxothalasin-2(1H)-yl)piperidine-2,6-dione (14 mg, 0.032 mmol) in toluene (0.7 mL) and stirred at 80° C. for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (C18, water (0.1% FA) / ACN (0.1% FA), gradient) to give 7.5 mg of a white solid (7.5 mg, 82% yield). MS (ESI, m / z): [M+1] + =[287.0]

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[0062] Example A-9: Compound [ka] Preparation of 9-1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] 6-Fluoro-1,2-dihydrobutalazin-1-one (100 mg, 0.36 mmol) and tert-butyl piperazine-1-carboxylate (81.2 mg, 0.36 mmol) were dissolved in NMP (1 mL), and DIPEA (5 equivalents) was added to the reaction mixture, which was then stirred at 120 °C overnight. The reaction mixture was quenched with water, extracted with EA, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4. The reaction mixture was loaded onto silica and separated by MPLC (HX / EA 30% -> 50%, 10 min) to give an oil product (110 mg, 66% yield).

[0063] 9-2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazine-1-carboxylate was dissolved in a 20% TFA solution in DCM (1 ml) and reacted at room temperature for 2 hours. The reaction was quenched with an aqueous solution saturated with NaHCO3 and extracted with EA. The organic layer was dried over MgSO4 and evaporated. The reaction mixture was purified by MPLC (MC / ME Me 0->10%) to give the product as a white solid (40 mg, 86% yield). MS (ESI, m / z): [M+1] + =[342.2].

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[0064] Example A-10: [ka] 10-1) Preparation of tert-butyl-4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] 3-(7-Fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) and tert-butyl piperazine-1-carboxylate (81.2 mg, 0.44 mmol) were dissolved in NMP (1 mL), and DIPEA (5 equivalents) was added to the reaction mixture, which was then stirred at 120 °C overnight. The reaction mixture was quenched with water, extracted with EA, and washed with saturated aqueous NH Cl and brine. The organic layer was dried over MgSO, and the reaction mixture was loaded onto silica and separated by MPLC (HX / EA 30% -> 50%, 10 min) to give the product as an oil (yield: 110 mg, 66%).

[0065] 10-2) Preparation of 3-(1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] tert-Butyl-4-[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl]piperazine-1-carboxylate (60 mg, 0.14 mmol) was added to 20% TFA in DCM (1 ml) and reacted at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EA. The organic layer was dried over MgSO4 and evaporated. The reaction mixture was purified by MPLC (MC / ME Me0->10%) to give a white solid as the product (yield: 40 mg / 86%). MS (ESI, m / z): [M+1] + =[342.2].

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[0066] Example A-11: Preparation of 3-(8-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of [ka] 3-(6-Fluoro-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was added to DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The reaction mixture was reacted at room temperature for 1 hour. The organic solvent was removed, and the mixture was extracted with EA and water. The mixture was purified by MPLC to obtain the product as a white solid (yield: 80 mg / 76%). MS (ESI, m / z): [M+1] + =[288.2].

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[0067] Example A-12: Preparation of 3-(7-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of [ka] 3-(7-Fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature for 1 hour. The organic solvent was removed, and the mixture was extracted with EA and water. The mixture was purified by MPLC to obtain the product as a white solid. (Yield: 78 mg / 75%) MS (ESI, m / z): [M+1] + =[288.2].

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[0068] Example A-13: Preparation of 3-(6-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of [ka] 3-(6-Fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The reaction mixture was reacted at room temperature for 1 hour. The organic solvent was removed, and EA and water were extracted. The mixture was purified by MPLC to obtain the product as a white solid. (Yield: 80 mg / 76%) MS (ESI, m / z): [M+1] + =[288.2].

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[0069] Example A-14: Preparation of 3-(5-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate [ka] 1-Bromopyridine-2,5-dione (11.5 g, 64.94 mmol) and benzoylbenzenecarboperoxate (786 mg, 3.24 mmol) were added sequentially to a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH2CHCl (250 ml) at room temperature. The reaction mixture was heated to reflux for 3 hours. The reaction was completed when the red color disappeared. After cooling, the reaction mixture was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude material was used in the next reaction without further purification. (16.5 g, 98.2%) MS (ESI, m / z): [M+1] + =[259.4]

[0070] 14-2) Preparation of methyl 2-formyl-3-methoxybenzoate [ka] NMO (12.6 g, 108.1 mmol) and 4 Å molecular sieves (50 g) were added sequentially to a solution of methyl 2-(bromomethyl)-3-methoxybenzoate (14.1 g, 54.1 mmol) in DCM (300 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (100 mL). The DCM layer was washed with water (250 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (8.3 g, 80.01%) MS (ESI, m / z): [M+1] + =[195.0].

[0071] 14-3) Preparation of 2-formyl-3-methoxybenzoic acid [ka] Lithium(1+) hydroxylate (2.4 g, 100.5 mmol) in HO (100 mL) was added to a solution of methyl 2-formyl-3-methoxybenzoate (6.5 g, 33.6 mmol) in THF (100 mL) at room temperature. After stirring for 2 hours, the reaction was concentrated under reduced pressure to evaporate the THF. After cooling to 0 °C, the reaction was acidified with 1 N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (250 mL). The combined ethyl acetate layers were dried over MgSO and concentrated under reduced pressure to give white crystals. (11.2 g, 82.6%) MS (ESI, m / z): [M+1] + =[199.2].

[0072] 14-4) Preparation of 5-methoxyphthalazin-1(2H)-one [ka] NH2NH2 monohydrate (10.3 g, 342 mmol) was added to a solution of 2-formyl-3-methoxybenzoic acid (8.2 g, 45.5 mmol) in MeOH (20 mL) at room temperature. After stirring for 2 hours, the reaction was concentrated under reduced pressure, poured into water (50 mL), and extracted twice with ethyl acetate (150 mL). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals. (9.2 g, 76.35%) MS (ESI, m / z): [M+1] + =[176.9].

[0073] 14-5) Preparation of 3-(5-methoxy-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1.0 M LDA (37.4 mL) was added dropwise to a suspension of 5-methoxyphthalazin-1(2H)-one (5.1 g, 28.9 mmol) in THF (250 mL) at 0 °C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione was added portionwise to the reaction. The reaction was heated to 80 °C and stirred for 2 hours. Upon completion of the reaction, the reaction was cooled to room temperature, poured into water (100 mL), the pH was adjusted to 3-4 with 6N HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound as white crystals. (7.2 g, 86.5% yield) MS (ESI, m / z): [M+1] + =[288.3].

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[0074] Example A-15: Preparation of 3-(6-bromo-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of 15-1) Preparation of 5-bromo-3-hydroxyisobenzofuran-1(3H)-one [ka] AIBN (401 mg, 2.44 mmol) was added to a mixture of 5-bromophthalide (5.2 g, 24.4 mmol) and N-bromosuccinimide (5.6 g, 31.7 mmol) in 200 mL of ClCH2CHCl and refluxed for 8 hours. After the reaction, TLC was performed. The succinimide was filtered, and the cake was washed with ClCH2CHCl (50 mL). The solvent was removed in vacuo, leaving a 5.2 g residue, to which 50 mL of water was added. The mixture was stirred for 4 hours, then refluxed. The mixture was cooled, and the product was filtered, neutralized, washed with water, and dried to give pale yellow-white crystals. (4.85 g, 86.7% yield) MS (ESI, m / z): [M+1] + =[229.6] and [230.5]

[0075] 15-2) Preparation of 6-bromophthalazin-1(2H)-one [ka] To a solution of 5-bromo-3-hydroxy-1,3-dihydro-2-benzofuran-1-one (1.5 g, 6.55 mmol) in MeOH (50 mL) was added NH2NH2H2O (315 mg, 9.82 mmol) at room temperature. The reaction was refluxed for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting solid was titrated with ethyl acetate to give white crystals. (1.31 g, 5.82 mmol) MS (ESI, m / z): [M+1] + =[226.3].

[0076] 15-3) Preparation of 3-(6-bromo-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1.0 M LDA (7.33 mL) was added dropwise to a suspension of 6-bromo-1,2-dihydrobutalazin-1-one (1.31 g, 5.82 mmol) in THF (150 mL) at 0 °C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione was added portionwise to the reaction. The reaction was heated to 80 °C and stirred for 2 hours. Upon completion of the reaction, the reaction was cooled to room temperature, poured into water (100 mL), the pH was adjusted to 3-4 with 6N HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The resulting solid was filtered and washed with ethyl acetate to give white crystals. (1.73 g, 5.15 mmol) MS (ESI, m / z): [M+1] + =[337.2].

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[0077] Example A-16: Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione diHCl compound [ka] Preparation of 16-1) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione dihydrochloride [ka] tert-Butyl piperazine-1-carboxylate (244 mg, 1.13 mmol) and ethyl bis(propan-2-yl)amine (423 mg, 3.24 mmol) were added sequentially to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (0.3 g, 1.09 mmol) in DMA (4 mL). The mixture was stirred at 120 °C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na SO and concentrated. The residue was purified by column chromatography to give a pale yellow oil. (415 mg, 86.2%) MS (ESI, m / z): [M+1] + =[442.4]

[0078] 16-2) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione dihydrochloride [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 8-nitro-1,2-dihydrophthalazin-1-one (60 mg, 0.314 mmol) in DMF (1 mL). The reaction was heated to 85 °C for 5 h. After cooling, the reaction mixture was poured into water (5 mL) and extracted twice with ethyl acetate (5 mL). The combined ethyl acetate was extracted with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals. (68.0 mg, 71.7% yield) MS (ESI, m / z): [M+1] + =[342.6].

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[0079] Example B: Preparation of BRD4 PROTAC based on WNY derivatives Example B-1: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(5-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)pent-4-rin-1-yl)-3-methoxybenzamide (ICT-0001515) Step 1) Synthesis of methyl (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoate [ka] Dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phospane (103 mg, 216 μmol) was added to (4R)-7-chloro-5-(cyclohexyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazol[4,3-f]pteridine (1.5 g, 4.32 mmol) and methyl 4-amino-3-methoxybenzoate (862 mg, 4.76 mmol) in toluene (10 mL) at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (1.52 g). MS (ESI, m / z): [M+H] + =[492.6].

[0080] Step 2) Synthesis of (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoic acid [ka] Lithium hydroxide(1+) (427 mg, 10.2 mol) in water (10 mL) was added to a solution of methyl 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoate (1.0 g, 2.03 mmol) in THF (10 mL) at room temperature. The reaction was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature and concentrated until the THF was removed. The resulting residue was acidified with 1.0 M HCl and adjusted to pH = 5. The resulting solid was filtered. The desired compound was obtained by drying in vacuo (0.81 g). MS (ESI, m / z): [M+H] + =[478.6].

[0081] Step 3) Synthesis of tert-butyl N-{5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaradin-6-yl]pent-4-phospho-1-yl}carbamate [ka] CuI (255 mg, 1.34 mmol) and Pd(PPh3)2Cl2 (940 mg, 1.34 mmol) were added to a solution of 3-(6-bromo-1-oxo-1,2-dihydroptalazin-2-yl)piperidine-2,6-dione (4.5 g, 13.4 mmol) in THF (150 mL), followed by the addition of TEA (4.06 g, 40.2 mmol). The mixture was stirred at 90 °C for 3 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over Na2SO4. It was concentrated. The residue was purified by EA / Hex (20-80%) MPLC to give the desired compound (3.9 g). MS (ESI, m / z): [M+H] + =[439.5].

[0082] Step 4) Synthesis of 3-[6-(5-aminopent-1-rin-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione [ka] A solution of tert-butyl 3-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}piperazin-1-yl)methyl]azetidine-1-carboxylate (3.9 g, 8.89 mmol) in 30% TFA in DCM was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (3.0 g). MS (ESI, m / z): [M+H] + =[339.4]

[0083] Step 5) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)pent-4-rin-1-yl)-3-methoxybenzamide (ICT-0001515) [ka] HATU (71.7 mg, 188 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl}-3-methoxybenzoic acid (75 mg, 157 μmol) and 3-[6-(5-aminopent-1-phospho-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (53.1 mg, 157 μmol) in 1 ml of DMF, followed by the addition of ethylbis(propan-2-yl)amine (40 mg, 314 μmol) at room temperature. The reaction was stirred for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (89 mg). MS (ESI, m / z): [M+H] + =[798.9]

[0084] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.07(s,1 H)8.47-8.53(m,1 H)8.41(s,1 H)8.34(dd,J=8.16,6.33 Hz,1 H)8.17-8.25(m,1 H)7.95(s,1 H)7.91(d,J=5.80 Hz,1 H)7.79-7.87(m,1 H)7.47-7.56(m,2 H)5.76-5.86(m,1 H)4.90(dd,J=8.01,3.59 Hz,1 H)4.11(dd,J=13.28,5.49 Hz,1 H)3.90-3.98(m,2 H)3.45(d,J=6.10 Hz,2 H)2.87-3.04(m,2 H)2.70(s,2 H)2.54-2.66(m,3 H)2.06-2.19(m,1 H)1.78-1.92(m,3 H)1.63-1.74(m,4 H)1.59(br.s.,1 H)1.23(s,1 H)1.00-1.21(m,3 H)0.90-0.99(m,1 H)0.75(t,J=7.25 Hz,2 H)

[0085] Example B-2: Synthesis of 3-(6-(4-((4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001516) Step 1) Synthesis of benzyl 4-(piperidine-4-monomethyl)piperazine-1-carboxylate [ka] K2CO3 (16.4 g, 119.5 mmol) was added to a solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (7.0 g, 23.9 mmol) and benzylpiperazine-1-carboxylate (5.26 g, 23.9 mmol) in 50 mL of acetonitrile at room temperature, and the reaction was stirred at 80 °C for 6 hours. The Boc-protected compound was treated with 50% TFA in DCM (20 mL) and stirred for 5 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound (6.01 g). MS (ESI, m / z): [M+H] + =[318.4].

[0086] Step 2) Synthesis of 3-(4-methyl-1-oxo-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] Ethylbis(propan-2-yl)amine (6.89 g, 20.7 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dioic acid (2.0 g, 6.91 mmol) and 4-(piperazin-1-yl)aniline (2.19 g, 6.91 mmol) in 5 mL of DMA at room temperature. The reaction was stirred at 130 °C for 16 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC to give the CBZ-protected compound. The compound was dissolved in MeOH (50 ml). 10% Pd / C (100 mg) was added. The reaction was stirred under a H2 balloon for 5 hours. The reaction was filtered and concentrated under reduced pressure to give the target compound (2.3 g). MS (ESI, m / z): [M+H] + =[453.7].

[0087] Step 3) Synthesis of 3-(6-(4-((4-(R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001516) [ka] HATU (95.5 mg, 251 μmol) was dissolved in 1 mL of DMF with 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (100 mg, 209 μmol) and 3-(4-methyl-1-oxo-6-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}-1,2-dihydroptaradin- To the solution was added 2-yl}piperidine-2,6-dione (98.4 mg, 209 μmol) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (54.1 mg, 419 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (130 mg). MS (ESI, m / z): [M+H] + =[913.1]

[0088] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.36-8.43(m,1 H)8.28(d,J=8.24 Hz,1 H)8.05(d,J=9.00 Hz,1 H)7.90-8.00(m,1 H)7.48(d,J=9.16 Hz,1 H)7.06(d,J=5.80 Hz,2 H)6.96(d,J=8.24 Hz,1 H)5.63-5.73(m,1 H)4.89(dd,J=8.09,3.66 Hz,1 H)4.02-4.14(m,3 H)3.91(s,3 H)3.39-3.44(m,1 H)2.89-3.00(m,4 H)2.69(s,4 H)2.53-2.64(m,3 H)2.48(s,4 H)2.39(br.s.,3 H)2.15-2.24(m,2 H)2.01-2.12(m,1 H)1.96-2.01(m,1 H)1.93(d,J=15.11 Hz,1 H)1.83(d,J=9.00 Hz,4 H)1.63-1.73(m,5 H)1.61(br.s.,1 H)1.19-1.25(m,4 H)1.08-1.16(m,3 H)0.74(t,J=7.32 Hz,3 H)

[0089] Example B-3: Synthesis of 3-((4-(4-(4-((((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (ICT-0001517) Step 1) Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate [ka] K2CO3 (17.4 g, 126 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (5 g, 31.4 mmol) and 1,2-difluoro-4-nitrobenzene (5.85 g, 31.4 mmol) in acetonitrile (10 ml). The reaction was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and then purified by column chromatography to give the title compound (9.3 g). MS (ESI, m / z): [M+H] + =[326.3]

[0090] Step 2) Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate [ka] 20 mL of saturated NH4Cl was added to a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (3 g, 9.22 mmol) and iron (10.3 g, 1840 mmol) in THF (2 ml). The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (2.6 g). MS (ESI, m / z): [M+H] + =[296.4].

[0091] Step 3) Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate [ka] NaHCO3 (4.27 g, 50.8 mmol) was added to a solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (3 g, 10.2 mmol) and 3-bromoperidine-2,6-dione (3.9 g, 20.3 mmol) in 10 ml of DMF at room temperature, followed by HCl. The reaction was stirred at 80 °C for 3 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (3.4 g). MS (ESI, m / z): [M+H] + =[407.5].

[0092] Step 4) Synthesis of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione [ka] The reaction mixture was stirred at room temperature for 2 hours in a solution of tert-butyl-4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate (3.4 g, 8.89 mmol) in 30% TFA in DCM. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (3.0 g). MS (ESI, m / z): [M+H] + =[307.3].

[0093] Step 5) Synthesis of 3-((4-(4-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (ICT-0001517) [ka] HATU (95.5 mg, 251 μmol) was added to 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (100 mg, 209 μmol) and 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione (64.1 mg, 209 μmol) in 1 mL of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (123 mg). MS (ESI, m / z): [M+H] + =[766.9]

[0094] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.79(s,1 H)8.40(s,1 H)8.30(d,J=8.24 Hz,1 H)7.94(s,2 H)7.07-7.13(m,2 H)7.00(d,J=8.24 Hz,2 H)6.87(t,J=9.31 Hz,1 H)6.53(dd,J=14.95,2.29 Hz,1 H)6.44(dd,J=8.70,2.14 Hz,1 H)5.88(d,J=7.78 Hz,1 H)4.89(dd,J=8.24,3.81 Hz,2 H)4.23-4.32(m,1 H)4.10(dd,J=13.58,6.10 Hz,1 H)3.92(s,5 H)2.68-2.80(m,6 H)2.57(dt,J=17.39,3.89 Hz,1 H)2.04-2.14(m,2 H)1.99(s,1 H)1.75-1.92(m,4 H)1.24(s,1 H)1.01-1.21(m,5 H)0.95(d,J=11.90 Hz,1 H)0.75(t,J=7.32 Hz,5 H)

[0095] Example B-4: Synthesis of 3-((4-(4-((4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (ICT-0001518) Step 1) Synthesis of tert-butyl 4-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate [ka] 1,2-Difluoro-4-nitrobenzene (5.61 g, 35.3 mmol) and potassium carbonate (24.4 g, 176 mmol) were added to a solution of tert-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (10 g, 35.3 mmol) in DMF (200 mL). The reaction was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (11 g). MS (ESI, m / z): [M+H] + =423.5

[0096] Step 2) Synthesis of tert-butyl 4-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate [ka] Iron powder (29.5 g, 521 mmol) was added to tert-butyl 4-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (11 g, 26 mmol) in saturated NH4Cl / THF (1:1) (200 mL). The reaction was stirred at 80°C for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure. The crude material was used in the next step without further purification. (MS (ESI, m / z): [M+H] + =393.5.

[0097] Step 3) Synthesis of tert-butyl 4-[(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate [ka] 3-Bromoperidine-2,6-dione (1.2 g, 6.1 mmol) was added to tert-butyl 4-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (1.2 g, 3.1 mmol) in DMF (25 mL). The reaction was stirred at 85 °C overnight. After the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =504.6

[0098] Step 4) Synthesis of 3-[(3-fluoro-4-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}phenyl)amino]piperidine-2,6-dione [ka] The reaction was stirred in a solution of tert-butyl 4-[(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (650 mg, 1.29 mmol) in 30% TFA in DCM for 2 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by DCM / MeOH (5-10%) amine column chromatography to give the title compound (485 mg). MS (ESI, m / z): [M+H]+ = 404.5.

[0099] Step 5) Synthesis of 3-((4-(4-((4-(4-((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (ICT-0001518) [ka] HATU (79.6 mg, 209 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (100 mg, 209 μmol) and 3-[6-(5-aminopent-1-phosphoin-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (84.5 mg, 209 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (51.4 mg, 419 μmol). The reaction was stirred for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (111 mg). MS (ESI, m / z): [M+H] + =[864.1]

[0100] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.79(s,1 H)8.39(s,2 H)8.28(d,J=8.24 Hz,2 H)7.94(s,1 H)7.06(s,2 H)6.95(d,J=8.24 Hz,2 H)6.83(t,J=9.31 Hz,2 H)6.50(dd,J=14.95,2.14 Hz,1 H)6.41(d,J=8.55 Hz,1 H)5.79(d,J=7.63 Hz,1 H)4.89(dd,J=8.09,3.81 Hz,1 H)4.21-4.29(m,1 H)3.99-4.14(m,2 H)3.91(s,5 H)3.11(d,J=11.14 Hz,3 H)2.97(dd,J=13.58,8.39 Hz,1 H)2.70(s,5 H)2.53-2.60(m,4 H)2.21(d,J=6.87 Hz,3 H)2.05-2.12(m,2 H)1.98-2.01(m,1 H)1.21-1.30(m,4 H)1.13(d,J=7.63 Hz,3 H)0.94(d,J=11.75 Hz,1 H)0.75(t,J=7.32 Hz,5 H)

[0101] Example B-5: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(5-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)pent-4-rin-1-yl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001534) Step 1) Synthesis of 3-[(3-fluoro-4-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}phenyl)amino]piperidine-2,6-dione [ka] CuI (85 mg, 446 μmol) and Pd(PPh3)2Cl2 (313 mg, 446 μmol) were added to a solution of 3-(6-bromo-1-oxo-1,2-dihydrohoptalazin-2-yl)piperidine-2,6-dione (1.5 g, 4.46 mmol) and pent-4-phospho-1-ol (488 mg, 5.8 mmol) in DMF (5 mL), followed by the addition of TEA (1.35 g, 13.4 mmol). The ethyl acetate organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The residue was purified by MPLC with EA / hexane (0-10%) to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =[340.4],

[0102] Step 2) Synthesis of 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaradin-6-yl)pent-4-phospho-1-yl methanesulfonate [ka] Methanesulfonyl chloride (1.32 g, 11.5 mmol) in CHCl (15 mL) was added to a solution of [3-(5-(5-bromorimidin-2-yl)phenyl]methanol (1.3 g, 3.83 mmol) in CHCl (50 mL), followed by the addition of trimethylamine (1.49 g, 11.5 mmol) at 0 °C, then stirred for 2 h. The reaction was warmed to room temperature and stirred for an additional 2 h. The reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The organic layers were combined, washed with brine solution (50 mL x 2), dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[418.1],

[0103] Step 3) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(5-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)pent-4-rin-1-yl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001534) [ka] Ethyl bis(4-methyl-4-methyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (40 mg, 71.5 μmol) and 5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaradin-5-yl]pent-4-phospholipidin-5-yl]pent-4-phospholipinat-1-yl methanesulfonate (29.8 mg, 71.5 μmol) were added at room temperature. The reaction mixture was stirred at 65° C. for 6 hours. The mixture was poured into water. It was extracted with ethyl acetate, dried over MgSO 4 , and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (49 mg). MS (ESI, m / z): [M+H] + =[882.1]

[0104] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.07(s,1 H)8.47-8.53(m,1 H)8.41(s,1 H)8.34(dd,J=8.16,6.33 Hz,1 H)8.17-8.25(m,1 H)7.95(s,1 H)7.91(d,J=5.80 Hz,1 H)7.79-7.87(m,1 H)7.47-7.56(m,2 H)5.76-5.86(m,1 H)4.90(dd,J=8.01,3.59 Hz,1 H)4.11(dd,J=13.28,5.49 Hz,1 H)3.90-3.98(m,2 H)3.45(d,J=6.10 Hz,2 H)2.87-3.04(m,2 H)2.70(s,2 H)2.54-2.66(m,3 H)2.06-2.19(m,1 H)1.78-1.92(m,3 H)1.63-1.74(m,4 H)1.59(br.s.,5 H)1.23(s,5 H)1.00-1.21(m,3 H)0.90-0.99(m,1 H)0.75(t,J=7.25 Hz,2 H)

[0105] Example B-6: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(1-((3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydroptarazin-5-yl)glycyl)-4-methylpiperidin-4-yl)-3-methoxybenzamide (ICT-0001547) Step 1) Synthesis of (3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-5-yl)glycine [ka] tert-Butyl 2-aminoacetate (118 mg, 899 μmol) was added to a solution of 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (0.2 g, 691 μmol) in DMA (2 mL) at room temperature, followed by the addition of ethyl bis(propan-2-yl)amine (179 mg, 1.88 mmol). The reaction was heated to 110° C. for 8 hours. The reaction was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was purified by column chromatography to give the intermediate, which was treated with 50% TFA in CHCl (4 mL). The reaction was stirred for 2 hours and then concentrated under reduced pressure to give the title compound (189 mg). MS (ESI, m / z): [M+H] + =[345.3].

[0106] Step 2) Synthesis of 3-(8-((2-(4-amino-4-methylpiperidin-1-yl)-2-oxoethyl)amino)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione dihydrochloride [ka] HATU was added to a solution of 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-5-yl]amino}acetic acid (250 mg, 726 μmol) and tert-butyl N-(4-methylpiperidin-4-yl)carbamate (156 mg, 726 μmol) in 2 mL of DMF at room temperature, followed by the addition of ethyl bis(propan-2-yl)amine (93.8 mg, 726 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, and dried over MgSO4. The mixture was then evaporated under reduced pressure and concentrated. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound. The product was reacted with 4.0 M HCl (10 equiv.) for 4 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in DCM, and the target compound was obtained by passing it through a NH-DM 1020 Chromatrex pad (6.01 g). MS (ESI, m / z): [M+H] + =[441.2].

[0107] Step 3) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-((3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydropetalazin-5-yl)glycy)-4-methylpiperidin-4-yl)-3-methoxybenzamide (ICT-0001547) [ka] HATU (79.6 mg, 209 μmol) was dissolved in 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (100 mg, 209 μmol) and 3-(8-((2-(4-(4-amino-4-methylpiperidin-1-yl)-2-oxoethyl)amino)-4-methyl-1-oxoptalazine-2(1H)) To the resulting solution was added ethyl bis(propan-2-yl)piperidine-2,6-dione (84.5 mg, 209 μmol), followed by the addition of ethyl bis(propan-2-yl)amine (51.4 mg, 419 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (111 mg). MS (ESI, m / z): [M+H] + =[864.1]

[0108] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.94(s,1 H)8.99-9.04(m,1 H)8.31-8.35(m,2 H)8.19-8.26(m,2 H)7.86-7.87(m,1 H)7.60(t,J=8.09 Hz,1 H)6.98-7.05(m,2 H)6.83-6.94(m,4 H)4.82(dt,J=7.90,3.76 Hz,2 H)3.98-4.08(m,2 H)3.81-3.88(m,5 H)3.39(br.s.,1 H)2.78-2.94(m,3 H)2.58(d,J=16.63 Hz,2 H)2.47-2.55(m,1 H)2.28-2.39(m,4 H)1.98-2.03(m,1 H)1.73(dd,J=6.94,2.82 Hz,1 H)1.49-1.67(m,9 H)1.13-1.24(m,2 H)1.00-1.09(m,3 H)0.67(t,J=7.32 Hz,5 H)

[0109] Example B-7: Synthesis of 3-(6-(4-(((S)-4-(4-(R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)morpholin-2-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001548) Step 1) Synthesis of tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]morpholine-4-carboxylate [ka] Methanesulfonyl chloride (4.43 g, 38.7 mmol) in CHCl (20 mL) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (7 g, 32.2 mmol) in DCM (100 mL), followed by triethylamine (4.89 g, 48.3 mmol) at 0° C. and stirred for 2 h. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL×3). The organic layers were combined and washed with brine solution (50 mL×2). After drying over anhydrous sodium sulfate, it was filtered and concentrated. The residue was used in the next step without further purification. (8.9 g) MS (ESI, m / z): [M+H] + =[296.4].

[0110] Step 2) Synthesis of benzyl 4-{[(2S)-morpholin-2-yl]methyl}piperazine-1-carboxylate [ka] K2CO3 (8.32 g, 60.2 mmol) was added to a solution of tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]morpholine-4-carboxylate (8.9 g, 30.1 mmol) and benzylpiperazine-1-carboxylate (6.63 g, 30.1 mmol) in 20 mL of DMF at room temperature, and the reaction was then stirred at 80 °C for 6 hours. The Boc-protected compound was treated with 50% TFA in DCM (20 mL) and stirred for 5 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound (6.01 g). MS (ESI, m / z): [M+H] + =[319.4].

[0111] Step 3) Synthesis of benzyl 4-{[(2S)-morpholin-2-yl]methyl}piperazine-1-carboxylate [ka] K2CO3 (8.32 g, 60.2 mmol) was added to a solution of tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]morpholine-4-carboxylate (8.9 g, 30.1 mmol) and benzylpiperazine-1-carboxylate (6.63 g, 30.1 mmol) in 20 ml of DMF at room temperature, and the reaction was stirred at 80 °C for 6 h. (6.01 g). MS (ESI, m / z): [M+H] + =[637.4].

[0112] Step 4) Synthesis of benzyl 4-{[(2S)-morpholin-2-yl]methyl}piperazine-1-carboxylate [ka] 10% Pd / C (300 mg) was added to a solution of 4-{[(2S)-morpholin-2-yl]methyl}piperazine-1-carboxylate (6.01 g, 14.3 mmol) in MeOH (50 m). The reaction was stirred under a H balloon for 5 h. The reaction was filtered and concentrated under reduced pressure to give the title compound (4.0 g). MS (ESI, m / z): [M+H] + =[320.4].

[0113] Step 5) Synthesis of 3-(4-methyl-6-(4-((R)-morpholin-2-yl)methyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of tert-butyl (2R)-2-[(piperazin-1-yl)methyl]morpholine-4-carboxylate (200 mg, 691 μmol), 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (296 mg, 1.04 mmol), and DIPEA (268 mg, 2.07 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and purified by NH-DM 1020 Chromatrex pad to obtain the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + = [455.5 g / mol].

[0114] Step 6) Synthesis of 3-(6-(4-(((S)-4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)morpholin-2-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001548) [ka] HATU (38.2 mg, 101 μmol) was added to 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol) and 3-[4-methyl-6-(4-{(2S)-morpholin-2-yl]methyl}piperazin-1-yl)-1-oxo-1,2-dihydroproptalazin-2-yl]piperidine-2,6-dione (38.1 mg, 83.8 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (21.7 mg, 168 μmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (52 mg). MS (ESI, m / z): [M+H] + =[915.1]

[0115] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.28-8.34(m,2 H)8.25(d,J=8.09 Hz,1 H)7.85(s,2 H)6.98-7.06(m,2 H)6.92(d,J=8.39 Hz,1 H)4.81(br.s.,1 H)4.01(dd,J=13.35,6.48 Hz,1 H)3.79-3.90(m,5 H)2.78-2.93(m,2 H)2.59-2.63(m,5 H)2.47-2.59(m,4 H)2.40(br.s.,3 H)1.95-2.04(m,1 H)1.58(d,J=9.77 Hz,4 H)1.05(d,J=7.63 Hz,2 H)0.60-0.71(m,5 H)0.00(s,1 H)

[0116] Example B-8: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl)ethyl)3-methoxybenzamide (ICT-0001549) Step 1) Synthesis of 3-(8-((2-(2-(2-(2-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione hydrochloride [ka] Ethyl bis(propan-2-yl)amine (285 mg, 2.2 mol) was added to 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydroptalazin-2-yl)piperidine-2,6-dione (0.2 g, 724 μmol) and tert-butyl N-(2-{2-[2-(2-aminoethoxy)ethoxy}ethyl)carbamate (387 mg, 1.32 mmol) in 1 mL of DMA at room temperature. The reaction was stirred at 120° C. for 3 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound. The intermediate was dissolved in dioxane (1 mL) and 5 mL of 4.0 M HCl in dioxane was added. After stirring for 3 hours, the reaction was concentrated under reduced pressure. The resulting solid was used in the next step without additional tablets (245 mg). MS (ESI, m / z): [M+H] + =[448.1].

[0117] Step 2) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydroptaladin-5-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)ethyl)3-methoxybenzamide (ICT-0001549) [ka] HATU (38.2 mg, 101 μmol) was added to a solution of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl}-methoxybenzoic acid (50 mg, 105 μmol) and 3-[8-(12-amino-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione hydrochloride (37.5 mg, 83.8 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (21.7 mg, 168 μmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (38 mg). MS (ESI, m / z): [M+H] + =[908.0]

[0118] 1H NMR(500 MHz,DMSO-d6)δ ppm 11.03(s,1 H)8.81(t,J=5.04 Hz,1 H)8.46(t,J=5.57 Hz,1 H)8.41(s,1 H)8.35(d,J=8.39 Hz,1 H)8.22(s,1 H)7.92(s,1 H)7.62(t,J=8.01 Hz,1 H)7.54(s,1 H)7.49(d,J=8.55 Hz,1 H)6.91(d,J=7.48 Hz,1 H)6.88(d,J=8.54 Hz,1 H)5.71(d,J=7.17 Hz,1 H)4.89(dd,J=8.24,3.81 Hz,1 H)4.11(dd,J=13.58,6.26 Hz,1 H)3.94(s,3 H)3.65(t,J=5.26 Hz,2 H)3.42(q,J=5.59 Hz,2 H)2.85-3.04(m,2 H)2.70(s,3 H)2.61(d,J=17.70 Hz,1 H)2.03-2.12(m,1 H)1.99(s,1 H)1.78-1.84(m,2 H)1.63-1.71(m,5 H)1.24(br.s.,2 H)1.01-1.20(m,5 H)0.95(d,J=10.83 Hz,1 H)0.74(t,J=7.32Hz,3H)

[0119] Example B-9: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1-dihydroptaladin-6-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001551) Step 1) Synthesis of 3-[1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione [ka] A solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl piperazine-1-carboxylate (483 mg, 2.59 mmol), and DIPEA (670 mg, 5.19 mmol) in NMP (2 mL) was stirred at 120 °C for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[356.5].

[0120] Step 2) Synthesis of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoic acid [ka] A solution of 3-[1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (200 mg, 586 μmol), tert-butyl 3-bromopropanoate (245 mg, 1.17 mmol), and DIPEA (379 mg, 2.93 mmol) in acetonitrile (10 mL) was stirred at 80° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. (170 mg) MS (ESI, m / z): [M+H] + =[470.5].

[0121] Step 3) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl)piperazine-1-dei)propanoyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001551) [ka] HATU (47.8 mg, 126 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (58.6 mg, 105 μmol) and 3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}propanoic acid (44.8 mg, 126 μmol), followed by the addition of ethylbis(propan-2-yl)amine (27.1 mg, 209 μmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (54 mg). MS (ESI, m / z): [M+H] + =[970.2]

[0122] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.34(s,1 H)8.25-8.30(m,1 H)8.06-8.13(m,1 H)8.00(d,J=9.00 Hz,1 H)7.85-7.89(m,1 H)7.40-7.44(m,2 H)7.02(s,1 H)5.57-5.65(m,1 H)4.82(dd,J=8.16,3.89 Hz,1 H)4.34(d,J=12.51 Hz,1 H)3.95-4.08(m,2 H)3.84-3.93(m,4 H)3.42-3.51(m,1 H)3.38(br.s.,3 H)3.20(br.s.,1 H)3.07(t,J=12.59 Hz,1 H)2.85-2.97(m,2 H)2.78-2.85(m,3 H)2.59-2.66(m,4 H)2.49-2.58(m,7 H)2.46-2.48(m,1 H)1.94-2.05(m,1 H)1.83(d,J=14.04 Hz,1 H)1.67-1.79(m,3 H)1.56-1.67(m,5 H)1.53(br.s.,2 H)1.28-1.48(m,2 H)1.16(br.s.,1 H)1.05(br.s.,3 H)0.98(d,J=9.61 Hz,1 H)0.80-0.93(m,1 H)0.67(t,J=7.32 Hz,3 H)

[0123] Example B-10: Synthesis of 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001553) Step 1) Synthesis of tert-butyl 4-[(piperazin-1-yl)methyl]piperidine-1-carboxylate [ka] K2CO3 (16.4 g, 119.5 mmol) was added to a solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (7.0 g, 23.9 mmol) and benzylpiperazine-1-carboxylate (5.26 g, 23.9 mmol) in 50 ml of acetonitrile at room temperature, and the reaction was then stirred at 80 °C for 6 hours. After filtering and concentrating the reaction under reduced pressure, the residue was purified by MPLC to give the title compound. The compound was dissolved in MeOH (50 ml) and 10% Pd / C (100 mg) was added. The reaction was stirred under a H2 balloon for 5 hours. The reaction was filtered and concentrated under pressure to give the title compound (4.3 g). MS (ESI, m / z): [M+H] + =[284.2].

[0124] Step 2) Synthesis of 3-(4-methyl-1-oxo-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] Ethylbis(propan-2-yl)amine (1.34 g, 10.4 mmol) was added to 3-(7-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidin-2-one (500 mg, 3.46 mmol) and tert-butyl 4-[(piperazin-1-yl)methyl]piperidine-1-carboxylate (580 mg, 3.46 mmol) in 3 ml of DMF at room temperature. The reaction mixture was stirred at 130 °C for 16 hours. The mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC to give the CBZ-protected compound. It was dissolved in 2 ml of DCM followed by 0.2 ml of TFA and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound, which was used in the next step without further purification. (370 mg) MS (ESI, m / z): [M+H] += [453.6 g / mol].

[0125] Step 3) Synthesis of 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001553) [ka] HATU (66.9 mg, 176 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (70 mg, 147 μmol) and 3-(7-fluoro-4-methyl-1-oxo-6-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (66.3 mg, 147 μmol) in 1 mL of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (89 mg). MS (ESI, m / z): [M+H] + =[913.2]

[0126] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)9.90(s,1 H)8.32-8.38(m,2 H)8.04(d,J=9.00 Hz,1 H)7.91(s,1 H)7.51-7.58(m,4 H)7.11(s,1 H)6.97(d,J=9.00 Hz,2 H)5.63(d,J=7.32 Hz,1 H)4.84(dd,J=8.09,3.81 Hz,1 H)4.07(dd,J=13.43,6.41 Hz,1 H)3.93(s,3 H)3.56(br.s.,4 H)2.94(dd,J=13.81,8.16 Hz,1 H)2.78-2.90(m,2 H)2.64(s,4 H)2.47-2.57(m,2 H)1.96-2.05(m,1 H)1.69-1.80(m,1 H)1.57-1.66(m,4 H)0.97-1.14(m,4 H)0.62-0.73(m,4 H)

[0127] Example B-11: Synthesis of 3-({4-[4-(4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-2-methoxybenzoyl)piperazin-1-yl]-3-fluorophenyl}amino)-1-methylpiperidine-2,6-dione (ICT-0001554) Step 1) Synthesis of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}-1-methylpiperidine-2,6-dione [ka] tert-Butyl-4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate (0.2 g, 492 μmol) was dissolved in methanol (1% acetic acid) (10 ml), and formaldehyde (73.8 mg, 2.46 mmol, 35% in water) and NaBH4 (46.5 mg, 1.23 mmol) were added and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was suspended in saturated Na2CO3 solution and extracted three times with CHCl2. The combined organic layers were dried over Na2SO4, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (DCM / MeOH = 99 / 1) to give the compound (200 mg). MS (ESI, m / z): [M+H] + =[421.5].

[0128] Step 2) Synthesis of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione [ka] The reaction mixture was stirred at room temperature for 1 hour in a solution of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}-1-methylpiperidine-2,6-dione (0.2 g, 492 μmol) in 30% TFA in DCM. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (120 mg). MS (ESI, m / z): [M+H] + =[321.5].

[0129] Step 3) Synthesis of 3-({4-[4-(4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-2-methoxybenzoyl)piperazin-1-yl]-3-fluorophenyl}amino)-1-methylpiperidine-2,6-dione (ICT-0001554) [ka] HATU (71.2 mg, 187 μmol) was added to 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-2-methoxybenzoic acid (59.6 mg, 125 μmol) and 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}-1-methylpiperidine-2,6-dione (40.0 mg, 125 μmol) in 1 mL of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (123 mg). MS (ESI, m / z): [M+H] + =[780.9]

[0130] 1 H NMR(500 MHz,DMSO-d6)δ ppm 8.32(s,2 H)8.23(s,1 H)7.87(s,1 H)7.03(s,2 H)6.93(d,J=8.09 Hz,1 H)6.78-6.81(m,1 H)6.48(s,1 H)6.45(s,1 H)6.37(d,J=8.70 Hz,2 H)5.87(d,J=7.93 Hz,2 H)4.82(dd,J=7.86,3.59 Hz,2 H)4.24-4.30(m,2 H)4.03(dd,J=13.89,6.41 Hz,1 H)3.85(s,5 H)2.86-2.92(m,3 H)2.71-2.78(m,2 H)2.65-2.69(m,1 H)2.62(s,4 H)2.29(s,1 H)1.74(d,J=3.97 Hz,1 H)1.56-1.66(m,4 H)1.05(br.s.,3 H)0.95-1.03(m,1 H)0.87(d,J=6.56 Hz,1 H)0.67(t,J=7.32 Hz,5 H)

[0131] Example B-12: Synthesis of 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001556) Step 1) Synthesis of benzyl 4-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}piperazine-1-carboxylate [ka] AcOH (3 mL) was added to a solution of benzylpiperazine-1-carboxylate (3.0 g, 13.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.71 g, 13.6 mmol) in MeOH (50 mL). After stirring at 25 °C for 1 hour, NaBHCN (2.61 g, 42.2 mmol) was added to the mixture, and the resulting mixture was stirred at 25 °C for 16 hours. The mixture reaction was quenched with aqueous NaHCO and extracted with EtOAc. The organic layer was washed with brine solution, NaSO, and concentrated. The residue was purified on silica gel by PE:EtOAc (5:1) column chromatography to give the title compound. (3.6 g) MS (ESI, m / z): [M+H] + =[404.5],

[0132] Step 2) Synthesis of tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate [ka] Benzyl 4-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}piperazine-1-carboxylate (3.6 g, 8.92 mmol) was dissolved in EtOH (50 ml) and 10% Pd / C (360 mg) was added. The reaction was stirred under a H balloon for 5 hours. The reaction was filtered and concentrated under reduced pressure to give the title compound (2.7 g). MS (ESI, m / z): [M+H] + =[270.2].

[0133] Step 3) Synthesis of 3-(4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate (2.7 g, 10.0 mmol), 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydroptalazin-2-yl)piperidine-2,6-dione (2.7 g, 1.04 mmol), and DIPEA (3.8 g, 2.07 mmol) in NMP solution (5 mL) was stirred at 130 °C for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 5 mL of DCM followed by 0.5 mL of TFA and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. (3.1 g) MS (ESI, m / z): [M+H] + = [441.2 g / mol].

[0134] Step 4) Synthesis of 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001556) [ka] HATU (47.8 mg, 126 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol) and 3-{1-oxo-6-[4-(piperidin-4-yl)piperazin-1-yl]-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (45.9 mg, 105 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (27.1 mg, 209 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (81 mg). MS (ESI, m / z): [M+H] + =[899.1]

[0135] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.32(s,2 H)8.21(d,J=7.63 Hz,1 H)8.02(d,J=8.55 Hz,1 H)7.87(s,2 H)7.01(s,1 H)6.90(d,J=7.78 Hz,1 H)5.56-5.67(m,1 H)4.82(dd,J=8.09,3.66 Hz,2 H)4.03(dd,J=13.35,6.18 Hz,2 H)3.84(s,5 H)2.79-2.95(m,3 H)2.62(s,6 H)2.46-2.58(m,2 H)1.95-2.07(m,1 H)1.70-1.80(m,2 H)1.51-1.67(m,8 H)1.19(t,J=7.02 Hz,1 H)1.11(d,J=7.63 Hz,1 H)1.05(br.s.,4 H)0.93-1.03(m,2 H)0.87(d,J=10.22 Hz,1 H)0.67(t,J=7.32 Hz,6 H)

[0136] Example B-13: Synthesis of 3-(6-(4-((1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)azetidin-3-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001557) Step 1) Synthesis of 1-Boc-azetidin-3-yl-methanol [ka] Methanesulfonyl chloride (5.11 g, 44.8 mmol) in CHCl (20 mL) was added to a solution of 1-Boc-azetidin-3-yl-methanol (5.0 g, 37.4 mmol) in CHCl (100 mL), followed by triethylamine (5.67 g, 56.1 mmol) at 0 °C and stirred for 2 h. The reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layers were combined, washed with brine solution (50 mL × 2), and dried over anhydrous sodium sulfate. It was then filtered and concentrated. The residue was used in the next step without further purification. (6.5 g) MS (ESI, m / z): [M+H] + =[380.1].

[0137] Step 2) Synthesis of 3-(6-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-4-methyl-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] K2CO3 (10.1 g, 73.5 mmol) was added to a solution of 1-Boc-azetidin-3-ylmethanol (6.5 g, 24.5 mmol) and 1-Z-piperazine (5.40 g, 24.5 mmol) in 50 ml of acetonitrile at room temperature, and the reaction was then stirred at 80 °C for 6 hours. After filtering the reaction and concentrating under reduced pressure, the residue was purified by MPLC to give the title compound. The resulting compound (7.1 g, 18.2 mmol) was dissolved in EtOH (50 ml) and 10% Pd / C (710 mg) was added. The reaction was stirred under a H2 balloon for 5 hours. The reaction was filtered, and the filtrate was concentrated to give the title compound (5.4 g). MS (ESI, m / z): [M+H] + =[256.2].

[0138] Step 3) Synthesis of 3-(6-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydroptarazin-2-yl)piperidine-2,6-dione [ka] A solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydroptalazine-2-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), 3-(6-(4-(azetidin-3-ylmethyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (441 mg, 1.73 mmol), and DIPEA (670 mg, 5.19 mmol) was stirred at 120° C. for 5 hours. Then, 0.2 ml of TFA was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to obtain the title compound, which was used in the next step without further purification. (420 mg) MS(ESI, m / z): [M+H] + =[425.2].

[0139] Step 4) Synthesis of 3-(6-(4-((1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)azetidin-3-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001557) [ka] HATU (47.8 mg, 126 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol) and 3-(6-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (44.4 mg, 105 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (27.1 mg, 209 μmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (63 mg). MS (ESI, m / z): [M+H] + =[885.1]

[0140] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.33(s,2 H)7.90(s,1 H)7.20(s,2 H)7.14(d,J=8.09 Hz,2 H)4.75-4.92(m,2 H)4.03(dd,J=13.28,6.10 Hz,1 H)3.86(s,5 H)2.78-2.98(m,1 H)2.62(s,6 H)2.49-2.58(m,1 H)2.47(s,1 H)2.29(br.s.,1 H)1.54-1.66(m,8 H)1.15-1.22(m,4 H)0.67(t,J=7.25 Hz,6 H)

[0141] Example B-14: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydroptaladin-5-yl)amino)ethyl)-3-methoxybenzamide (ICT-0001558) Step 1) Synthesis of 3-(8-((2-aminoethyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydroptalazin-2-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), N-tert-Boc-ethylenediamine (277 mg, 1.73 mmol), and DIPEA (670 mg, 3.46 mmol) in NMP (2 mL) was stirred at 110° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. (380 mg) MS (ESI, m / z): [M+H] + =[316.1].

[0142] Step 2) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydroptaladin-5-yl)amino)ethyl)-3-methoxybenzamide (ICT-0001558) [ka] HATU (34.3 mg, 146 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (58 mg, 121 μmol) and 3-{8-[(2-aminoethyl)amino]-1-oxo-1,2-dihydroptaradin-2-yl}piperidine-2,6-dione (38.3 mg, 121 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (31.4 mg, 243 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (63.3 mg). MS (ESI, m / z): [M+H] + =[775.9]

[0143] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.03(s,1 H)8.42(s,1 H)8.36(d,J=8.55 Hz,1 H)8.24(s,1 H)7.93(s,1 H)7.68(t,J=7.93 Hz,1 H)7.51-7.55(m,1 H)7.49(d,J=8.54 Hz,1 H)7.13(d,J=8.85 Hz,1 H)6.94(d,J=7.63 Hz,1 H)4.86-4.97(m,1 H)4.12(dd,J=13.43,6.26 Hz,1 H)3.95(s,4 H)3.49(br.s.,4 H)2.98-3.05(m,1 H)2.70(s,5 H)2.61-2.67(m,1 H)2.55(br.s.,1 H)2.37(s,1 H)2.09(s,2 H)1.64-1.72(m,2 H)0.75(t,J=7.32 Hz,5 H)

[0144] Example B-15: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001559) Step 1) Synthesis of 2-(2-(2-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)acetic acid [ka] 6-Fluoro-1,2-dihydrophthalazin-1-one (300 mg, 1.09 mmol) and 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetic acid (407 mg, 1.09 mmol) were dissolved in NMP (3 mL), and DIPEA (5 equivalents) was added to the reaction mixture. The mixture was stirred at 130 °C overnight. The reaction was quenched with water and extracted with DCM, NH4Cl, and brine solution. The mixture was dried over MgSO4. The reaction mixture was loaded onto a silica gel column and separated by MPLC (HX / EA 30% -> 50%, 10 min). The product was obtained as an oil. The compound was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound, which was used in the next step without further purification. (170 mg) MS (ESI, m / z): [M+H] + =[463.5],

[0145] Step 2) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001559) [ka] HATU (47.8 mg, 126 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (70 mg, 125 μmol) and 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaradin-6-yl]amino}ethoxy)ethoxy]ethoxy}acetic acid (48.4 mg, 105 μmol). Ethyl bis(propan-2-yl)amine was then added. The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (72 mg). MS (ESI, m / z): [M+H] + =[1005.2]

[0146] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)8.32(s,2 H)8.20(d,J=8.24 Hz,1 H)8.06-8.11(m,1 H)7.81-7.89(m,3 H)7.52(d,J=8.09 Hz,1 H)7.03(dd,J=8.85,2.14 Hz,1 H)6.93-6.99(m,2 H)6.86(d,J=9.61 Hz,2 H)6.68-6.75(m,1 H)4.75-4.89(m,2 H)3.95-4.06(m,2 H)3.78-3.89(m,9 H)3.45-3.55(m,13 H)2.77-2.91(m,4 H)2.62(s,5 H)2.47-2.58(m,1 H)1.67-1.76(m,1 H)1.53-1.66(m,4 H)1.04(d,J=6.56 Hz,2 H)0.88(d,J=6.41 Hz,2 H)0.67(t,J=7.32 Hz,5 H)

[0147] Example B-16: Synthesis of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]-3-methoxybenzamide (ICT-0001560) Step 1) Synthesis of tert-butyl N-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]carbamate [ka] tert-Butyl N-{1-[2-(piperazin-1-yl)piperidin-4-yl}carbamate (0.1 g, 320 μmol) and ethyl bis(propan-2-yl)amine (279 μL, 1.6 mmol) were added to a solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl) (92.6 mg, 320 μmol) in NMP (2 mL). The mixture was then reduced pressure and concentrated. The residue was purified by column chromatography in hexane / ethyl acetate (50-90%) to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =582.7.

[0148] Step 2) Synthesis of 3-(6-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione [ka] A solution of tert-butyl N-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]carbamate (150 mg, 258 μmol) in 30% TFA in DCM (1 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, it was concentrated under reduced pressure. After completion of the reaction, it was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (120 mg). MS (ESI, m / z): [M+H] + =482.6.

[0149] Step 3) Synthesis of 3-(6-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione (ICT-0001560) [ka] A solution of 3-(6-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (124 mg, 257 μmol), HATU (196 mg, 515 μmol) and ethylbis(propan-2-yl)amine (333 mg, 2.57 mmol) in DMF (2 mL) was added to 3-(6-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-propan-2-yl)amine) in DMF (2 mL). -methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxybenzoic acid (123 mg, 257 μmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (82 mg). MS (ESI, m / z): [M+H] + =942.2

[0150] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.41(s,1 H)8.34(d,J=8.09 Hz,1 H)8.11-8.21(m,1 H)8.08(d,J=8.85 Hz,1 H)7.93(s,1 H)7.45-7.55(m,3 H)7.10(s,1 H)5.64-5.77(m,1 H)4.90(dd,J=8.24,3.81 Hz,1 H)4.12(dd,J=13.58,6.87 Hz,1 H)3.93-3.98(m,3 H)3.42-3.48(m,5 H)2.86-3.04(m,4 H)2.70(s,3 H)2.56-2.66(m,7 H)2.37(s,1 H)1.96-2.13(m,4 H)1.89-1.94(m,1 H)1.74-1.86(m,4 H)1.58-1.74(m,8 H)1.22-1.26(m,2 H)1.05-1.18(m,4 H)0.93-1.00(m,1 H)0.86(t,J=7.17 Hz,1 H)0.75(t,J=7.32 Hz,3 H)

[0151] Example B-17: Synthesis of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001561) Step 1) Synthesis of tert-butyl N-(1-{2-[4-(2-fluoro-4-nitrophenyl)piperazine-1-dei]ethyl}piperidin-4-yl)carbamate [ka] tert-Butyl N-{1-[2-(piperazin-1-yl)ethyl]piperidin-4-yl}carbamate (0.1 g, 320 μmol) and dipotassium carbonate (221 mg, 1.6 mmol) were added to a solution of 1,2-difluoro-4-nitrobenzene (51.6 mg, 320 μmol) in DMF (1 mL). The reaction was stirred at 85°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (0-60%) to give the title compound (145 mg). MS (ESI, m / z): [M+H] + =452.5.

[0152] Step 2) Synthesis of tert-butyl N-(1-{2-[4-(4-amino-2-fluorophenyl)piperazine-1-dei]ethyl}piperidin-4-yl)carbamate [ka] Iron powder (179 mg, 3.2 mmol) was added to tert-butyl N-(1-{2-[4-(2-(2-fluoro-4-nitrophenyl)piperazin-1-yl]ethyl}piperidin-4-yl)carbamate (145 mg, 3.2 μmol) in saturated NHCl / THF (1:1) (2 mL). The reaction was stirred at 85° C. for 2 h. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with DCM / MeOH (0-5%) to give the title compound (0.65 g). (ESI, m / z): [M+H] + =422.5.

[0153] Step 3) Synthesis of tert-butyl N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}carbamate [ka] 3-Bromoperidin-2,6-dione (182 mg, 949 μmol) and sodium bicarbonate (239 mg, 2.85 mmol) were added to tert-butyl N-(1-{2-[4-(4-amino-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-4-yl)carbamate (0.2 g, 474 μmol) in DMF (3 mL). 3-Bromopiperidine-2,6-dione (182 mg, 949 μmol) and sodium bicarbonate (239 mg, 2.85 mmol) were added to a solution of tert-butyl N-(1-{2-[4-amino-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-4-yl)carbamate and dried over MgSO4. The mixture was then evaporated under reduced pressure and concentrated. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (65 mg). MS (ESI, m / z): [M+H] + =533.7.

[0154] Step 4) Synthesis of 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione [ka] The reaction mixture of tert-butyl N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}carbamate (65 mg, 122 μmol) in 30% TFA in DCM (5 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (110 mg). MS (ESI, m / z): [M+H] + =433.5.

[0155] Step 5) Synthesis of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001561) [ka] 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione (111 mg, 257 μmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium hexafluoro-λ-phosphanoid A solution of 3-[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl}amino}-3-methoxybenzoic acid (123 mg, 257 μmol) in DMF (2 mL) with ethyl bis(propan-2-yl)amine (333 mg, 2.57 mmol) was added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (130 mg). MS (ESI, m / z): [M+H] + =893.1

[0156] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.79(s,1 H)8.61(d,J=3.51 Hz,2 H)8.38-8.43(m,4 H)8.35(d,J=8.39 Hz,2 H)8.23-8.26(m,2 H)7.94(s,2 H)7.48-7.54(m,5 H)7.40(dd,J=8.32,4.20 Hz,2 H)6.83(t,J=9.31 Hz,1 H)6.52(dd,J=14.88,1.75 Hz,1 H)6.39-6.47(m,1 H)5.84(d,J=7.48 Hz,1 H)4.90(dd,J=8.16,3.74 Hz,2 H)4.26(br.s.,1 H)4.12(dd,J=13.58,6.26 Hz,2 H)3.96(s,6 H)2.96-3.04(m,4 H)2.85-2.90(m,3 H)2.69-2.72(m,7 H)1.21-1.27(m,5 H)0.95(d,J=10.53 Hz,1 H)0.75(t,J=7.32 Hz,7 H)

[0157] Example B-18: Synthesis of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001562) Step 1) Synthesis of tert-butyl N-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]carbamate [ka] tert-Butyl N-(1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}piperidin-4-yl) and ethyl bis(propan-2-yl)amine (207 mg, 1.61 mmol) were added to a solution of 3-(6-fluoro-4-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (93 mg, 321 μmol) in NMP (2 mL). The mixture was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (50-90%) to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =581.7.

[0158] Step 2) Synthesis of 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperidin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione [ka] The reaction mixture of tert-butyl N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}carbamate (64 mg, 120 μmol) in 30% TFA in DCM (1 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, it was concentrated under reduced pressure. After completion of the reaction, it was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (120 mg). MS (ESI, m / z): [M+H] + =432.6.

[0159] Step 3) Synthesis of 3-(6-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione (ICT-0001562) [ka] To 3-[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (56 mg, 116 μmol) in DMF (2 mL) was added 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperidin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione (50 mg, 116 μmol), HATU (88.1 mg, 232 μmol), and ethyl bis(propan-2-yl)amine (74.9 mg, 579 μmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (38 mg). MS (ESI, m / z): [M+H] + =942.2

[0160] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.79(s,1 H)8.40-8.47(m,2 H)8.35(d,J=8.55 Hz,2 H)7.95(s,1 H)7.49-7.55(m,3 H)6.84(t,J=9.23 Hz,2 H)6.47-6.56(m,2 H)6.42(d,J=8.54 Hz,1 H)5.81(d,J=7.78 Hz,1 H)4.90(dd,J=7.86,3.43 Hz,2 H)4.20-4.30(m,1 H)4.12(dd,J=13.66,6.18 Hz,2 H)3.96(s,6 H)3.12(d,J=10.22 Hz,3 H)3.00(dd,J=13.50,8.32 Hz,2 H)2.70(s,6 H)2.64(s,1 H)2.53-2.62(m,4 H)2.37(s,1 H)2.06-2.11(m,1 H)1.79-1.89(m,1 H)1.74(d,J=10.53 Hz,1 H)1.66-1.70(m,5 H)1.34(br.s.,1 H)1.21-1.27(m,2 H)1.10-1.19(m,3 H)0.75(t,J=7.32 Hz,6 H)

[0161] Example B-19: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001563) Step 1) Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] Under a nitrogen atmosphere, a mixture of 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydropetalazin-2-yl]piperidine-2,6-dione (200 mg, 563 μmol), tert-butyl 2-bromoacetate (121 mg, 619 μmol), and DIPEA (109 mg, 844 μmol) in DCM was stirred at 35° C. for 5 hours. The residue was purified by column chromatography (EA / hexane 50%). The compound was dissolved in 1 ml of DCM followed by 0.2 ml of TFA. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to obtain the title compound, which was used in the next step without further purification. (170 mg) MS (ESI, m / z): [M+H] + =[470.5],

[0162] Step 2) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001563) [ka] HATU was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (70 mg, 125 μmol) and 3-(6-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydrobutalazin-2-ylpiperidine-2,6-dione (43.3 mg, 105 μmol) in 1 ml of DMF at room temperature. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[956.2].

[0163] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)8.32(s,2 H)8.17-8.24(m,1 H)8.05(d,J=8.70 Hz,1 H)7.90(br.s.,1 H)7.47(d,J=8.85 Hz,1 H)6.97-6.99(m,1 H)6.88(d,J=8.09 Hz,1 H)5.63(d,J=7.93 Hz,1 H)4.82(dd,J=8.09,3.51 Hz,1 H)4.02(dd,J=13.66,5.87 Hz,1 H)3.84(s,4 H)2.80-2.94(m,2 H)2.62(s,13 H)2.46-2.59(m,2 H)2.43(m,11H)1.96-2.05(m,1 H)1.69-1.79(m,2 H)1.53-1.65(m,4 H)1.39(br.s.,1 H)1.12-1.24(m,1 H)1.05(br.s.,2 H)0.99(d,J=11.60 Hz,1 H)0.87(d,J=11.60 Hz,1 H)0.68(t,J=7.32 Hz,5 H)

[0164] Example B-20: 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide 4- Synthesis of {[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001564) Step 1) Synthesis of tert-butyl N-(1-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}piperidin-4-yl) [ka] tert-Butyl N-{1-[2-(piperidin-4-yl)ethyl]piperidin-4-yl}carbamate (0.1 g, 642 μmol) and dipotassium carbonate (444 mg, 3.21 mmol) were added to a solution of 1,2-difluoro-4-nitrobenzene (200 mg, 642 μmol) in DMF (1 mL). The reaction was stirred at 85°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (0-60%) to give the title compound (145 mg). MS (ESI, m / z): [M+H] + =451.6

[0165] Step 2) Synthesis of tert-butyl N-(1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}piperidin-4-yl)carbamate [ka] Iron powder (174 mg, 3.1 mmol) was added to tert-butyl N-(1-{2-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]ethyl}piperidin-4-yl)carbamate (145 mg, 3.1 mmol) in saturated NH4Cl / THF (1:1) (2 mL). The reaction was stirred at 85 °C for 2 h. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with DCM / MeOH (0-5%) to give the title compound (180 mg). (ESI, m / z): [M+H] + =421.6.

[0166] Step 3) Synthesis of tert-butyl N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}carbamate [ka] 3-Bromoperidine-2,6-dione (164 mg, 856 μmol) and sodium bicarbonate (216 mg, 2.57 mmol) were added to tert-butyl N-(1-{2-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]ethyl}piperidin-4-yl)carbamate (180 mg, 428 μmol) in DMF (2 mL). The reaction was stirred at 85° C. for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (125 mg). MS (ESI, m / z): [M+H] + =532.7.

[0167] Step 4) Synthesis of 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperidin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione [ka] A solution of tert-butyl N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}carbamate (125 mg, 235 μmol) in 30% TFA in DCM (5 mL) was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (101 mg). MS (ESI, m / z): [M+H] + =432.6.

[0168] Step 5) Synthesis of 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001564) [ka] 3-[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (55 mg, 116 μmol) in DMF (2 mL) was added to 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperidin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione (50 mg, 116 μmol), HATU (88 mg, 232 μmol), and ethyl bis(propan-2-yl)amine (75 mg, 579 μmol). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (62 mg). MS (ESI, m / z): [M+H] + =892.1

[0169] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.41(s,1 H)8.35(d,J=8.39 Hz,1 H)8.06(d,J=9.00 Hz,1 H)7.94(s,1 H)7.47-7.55(m,3 H)7.07(s,1 H)5.68(d,J=7.78 Hz,1 H)4.90(dd,J=8.16,3.74 Hz,1 H)4.04-4.15(m,3 H)3.96(s,3 H)2.87-3.04(m,5 H)2.70(s,3 H)2.53-2.67(m,3 H)2.49(s,3 H)2.02-2.11(m,1 H)1.81(s,3 H)1.79(s,2 H)1.64-1.73(m,5 H)1.61(br.s.,4 H)1.26(d,J=6.56 Hz,8 H)1.03-1.17(m,3 H)0.95(d,J=10.83 Hz,1 H)0.75(t,J=7.32 Hz,3H)

[0170] Example B-21: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)-3-methoxybenzamide (ICT-0001566) Step 1) Synthesis of tert-butyl N-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamate [ka] Iron powder (658 mg, 11.8 mmol) was added to tert-butyl N-[1-(2-fluoro-4-nitrophenyl)piperazin-4-yl]carbamate (0.4 g, 1.2 mmol) in saturated NH4Cl / THF (1:1) (10 mL). The reaction was stirred at 85 °C for 2 h. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with DCM / MeOH (0-5%) to give the title compound (0.3 g). (ESI, m / z): [M+H] + =310.4.

[0171] Step 3) Synthesis of tert-butyl N-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)carbamate [ka] 3-Bromoperidine-2,6-dione (372 mg, 1.94 mmol) and sodium bicarbonate (670 mg, 4.85 mmol) were added to a solution of tert-butyl N-[1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamate (0.3 g, 970 μmol) in DMF (3 mL). 3-Bromoperidine-2,6-dione (372 mg, 1.94 mmol) and sodium bicarbonate (670 mg, 4.85 mmol) were added to the reaction mixture at 85 °C for 3 hours. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (393 mg). MS (ESI, m / z): [M+H] + =421.5.

[0172] Step 4) Synthesis of 3-[4-(4-aminopiperidin-1-yl)-3-fluorophenyl]piperidine-2,6-dione [ka] A solution of tert-butyl N-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)carbamate (408 mg, 970 μmol) in 30% TFA in DCM (30 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (310 mg). MS (ESI, m / z): [M+H] + =321.4.

[0173] Step 5) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)-3-methoxybenzamide (ICT-0001566) [ka] 3-{[4-(4-(4-aminopiperidin-1-yl)-3-fluorophenyl]amino}piperidine-2,6-dione (50 mg, 156 μmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium (119 mg, 312 μmol) and ethylbis(propan-2-yl)amine (202 mg, 1.56 mmol) in DMF (1 mL) with 4-{[(4R)-5-(cyclohexylmethyl) )-4-Ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (74.5 mg, 156 μmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (130 mg). MS (ESI, m / z): [M+H] + =780.9

[0174] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.34(s,1 H)8.28(d,J=8.39 Hz,1 H)8.13(d,J=7.93 Hz,1 H)7.86(s,1 H)7.40-7.49(m,2 H)6.81(t,J=9.31 Hz,1 H)6.45(dd,J=15.03,1.91 Hz,1 H)6.36(d,J=8.55 Hz,1 H)5.75(d,J=7.63 Hz,1 H)4.83(dd,J=7.86,3.74 Hz,1 H)4.16-4.24(m,1 H)4.05(dd,J=13.66,6.18 Hz,1 H)3.89(s,3 H)3.79-3.87(m,1 H)3.10(d,J=11.14 Hz,2 H)2.92(dd,J=13.43,8.24 Hz,1 H)2.54-2.72(m,7 H)2.46-2.54(m,1 H)1.98-2.04(m,1 H)1.80-1.83(m,2 H)1.65-1.78(m,5 H)1.58-1.63(m,4 H)1.17(s,1 H)0.94-1.14(m,4 H)0.89(d,J=10.22 Hz,1 H)0.68(t,J=7.32Hz,3H)

[0175] Example B-22: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001567) Step 1) Synthesis of 3-[6-(4-aminopiperidin-1-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione [ka] A solution of tert-butyl (2R)-2-[(piperazin-1-yl)methyl]morpholine-4-carboxylate (300 mg, 1.04 mmol), 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (208 mg, 1.04 mmol), and DIPEA (402 mg, 3.11 mmol) in NMP (2 mL) was stirred at 140° C. for 6 hours. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was triturated with DCM and passed through an NH-DM 1020 Chromatrex pad to obtain the title compound, which was used in the next step without further purification. (130 mg) MS (ESI, m / z): [M+H] + = [370.4 g / mol].

[0176] Step 2) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001567) [ka] HATU (103 mg, 271 μmol) was added to 3-[6-(4-aminopiperidin-1-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (50 mg, 135 μmol) and 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (64.6 mg, 135 μmol) in 1 mL of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] +=[830.0]

[0177] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.34(s,1 H)8.28(d,J=8.39 Hz,1 H)8.13(d,J=7.93 Hz,1 H)7.86(s,1 H)7.40-7.49(m,2 H)6.81(t,J=9.31 Hz,1 H)6.45(dd,J=15.03,1.91 Hz,1 H)6.36(d,J=8.55 Hz,1 H)5.75(d,J=7.63 Hz,1 H)4.83(dd,J=7.86,3.74 Hz,1 H)4.16-4.24(m,1 H)4.05(dd,J=13.66,6.18 Hz,1 H)3.89(s,3 H)3.79-3.87(m,1 H)3.10(d,J=11.14 Hz,2 H)2.92(dd,J=13.43,8.24 Hz,1 H)2.54-2.72(m,7 H)2.46-2.54(m,1 H)1.98-2.04(m,1 H)1.80-1.83(m,2 H)1.65-1.78(m,5 H)1.58-1.63(m,4 H)1.17(s,1 H)0.94-1.14(m,4 H)

[0178] Example B-23: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl}piperazin-1-yl}piperidin-4-yl]piperidin-4-yl]-3-methoxybenzamide (ICT-0001568) Step 1) Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] Under a nitrogen atmosphere, a mixture of 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazine-2,6-dione (113 mg, 613 μmol) and tert-butyl N-{1-[3-(piperazin-1-yl)propyl]piperidin-4-yl}carbamate (200 mg, 613 μmol), DIPEA (396 mg, 3.06 mmol) in NMP was stirred at 140 °C for 8 hours. The residue was purified by column chromatography (EA / hexane 50%). The compound was dissolved in 1 ml of DCM. Then, 0.2 ml of TFA was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to obtain the title compound, which was used in the next step without further purification. (110 mg) MS(ESI, m / z): [M+H] + =[596.7],

[0179] Step 2) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001568) [ka] HATU (115 mg, 303 μmol) was added to 3-[6-(4-aminopiperidin-1-yl)-4-methyl-1-oxo-1,2-dihydroptaradin-2-yl]piperidine-2,6-dione (75 mg, 151 μmol) and 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (72.3 mg, 151 μmol), followed by the addition of ethylbis(propan-2-yl)amine (97.8 mg, 757 μmol) in 1 ml of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[956.2]

[0180] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.34(s,1 H)8.27(d,J=8.39 Hz,1 H)7.86(s,1 H)7.40-7.44(m,2 H)6.83(t,J=9.31 Hz,1 H)6.52(dd,J=14.88,1.75 Hz,1 H)6.40-6.47(m,1 H)4.83(dd,J=8.24,3.66 Hz,1 H)4.26(br.s.,1 H)4.12(dd,J=13.58,6.26 Hz,2 H)4.04(dd,J=13.73,6.10 Hz,1 H)3.94(s,6 H)3.88(s,3 H)2.96-3.04(m,4 H)2.92(dd,J=13.50,8.16 Hz,1 H)2.85-2.90(m,4 H)2.69-2.73(m,7 H)2.60-2.67(m,4 H)2.49-2.54(m,1 H)2.01-2.03(m,3 H)1.56-1.63(m,4 H)1.21-1.26(m,5 H)1.16-1.21(m,4 H)0.96(s,1 H)0.67(t,J=7.32 Hz,3 H)

[0181] Example B-24: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-({4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}methyl)piperidin-4-yl]-3-methoxybenzamide (ICT-0001569) Step 1) Synthesis of tert-butyl N-{1-[(4-nitrophenyl)methyl]piperidin-4-yl}carbamate [ka] tert-Butyl N-(piperidin-4-yl)carbamate (1.21 g, 6.02 mmol) and triethylamine (937 mg, 9.26 mmol) were added to a solution of 1-(bromomethyl)-4-nitrobenzene (1 g, 4.63 mmol) in CHCl (1 mL). The reaction was stirred at room temperature for 6 hours. After the reaction was complete, the reaction was poured into water and washed twice. The organic layer was dried over MgSO and then concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (0-60%) to give the title compound (1.55 g). MS (ESI, m / z): [M+H] + =336.4.

[0182] Step 2) Synthesis of tert-butyl N-{1-[(4-aminophenyl)methyl]piperidin-4-yl}carbamate [ka] Iron powder (3.75 g, 67.1 mmol) was added to tert-butyl N-{1-[(4-nitrophenyl)methyl]piperidin-4-yl}carbamate (1.5 g, 67.1 mmol) in saturated NH4Cl / THF (1:1) (20 mL). The reaction was stirred at 85 °C for 2 h. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography with DCM / MeOH (0-5%) to give the title compound (1.60 g). (ESI, m / z): [M+H] + =306.4

[0183] Step 3) Synthesis of tert-butyl N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}carbamate [ka] 3-Bromoperidine-2,6-dione (8.05 g, 41.9 mmol) and sodium bicarbonate (4.4 g, 52.4 mmol) were added to a solution of tert-butyl N-{1-[(4-aminophenyl)methyl]piperidin-4-yl}carbamate (1.6 g, 5.24 mmol) in DMF (10 mL). 3-Bromoperidine-2,6-dione (8.05 g, 41.9 mmol) and sodium bicarbonate (4.4 g, 52.4 mmol) were stirred at 85 °C for 3 hours. After the reaction was complete, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (2.4 g). MS (ESI, m / z): [M+H] + =417.5.

[0184] Step 4) Synthesis of 3-[(4-{4-[2-(4-aminopiperidin-1-yl)ethyl]piperazin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione [ka] tert-Butyl N-[1-({4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}methyl)piperidin-4-yl]carbamate (2.46 g, 5.91 mmol) in 30% TFA DCM (5 mL). The reaction was stirred at room temperature for 30 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by amine column chromatography using DCM / MeOH (0-5%) to give the title compound (1.66 g). MS (ESI, m / z): [M+H] + =317.4

[0185] Step 5) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-({4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}methyl)piperidin-4-yl]-3-methoxybenzamide (ICT-0001569) [ka] To 3-({4-[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol) in DMF (2 mL) was added 3-({4-[(4-aminopiperidin-1-yl)methyl}phenyl}amino)piperidine-2,6-dione (49.7 mg, 157 μmol), HAT U (119 mg, 314 μmol) and ethylbis(propan-2-yl)amine (27 mg, 209 μmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (35 mg). MS (ESI, m / z): [M+H] + =770.1

[0186] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.81(s,1 H)8.38-8.46(m,1 H)8.34(d,J=8.39 Hz,1 H)8.21(d,J=6.71 Hz,1 H)7.87-7.99(m,1 H)7.44-7.54(m,2 H)7.07(m,J=7.93 Hz,2 H)6.66(m,J=8.39 Hz,2 H)4.90(dd,J=8.24,3.81 Hz,1 H)4.27-4.37(m,1 H)4.12(dd,J=13.66,6.33 Hz,1 H)3.92-3.99(m,3 H)3.85(br.s.,1 H)3.55-3.67(m,2 H)3.51(br.s.,1 H)2.99(dd,J=13.58,8.24 Hz,2 H)2.65-2.80(m,5 H)2.06-2.15(m,1 H)1.76-1.99(m,4 H)1.63-1.73(m,4 H)1.60(br.s.,2 H)1.04-1.28(m,10 H)0.75(t,J=7.40 Hz,3 H)

[0187] Example B-25: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenoxy}ethoxy)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001570) Step 1) Synthesis of 2-[2-(2-fluoro-4-nitrophenoxy)ethoxy]ethan-1-ol [ka] Potassium 2-methylpropane-2-oleate (354 mg, 3.14 mmol) was added in portions to a stirred solution of 2-(2-hydroxyethoxy)ethan-1-ol (667 mg, 6.29 mmol) in THF (3 mL) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by the slow addition of 3-chloro-4-fluoronitrobenzene (200 mg, 1.26 mmol) (the reaction turned dark). The mixture was stirred at 0 °C for 10 min, followed by the removal of the ice bath. The reaction was allowed to warm to room temperature (10 min) and stirred for 1 h. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (50 mL) and HO (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organic layers were dried (NaSO), filtered, and the solvent removed in vacuo to leave the product. The residue was purified by column chromatography using hexane / ethyl acetate (0-60%) to give the title compound (0.4 g). MS (ESI, m / z): [M+H] + =246.2.

[0188] Step 2) Synthesis of 2-[2-(2-fluoro-4-nitrophenoxy)ethoxy]ethyl methanesulfonate [ka] Methanesulfonyl chloride (374 mg, 3.26 mmol) in CHCl (15 mL) was added to 2-[2-(2-(2-fluoro-4-nitrophenoxy)ethoxy]ethan-1-ol (400 mg, 1.63 mmol) in CHCl (50 mL) followed by trimethylamine (413 mg, 4.08 mmol) at 0 °C and then stirred for 2 h. The reaction was warmed to room temperature and stirred for an additional 2 h. The reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layers were combined, washed with brine solution (50 mL × 2), dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was used in the next step without further purification. (527 mg), MS (ESI, m / z): [M+H] + =[551.0],

[0189] Step 3) Synthesis of tert-butyl N-(1-{2-[2-(2-fluoro-4-nitrophenoxy)ethoxy]ethyl)piperidin-4-yl)carbamate: [ka] Ethyl bis(propan-2-yl)amine (1.05 g, 8.16 mmol) was added to a solution of 2-[2-(2-(2-fluoro-4-nitrophenoxy)ethoxy]ethyl methanesulfonate (527 mg, 1.63 mmol) tert-butyl N-(piperidin-4-yl)carbamate (427 mg, 4.08 mmol) in 50 ml of acetonitrile at room temperature, and the reaction was stirred at 80° C. for 6 hours. (6.01 g). MS (ESI, m / z): [M+H] + =[318.4].

[0190] Step 4) Synthesis of tert-butyl N-(1-{2-[2-(4-amino-2-fluorophenoxy)ethoxy]ethyl}piperidin-4-yl)carbamate [ka] 10 mL of saturated NH4Cl was added to a solution of tert-butyl N-(1-{2-[2-(2-(2-(2-nitrophenoxy)ethoxy]ethyl}piperidin-4-yl)carbamate (0.9 g, 2.11 mmol) and iron (2.35 g, 42.1 mmol) in THF (10 ml). The reaction was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (0.75 g). MS (ESI, m / z): [M+H] + =[398.5].

[0191] Step 5) Synthesis of tert-butyl N-{1-[2-(2-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenoxy}ethoxy)ethyl]piperidin-4-yl}carbamate [ka] 3-Bromoperidine-2,6-dione (2.9 g, 15.1 mmol) and sodium bicarbonate (1.59 g, 18.9 mmol) were added to tert-butyl N-(1-{2-[2-(4-amino-2-fluorophenoxy)ethoxy]ethyl}piperidin-4-yl)carbamate (750 mg, 1.89 mmol) in DMF (10 mL). 3-Bromopiperidine-2,6-dione (2.9 g, 15.1 mmol) and sodium bicarbonate (1.59 g, 18.9 mmol) were added to the reaction in DMF (10 mL). The mixture was then reduced in vacuo and concentrated. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (960 mg). MS (ESI, m / z): [M+H] + =509.6

[0192] Step 6) Synthesis of 3-[(4-{2-[2-(4-aminopiperidin-1-yl)ethoxy]ethoxy}-3-fluorophenyl)amino]piperidine-2,6-dione [ka] The reaction mixture of tert-butyl N-{1-[2-(2-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenoxy}ethoxy)ethyl]piperidin-4-yl}carbamate (750 mg, 1.89 mmol) in 30% TFA in DCM (5 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (560 mg). MS (ESI, m / z): [M+H] + =409.5

[0193] Step 7) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenoxy}ethoxy)ethyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001570) [ka] 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol), HATU (99.5 mg, 262 μmol), and ethylbis(propan-2-yl)amine (27 mg, 209 μmol) were added to a solution of 3-[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol), HATU (99.5 mg, 262 mol), and ethylbis(propan-2-yl)amine (27 mg, 209 μmol). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (38 mg). MS (ESI, m / z): [M+H] + =869.0

[0194] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.49(d,J=3.97 Hz,1 H)8.24-8.37(m,2 H)8.17(d,J=7.48 Hz,1 H)7.86(s,1 H)7.40-7.47(m,2 H)7.30(dd,J=8.32,4.35 Hz,1 H)6.86(t,J=9.31 Hz,1 H)6.51(dd,J=14.19,2.59 Hz,1 H)6.35(d,J=9.00 Hz,1 H)5.73(d,J=7.78 Hz,1 H)4.83(dd,J=8.24,3.81 Hz,1 H)4.14-4.24(m,1 H)4.05(dd,J=13.43,6.41 Hz,1 H)3.93-4.00(m,2 H)3.88(s,3 H)3.57-3.68(m,4 H)3.32-3.45(m,8 H)2.92(dd,J=13.73,8.24 Hz,1 H)2.59-2.69(m,4 H)1.98-2.07(m,1 H)1.89(d,J=16.94 Hz,2 H)1.78-1.84(m,2 H)1.70-1.77(m,2 H)1.56-1.69(m,5 H)1.11-1.22(m,2 H)1.01-1.10(m,2 H) 0.68(t, J = 7.32 Hz, 3 H)

[0195] Example B-26: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001571) Step 1) Synthesis of tert-butyl 3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoate [ka] tert-Butyl 3-bromopropanoate (232 mg, 979 μmol) and ethyl bis(propan-2-yl)amine (169 mg, 1.31 mmol) were added to a solution of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione (0.2 g, 653 μmol) in DCM (5 mL). tert-Butyl 3-bromopropanoate (232 mg, 979 μmol) and ethyl bis(propan-2-yl)amine (169 mg, 1.31 mmol) were stirred overnight. After the reaction was complete, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (205 mg). MS (ESI, m / z): [M+H] + =463.6.

[0196] Step 2) Synthesis of 5-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)pentanoic acid [ka] A solution of tert-butyl 5-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)pentanoate (200 mg, 432 μmol) in 30% TFA in DCM (100 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (402 mg). MS (ESI, m / z): [M+H] + =407.5.

[0197] Step 3) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[5-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)pentanoyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001571) [ka] To 5-(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (110 mg, 197 μmol) in DMF (2 mL) was added 5-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)pentanoic acid (80 mg, 197 μmol), HATU (149 mg, 393 μmol), and ethyl bis(propan-2-yl)amine (127 mg, 983 μmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) column chromatography to give the title compound (141 mg). MS (ESI, m / z): [M+H] + =949.2.

[0198] Example B-27: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001572) Step 1) Synthesis of tert-butyl (1-(3-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)propyl)piperidin-4-yl)carbamate: [ka] A solution of tert-butyl N-{1-[3-(piperazin-1-yl)propyl]piperidin-4-yl}carbamate (200 mg, 613 μmol) and tert-butyl N-{1-[3-(piperazin-1-yl)propyl]piperidin-4-yl}carbamate (99 mg, 613 μmol), DIPEA (423 mg, 3.06 mmol) was stirred at 85° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (0-60%) to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =466.6

[0199] Step 2) Synthesis of 5-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)pentanoic acid [ka] 20 mL of saturated NH4Cl was added to a solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (3 g, 9.22 mmol) and iron (210 mg, 451 μmol) in THF (2 ml). The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (190 mg). MS (ESI, m / z): [M+H] + =[436.6].

[0200] Step 3) Synthesis of tert-butyl N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propyl]piperidin-4-yl}carbamate [ka] NaHCO3 (96 mg, 1.15 mmol) was added to tert-butyl N-(1-{3-[4-(4-amino-2-fluorophenyl)piperazin-1-yl]propyl}piperidin-4-yl)carbamate (100 mg, 230 μmol) and 3-bromoperidine-2,6-dione (88 mg, 459 μmol) in 10 ml of DMF at room temperature, and the reaction was then stirred at 80 °C for 3 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (140 mg). MS (ESI, m / z): [M+H] + =[463.6].

[0201] Step 4) Synthesis of 5-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)pentanoic acid [ka] The reaction of tert-butyl N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propyl]piperidin-4-yl}carbamate (140 mg, 256 μmol) in 30% TFA in DCM was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (110 mg). MS (ESI, m / z): [M+H] + =[447.6].

[0202] Step 5) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001572) [ka] HATU (79.6 mg, 209 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxybenzoic acid (50 mg, 105 μmol) and 3-[(4-{4-[3-(4-aminopiperidin-1-yl)propyl]piperazin-1-yl}-3-fluorophenyl)amino]piperidine-2,6-dione (46.8 mg, 105 μmol) in 1 ml of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (67.7 mg, 523 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (45 mg). MS (ESI, m / z): [M+H] + =[907.1]

[0203] Example B-28: Synthesis of 3-{6-[4-(4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-4-methyl-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0001576) Step 1) Synthesis of 3-{6-[4-(4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-4-methyl-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0001576) [ka] HATU was added to 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (50 mg, 141 μmol) and 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (67.2 mg, 141 μmol) in 1 ml of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (38 mg). MS (ESI, m / z): [M+H] + =

[0816]

[0204] 1H NMR(400 MHz,DMSO-d6)δ=11.03(s,1H),10.30(s,1H),8.83(t,J=5.14 Hz,1H),8.22(s,1H),7.62(t,J=8.01 Hz,1H),7.49(d,J=8.6 Hz,2H),7.43(d,J=8.6 Hz,2H),7.36(s,1H),7.23-7.11(m,2H),6.91(d,J=7.95 Hz,2H),6.62(d,J=7.49 Hz,1H),5.76-5.66(m,1H),4.60(t,J=7.09 Hz,1H),3.76(m,2H),3.67(m,2H),3.60(m,4H),3.50(m,2H),3.38(m 2H),2.93-2.82(m,1H),2.63-2.53(m,5H),2.48-2.38(m,4H),2.10(m,1H),1.63(s,3H).

[0205] Example B-29: Synthesis of 3-{6-[4-(4-{(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-1-oxo-1,2-dihydropetalazin-2-yl}piperidine-2,6-dione (ICT-0001577) Step 1) Synthesis of 3-{6-[4-(4-{(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-1-oxo-1,2-dihydropetalazin-2-yl}piperidine-2,6-dione (ICT-0001577) [ka] HATU was added to 3-[1-oxo-6-(piperazin-1-yl)-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (50 mg, 146 μmol) and 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (35 mg, 73.2 μmol) in 1 ml of DMF at room temperature. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (17 mg). MS (ESI, m / z): [M+H] + =[801.9]

[0206] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.34(s,1 H)8.26(d,J=8.24 Hz,1 H)8.19(s,1 H)8.01(d,J=9.00 Hz,1 H)7.88(s,1 H)7.44(dd,J=9.08,2.06 Hz,1 H)7.18-7.25(m,1 H)7.07(s,1 H)6.97(d,J=8.24 Hz,1 H)5.69(dd,J=11.83,5.11 Hz,1 H)4.83(dd,J=8.16,3.74 Hz,1 H)4.04(dd,J=13.58,6.10 Hz,1 H)3.86(s,3 H)3.46(br.s.,3 H)2.80-2.95(m,2 H)2.63(s,3 H)2.46-2.58(m,2 H)1.99-2.06(m,1 H)1.69-1.80(m,2 H)1.56-1.67(m,5 H)1.54(br.s.,1 H)0.95-1.11(m,3 H)0.83-0.94(m,1 H)0.68(t,J=7.32 Hz,3 H)

[0207] Example B-30: Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001578) Step 1) Synthesis of tert-butyl 3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoate [ka] tert-Butyl 3-bromopropanoate (164 mg, 783 μmol) and ethyl bis(propan-2-yl)amine (422 mg, 3.3 mmol) were added to a solution of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione (0.2 g, 653 μmol) in DCM (5 mL). tert-Butyl 3-bromopropanoate (164 mg, 783 μmol) and ethyl bis(propan-2-yl)amine (422 mg, 3.3 mmol) were stirred overnight. After the reaction was complete, the mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (90 mg). MS (ESI, m / z): [M+H] + =435.5.

[0208] Step 2) Synthesis of 3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoic acid [ka] tert-Butyl 3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)piperazin-1-yl) in 30% TFA in DCM (100 mL) was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (70 mg). MS (ESI, m / z): [M+H] + =379.4.

[0209] Step 3) Synthesis of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoyl]piperidin-4-yl}-3-methoxybenzamide (ICT-0001578) [ka] 5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (104 mg, 185 μmol) in a solution of 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propanoic acid (70 mg, 185 μmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium (141 mg, 370 μmol) and ethylbis(propan-2-yl)amine (239 mg, 1.85 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (141 mg). MS (ESI, m / z): [M+H] + =921.1

[0210] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.34(s,1 H)8.27(d,J=8.39 Hz,1 H)7.86(s,1 H)7.40-7.44(m,2 H)6.83(t,J=9.31 Hz,1 H)6.52(dd,J=14.88,1.75 Hz,1 H)6.40-6.47(m,1 H)4.83(dd,J=8.24,3.66 Hz,1 H)4.26(br.s.,1 H)4.12(dd,J=13.58,6.26 Hz,2 H)4.04(dd,J=13.73,6.10 Hz,1 H)3.94(s,6 H)3.88(s,3 H)2.96-3.04(m,4 H)2.92(dd,J=13.50,8.16 Hz,1 H)2.85-2.90(m,4 H)2.69-2.73(m,7 H)2.60-2.67(m,4 H)2.49-2.54(m,1 H)2.01-2.03(m,1 H)1.56-1.63(m,4 H)1.21-1.26(m,5 H)1.16-1.21(m,4 H)0.96(s,1 H)0.67(t,J=7.32 Hz,3 H)

[0211] Example B-31: Synthesis of 3-(8-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001583) Step 1) Synthesis of 3-(4-methyl-1-oxo-8-((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydroptalazin-2-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120 °C for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[399.5].

[0212] Step 2) Synthesis of 3-(8-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001583) [ka] HATU (66.9 mg, 176 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-3-methoxybenzoic acid (70 mg, 147 μmol) and 3-(4-methyl-1-oxo-8-{[2-(piperazin-1-yl)ethyl]amino}-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione hydrate (61 mg, 147 μmol) in 1 mL of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[859.1].

[0213] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.94(s,1 H)8.99-9.04(m,1 H)8.31-8.35(m,2 H)8.19-8.26(m,2 H)7.86-7.87(m,1 H)7.60(t,J=8.09 Hz,1 H)6.98-7.05(m,2 H)6.83-6.94(m,4 H)4.82(dt,J=7.90,3.76 Hz,2 H)3.98-4.08(m,2 H)3.81-3.88(m,5 H)3.39(br.s.,1 H)2.78-2.94(m,3 H)2.58(d,J=16.63 Hz,2 H)2.47-2.55(m,1 H)2.28-2.39(m,4 H)1.98-2.03(m,1 H)1.73(dd,J=6.94,2.82 Hz,1 H)1.49-1.67(m,9 H)1.13-1.24(m,2 H)1.00-1.09(m,3 H)0.67(t,J=7.32 Hz,5 H)

[0214] Example B-32: Synthesis of 3-(8-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001584) Step 1) Synthesis of 3-(4-methyl-1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl piperazine-1-carboxylate (483 mg, 2.59 mmol), and DIPEA (670 mg, 5.19 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. (420 mg), MS (ESI, m / z): [M+H] + =[356.5].

[0215] Step 2) Synthesis of 3-(8-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001584) [ka] HATU (83.6 mg, 220 μmol) was added to 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoic acid (70 mg, 147 μmol) and 3-[4-methyl-1-oxo-8-(piperazin-1-yl)-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (52.1 mg, 147 μmol) in 1 mL of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 mmol). The reaction was stirred for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (86 mg). + =[816.5]

[0216] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.40(s,1 H)8.30(dd,J=8.16,6.03 Hz,1 H)7.94(d,J=2.29 Hz,1 H)7.84(t,J=8.01 Hz,1 H)7.49(d,J=7.93 Hz,1 H)7.39(d,J=8.24 Hz,1 H)7.13(d,J=1.53 Hz,1 H)7.02(d,J=8.39 Hz,1 H)4.89(dd,J=8.09,3.66 Hz,1 H)4.07-4.15(m,1 H)3.88-3.97(m,4 H)2.85-3.01(m,2 H)2.70(s,4 H)2.54-2.67(m,2 H)2.49(s,3 H)2.04-2.12(m,1 H)1.81(d,J=6.71 Hz,1 H)1.62-1.75(m,5 H)1.59(br.s.,1 H)1.02-1.19(m,4 H)0.86-1.02(m,2 H)0.75(t,J=7.32 Hz,4 H)

[0217] Example B-33: Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(1-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001592) Step 1) Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidine-4-carboxylic acid [ka] A solution of 3-(7-fluoro-4-methyl-1-oxo-1,2-dihydroptarazin-2-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol), tert-butyl piperidine-4-carboxylate (769 mg, 4.15 mmol), and DIPEA (894 mg, 6.91 mmol) in NMP (2 mL) was stirred at 120 °C for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound (1.10 g), which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[399.5].

[0218] Step 2) Synthesis of 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidine-4-carbonyl)piperidin-4-yl)piperidin-4-yl)-3-methoxybenzamide (ICT-0001592) [ka] 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H, HATU (66.9 mg, 176 μmol) was added to a solution of 5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxy-N-(piperidin-4-yl)benzamide (70 mg, 125 μmol) and 1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaradin-6-yl]piperidine-4-carboxylic acid (58.4 mg, 147 μmol) in 1 mL of DMF at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (28.4 mg, 220 μmol). The reaction mixture was stirred for 6 hours. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual acid was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (78 mg). MS (ESI, m / z): [M+H] + =[941.1]

[0219] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.90(s,1 H)8.32(s,1 H)8.19(d,J=8.09 Hz,1 H)7.98(d,J=9.00 Hz,1 H)7.91(br.s.,1 H)7.79(d,J=7.48 Hz,1 H)7.39-7.47(m,1 H)7.00(s,1 H)6.97(s,1 H)6.86(d,J=8.24 Hz,1 H)5.61(d,J=6.56 Hz,1 H)4.82(dd,J=8.16,3.59 Hz,1 H)3.98-4.07(m,3 H)3.84(s,3 H)3.75(br.s.,1 H)2.78-2.95(m,4 H)2.62(s,3 H)2.45-2.60(m,3 H)2.27-2.42(m,4 H)1.95-2.04(m,1 H)1.73(s,2 H)1.71(s,3 H)1.50-1.68(m,8 H)1.05(d,J=7.32 Hz,2 H)0.99(d,J=10.83 Hz,1 H)0.87(d,J=11.60 Hz,1 H)0.67(t,J=7.32 Hz,3 H)0.00(s,1 H)

[0220] Example B-34: Synthesis of 3-(6-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001599) Step 1) Synthesis of 3-(4-methyl-1-oxo-6-((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[399.5].

[0221] Step 2) Synthesis of 3-(6-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001599) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF with (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(4-methyl-1-oxo-6-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piper ... To a solution of peridine-2,6-dione (61 mg, 147 umol) was added, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 umol) at room temperature. The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[859.1]

[0222] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.84-10.93(m,1 H)8.32(s,1 H).22(d,J=8.24 Hz,1 H)7.82-7.94(m,2 H)7.05(dd,J=8.85,1.83 Hz,1 H)7.00(s,1 H)6.90(d,J=7.93 Hz,1 H)6.60-6.78(m,2 H)5.59(d,J=6.41 Hz,1 H)4.82(dd,J=8.16,3.74 Hz,1 H)4.02(dd,J=13.50,6.03 Hz,1 H)3.79-3.89(m,3 H)2.77-2.99(m,2 H)2.58-2.68(m,10 H)2.35-2.56(m,10 H)1.93-2.05(m,1 H)1.68-1.81(m,2 H)1.47-1.68(m,6 H)0.93-1.14(m,3 H)0.80-0.93(m,1 H)0.67(t,J=7.40Hz,3H)

[0223] Example B-35: Synthesis of 3-(7-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001600) Step 1) Synthesis of 3-(4-methyl-1-oxo-7-((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120 °C for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the titled compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[399.5].

[0224] Step 2) Synthesis of 3-(7-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001600) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF with (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(4-methyl-1-oxo-7-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl) ) piperidine-2,6-dione (61 mg, 147 umol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 umol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[859.1]

[0225] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.90(s,1 H)8.32(s,1 H)8.21(d,J=8.09 Hz,1 H)7.86(s,1 H)7.60(d,J=8.54 Hz,1 H)7.10-7.22(m,2 H)7.00(s,1 H)6.89(d,J=8.24 Hz,1 H)6.69(br.s.,1 H)4.81(dd,J=8.01,3.59 Hz,1 H)4.02(dd,J=13.50,5.87 Hz,1 H)3.84(s,3 H)2.78-2.93(m,2 H)2.47-2.67(m,10 H)2.35-2.45(s,10 H)1.92-2.05(m,1 H)1.67-1.78(m,2 H)1.47-1.67(m,6 H)0.93-1.12(m,4 H)0.80-0.93(m,1 H)0.67(t,J=7.25 Hz,3 H)

[0226] Example B-36: Synthesis of 3-(8-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001601) Step 1) Synthesis of 3-(1-oxo-8-((2-(piperazin-1-yl)ethyl)amino)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[385.5].

[0227] Step 2) Synthesis of 3-(8-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001601) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF in a solution of (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(1-oxo-8-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piperazin-2(1H)-yl)benzoic acid. Lysine-2,6-dione (61 mg, 147 μmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[845.1]

[0228] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.75-8.86(m,1 H)8.32(s,1 H)8.21(d,J=8.24 Hz,1 H)8.15(s,1 H)7.86(s,1 H)7.58(t,J=7.93 Hz,1 H)7.00(s,1 H)6.77-6.93(m,3 H)4.81(dd,J=8.09,3.66 Hz,1 H)4.02(dd,J=13.66,6.33 Hz,1 H)3.84(s,3 H)2.76-2.96(m,2 H)2.50-2.68(m,10 H)2.34-2.47(m,10 H)1.97-2.07(m,1 H)1.67-1.80(m,2 H)1.45-1.67(m,6 H)0.93-1.10(m,2 H)0.86(d,J=11.75 Hz,1 H)0.67(t,J=7.32 Hz,3 H)

[0229] Example B-37: Synthesis of 3-(5-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001602) Step 1) Synthesis of 3-(1-oxo-5-((2-(piperazin-1-yl)ethyl)amino)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(5-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[385.5].

[0230] Step 2) Synthesis of 3-(5-((2-(4-(4-((((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001602) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF in a solution of (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(1-oxo-5-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piper ... Lysine-2,6-dione (61 mg, 147 μmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[845.1]

[0231] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.96(s,1 H)8.56(s,1 H)8.32(s,2 H)8.21(d,J=8.24 Hz,2 H)7.87(s,1 H)7.54(t,J=7.93 Hz,1 H)7.34(d,J=7.78 Hz,1 H)6.94-7.02(m,3 H)6.89(d,J=8.09 Hz,2 H)6.63(br.s.,1 H)5.70(dd,J=11.37,4.96 Hz,1 H)4.82(dd,J=8.01,3.74 Hz,2 H)4.02(dd,J=13.50,6.03 Hz,2 H)3.84(s,5 H)2.80-2.94(m,3 H)2.00-2.06(m,2 H)1.70-1.78(m,3 H)1.51-1.65(m,9 H)0.95-1.08(m,5 H)0.86(d,J=11.29 Hz,1 H)0.67(t,J=7.32 Hz,5 H)

[0232] Example B-38: Synthesis of 3-(6-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001603) Step 1) Synthesis of 3-(1-oxo-6-((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[385.5].

[0233] Step 2) Synthesis of 3-(6-((2-(4-(4-((((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001603) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF in a solution of (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(1-oxo-6-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piper ... Lysine-2,6-dione (61 mg, 147 μmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[845.1]

[0234] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)8.32(s,2 H)8.21(d,J=8.24 Hz,1 H)8.11(s,2 H)7.81-7.89(m,3 H)7.05(dd,J=8.85,1.68 Hz,1 H)7.00(s,2 H)6.89(d,J=8.24 Hz,1 H)6.69-6.78(m,3 H)5.66(dd,J=11.67,4.81 Hz,1 H)4.81(dd,J=8.16,3.74 Hz,1 H)4.02(dd,J=13.50,6.03 Hz,1 H)3.22-3.26(m,3 H)2.77-2.94(m,3 H)2.68(s,1 H)2.62(s,5 H)2.50-2.56(m,4 H)1.95-2.04(m,1 H)1.67-1.79(m,3 H)0.92-1.11(m,7 H)0.87(d,J=12.05 Hz,2 H)0.67(t,J=7.32 Hz,5 H)

[0235] Example B-39: Synthesis of 3-(7-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001604) Step 1) Synthesis of 3-(1-oxo-7-((2-(piperazin-1-yl)ethyl)amino)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (500 mg, 1.73 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (595 mg, 2.57 mmol), and DIPEA (447 mg, 3.46 mmol) in NMP (2 mL) was stirred at 120° C. for 5 hours. The reaction mixture was purified by column chromatography to give the Boc-protected compound, which was dissolved in 1 mL of DCM followed by 0.2 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved and passed through an NH-DM 1020 Chromatrex pad in DCM to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =[385.5].

[0236] Step 2) Synthesis of 3-(7-((2-(4-(4-((((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001604) [ka] HATU (66.9 mg, 176 umol) was dissolved in 1 ml of DMF in a solution of (R)-4-((5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)-3-methoxybenzoic acid (70 mg, 147 umol) and 3-(1-oxo-7-(((2-(piperazin-1-yl)ethyl)amino)phthalazin-2(1H)-yl)piper ... Lysine-2,6-dione (61 mg, 147 μmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (37.9 mg, 293 μmol) at room temperature. The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =[859.1]

[0237] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.93(s,1 H)8.32(s,2 H)8.22(d,J=8.09 Hz,1 H)8.05-8.12(m,2 H)7.87(s,2 H)7.58(d,J=9.00 Hz,1 H)7.15(d,J=6.71 Hz,3 H)7.00(s,2 H)6.90(d,J=7.93 Hz,1 H)6.75(br.s.,1 H)5.68(d,J=6.56 Hz,1 H)4.82(dd,J=8.09,3.66 Hz,1 H)4.02(dd,J=13.58,5.95 Hz,1 H)3.84(s,5 H)2.79-2.93(m,3 H)2.62(s,5 H)1.97-2.05(m,2 H)1.67-1.78(m,3 H)1.49-1.67(m,10 H)0.87(d,J=11.14 Hz,1 H)0.67(t,J=7.32 Hz,5 H) [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] A:IC 50 or DC 50 <100nM B: 100nM <IC 50 or DC 50 <1uM C:1uM <IC 50 or DC 50

[0238] Example C: Preparation of JQ1-based BRD4 PROTAC Example C-1: Synthesis of 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000953) Step 1) Synthesis of 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione and 3-(6-fluoro-4-methyl-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] tert-Butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (92 mg, 0.35 mmol) was added to a solution of 3-(6,7-difluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.32 mmol) in DMA (1 mL) at ambient temperature, followed by the addition of ethyl bis(propan-2-yl)amine (46.3 mg, 0.35 mmol). The reaction was heated to 120° C. for 16 hours. After completion of the reaction, the reaction was poured into water and extracted with ethyl acetate (25 mL×2). The organic layer was separated. The crude product was obtained by drying, filtering, and concentrating with MgSO4. It was purified by MPLC (1-5% MeOH in CHCl2) to give the Boc-protected compound, which was treated with 50% TFA in DCM (5 mL) and stirred for 5 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM1020 Chromatrex pad to give the regioisomeric mixture, which was purified on a C-18 column (0-80% acetonitrile in water) to give the two compounds in a 3:5 ratio. The less polar compound was identified as 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione, and the more polar compound was identified as 3-(6-fluoro-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione. MS (ESI, m / z): [M+H] + =471.3 and 471.2

[0239] Step 2) Synthesis of 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000953) [ka] HATU (36.8 mg, 0.1 mmol) was dissolved in (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazine-1-(4-(piperidin-4-yl)piperazine-2(1))) in DMF (5 ml). To the resulting solution was added 2,6-dione (40.8 mg, 0.1 mmol) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residual compound was obtained by purifying MeOH / DCM (0-20%) by MPLC (48.2 mg). MS (ESI, m / z): [M+H] + =854.2

[0240] 1 H NMR (500 MHz, DMSO-d6) δ ppm 1 H NMR(400 MHz,DMSO-d6)d ppm 11.02(s,1 H)7.86(d,J=13.08 Hz,1 H)7.40-7.54(m,4 H)7.31(d,J=8.31 ​​Hz,1 H)4.58(t,J=6.54 Hz,1 H)3.29(br.s.,3 H)2.54-2.65(m,11 H)2.42(s,3 H)2.25(br.s.,1 H)1.64(s,3 H)1.11-1.29(m,17 H)

[0241] Example C-2: Synthesis of 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-dei)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000971) Step 1) Synthesis of 3-(7-fluoro-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione and 3-(6-fluoro-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of tert-butyl 4-(piperazin-1-yl)piperidine-2,6-dione (100 mg, 0.32 mmol) in DMA (3 mL) was added at ambient temperature, followed by the addition of ethyl bis(propan-2-yl)amine (46.3 mg, 0.35 mmol). The crude product was dried, filtered, and concentrated over MgSO4. It was purified by MPLC (1-5% MeOH in CHCl2) to give the Boc-protected compound, which was treated with 50% TFA in DCM (5 mL) and stirred for 5 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM1020 Chromatrex pad to give the regioisomeric mixture. 0-80% acetonitrile in water was purified on a C-18 column to give two compounds in a 3:5 ratio. The less polar compound was defined as 3-(7-fluoro-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione, and the more polar compound was defined as 3-(6-fluoro-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione. MS (ESI, m / z): [M+H] + =471.3 and 471.2

[0242] Step 2) Synthesis of 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000971) [ka] HATU (36.8 mg, 0.1 mmol) was dissolved in DMF (5 ml) with (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(7-fluoro-1-oxo-6-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)-2-(4-chlorophenyl ... ) piperazine-2,6-dione (40 mg, 0.1 mmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =840.2

[0243] 1H NMR(500 MHz,DMSO-d6)δ ppm 10.99(s,1 H)8.34(s,1 H)7.87(d,J=12.72 Hz,1 H)7.60(d,J=8.19 Hz,1 H)7.35-7.47(m,4 H)5.73(dd,J=12.10,4.89 Hz,1 H)4.52(t,J=6.72 Hz,1 H)3.64(br.s.,16 H)3.20-3.38(m,4 H)3.10(s,2 H)2.58(br.s.,1 H)2.54(s,3 H)2.46-2.52(m,1 H)2.36(s,3 H)1.57(s,3 H)

[0244] Example C-3: Synthesis of 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-dei)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000972) Step 1) Synthesis of 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoro-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione (ICT-0000972) [ka] HATU (36.8 mg, 0.1 mmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(6-fluoro-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperazine-2,6-dione (40 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =840.2

[0245] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.06(s,1 H)8.37(s,1 H)7.86(d,J=12.84 Hz,1 H)7.77(d,J=8.44 Hz,1 H)7.35-7.54(m,5 H)4.59(t,J=6.72 Hz,1 H)3.32-3.45(m,1 H)3.30(br.s.,3 H)3.17(s,3 H)2.53-2.70(m,5 H)2.42(s,3 H)1.64(s,3 H)

[0246] Example C-4: Synthesis of 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-dei)acetyl)azetidin-3-yl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000973) Step 1) Synthesis of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate [ka] Sodium cyanoborohydride (4.07 g, 102 mmol) was added to a solution of tert-butyl 3-oxoazetidine-1-carboxylate (12.8 g, 74.9 mmol) and benzylpiperazine-1-carboxylate (15 g, 68.1 mmol) in methanol (300 ml) and AcOH solution (6 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with HX / EA (20-90%) to give the title compound (22 g). MS (ESI, m / z): [M+H] + =376.0.

[0247] Step 2) Synthesis of tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate [ka] Pd / C (10 wt%, 50 mg) was added to a solution of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (1 g, 2.66 mmol) in MeOH (10 ml) and stirred at room temperature under an H atmosphere for 5 hours. The solution was filtered through a Celite 545 pad. The solvent was removed under reduced pressure to give the title compound (0.7 g). MS (ESI, m / z): [M+H] + =242.0.

[0248] Step 3) Synthesis of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate [ka] A solution of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (642 mg, 2.4 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (643 mg, 2.66 mmol), and DIPEA (0.93 ml, 5.33 mmol) in NMP (15 mL) was stirred at 120° C. for 20 hours. MS (ESI, m / z): [M+H] + =497.3.

[0249] Step 4) Synthesis of 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (0.3 ml) was added to a solution of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate (180 mg, 0.4 mmol) in DCM (1 ml) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound, which was used in the next step without further purification (140 mg). MS (ESI, m / z): [M+H] + =397.3.

[0250] Step 5) Synthesis of 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)piperazin-1-yl)-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione (ICT-0000973) [ka] HATU (36.8 mg, 0.1 mmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (38 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =780.2

[0251] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.03(s,1 H)8.29(s,1 H)8.12(d,J=8.93 Hz,1 H)7.62(dd,J=9.23,2.14 Hz,1 H)7.39-7.53(m,5 H)5.78(dd,J=11.98,5.62 Hz,1 H)4.62(d,J=5.50 Hz,1 H)4.52(td,J=7.03,2.45 Hz,1 H)4.08-4.23(m,1 H)3.20-3.43(m,1 H)3.11-3.20(m,1 H)2.86-3.00(m,1 H)2.59-2.66(m,4 H)2.53-2.59(m,1 H)2.42(s,3 H)1.63(s,3 H)

[0252] Example C-5: Synthesis of 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000974) Step 1) Synthesis of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate [ka] A solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (642 mg, 2.4 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (643 mg, 2.66 mmol), and DIPEA (0.93 ml, 5.33 mmol) in NMP (15 mL) was stirred at 120° C. for 20 hours. MS (ESI, m / z): [M+H] + =411.3.

[0253] Step 2) Synthesis of 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)-4-methyl-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (0.3 ml) was added to a solution of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate (180 mg, 0.4 mmol) in DCM (1 ml) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was depressurized and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound, which was used in the next step without further purification (140 mg). MS (ESI, m / z): [M+H] + =411.3.

[0254] Step 3) Synthesis of 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000974) [ka] HATU (36.8 mg, 0.1 mmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][-1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (40 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =794.2

[0255] 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.00(s,1 H)8.14(d,J=8.93 Hz,1 H)7.62(d,J=8.93 Hz,1 H)7.41-7.54(m,4 H)7.23(s,1 H)5.70(dd,J=11.86,4.89 Hz,1 H)4.64(br.s.,1 H)4.52(td,J=6.94,2.26 Hz,1 H)3.13-3.43(m,4 H)2.90(d,J=11.49 Hz,1 H)2.58-2.68(m,5 H)2.42(s,3 H)1.63(s,3 H)

[0256] Example C-6: Synthesis of 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-dei)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000982) Step 1) Synthesis of 3-(4-methyl-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] Ethyl bis(2-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and tert-butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (980 mg, 3.46 mmol) were added to a solution of 3-(7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and tert-butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (980 mg, 3.46 mmol) in 5 mL of DMA at room temperature. The reaction was heated at 120 °C for 16 h. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC MeOH / DCM (0-10%) to give the protected compound. This was treated with 50% TFA in DCM (5 mL) and stirred for 5 h. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound (550 mg). MS (ESI, m / z): [M+H] + =453.6.

[0257] Step 2) Synthesis of 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000982) [ka] HATU (36.8 mg, 0.1 mmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(4-methyl-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperazine-2,6-dione (42 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =836.2

[0258] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.99(s,1 H)7.79(d,J=9.05 Hz,1 H)7.61(d,J=8.93 Hz,1 H)7.54(s,1 H)7.41-7.52(m,4 H)4.58(t,J=6.72 Hz,1 H)3.41(br.s.,3 H)2.62(br.s.,1 H)2.52-2.62(m,8 H)2.46(s,3 H)2.42(s,3 H)1.88-2.02(m,3 H)1.63(s,3 H)1.14-1.27(m,1 H)

[0259] Example C-7: Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pent-4-rin-1-yl}oxy)phenyl]acetamide (ICT-00001409) Step 1) Synthesis of 3-[6-(5-hydroxypentyl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione [ka] CuI (85 mg, 446 μmol) and Pd(PPh3)2Cl2 (313 mg, 446 μmol) were added to a solution of 3-(6-bromo-1-oxo-1,2-dihydrohoptalazin-2-yl)piperidine-2,6-dione (1.5 g, 4.46 mmol) and pent-4-phospho-1-ol (488 mg, 5.8 mmol) in DMF (5 mL), followed by the addition of TEA (1.35 g, 13.4 mmol). The ethyl acetate organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The residue was purified by MPLC with EA / hexane (0-10%) to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =[340.4],

[0260] Step 2) Synthesis of 5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-ylpent-4-phospho-1-yl methanesulfonate] [ka] Ethylbis(propan-2-yl)amine (263 mg, 2.03 mmol) was added to a solution of 3-[6-(5-hydroxypent-1-phosphoin-1-yl)-1-oxo-1,2-dihydroptalazin-2-yl]piperidine-2,6-dione (230 mg, 678 μmol) and methanesulfonyl chloride (93.2 mg, 813 μmol) in DCM (20 ml). The reaction was stirred at 0° C. for 1 hour. The mixture was stirred at room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification by column chromatography then afforded the title compound (220 mg). MS (ESI, m / z): [M+H] + =418.4

[0261] Step 3) Synthesis of tert-butyl N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pent-4-rin-1-yl}oxy)phenyl]carbamate [ka] Cesium carbonate (687 mg, 2.11 mmol) and potassium iodide (17.5 mg, 105 μmol) were added to a solution of 5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]pent-4-lin-1-yl methanesulfonate (220 mg, 527 μmol) and tert-butyl N-(4-hydroxyphenyl)carbamate (110 mg, 527 μmol) in 1 mL of DMF at room temperature. The mixture was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the Boc-protected compound, which was dissolved in 1 mL of DCM, followed by 0.2 mL of TFA, and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 chromatrex pad to give the title compound, which was used in the next step without further purification. (36 mg) MS (ESI, m / z): [M+H]+ =[431.5].

[0262] Step 4) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pent-4-phospho-1-yl}oxy)phenyl]acetamide (ICT-00001409) [ka] HATU (42.4 mg, 112 μmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (22.4 mg, 55.8 μmol) and 3-{6-[5-(4-aminophenoxy)pent-1-phosphoin-1-yl]-1-oxo-1,2-dihydrofoptalazin-2-yl}piperidine-2,6-dione (24 mg, 55.8 μmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (72 mg, 167 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =814.3

[0263] 1H NMR(500 MHz,DMSO-d6)δ ppm 11.00(s,1 H)10.12(s,1 H)8.37(s,1 H)8.15(d,J=7.78 Hz,3 H)7.95(s,1 H)7.78(d,J=8.09 Hz,1 H)7.48(d,J=8.55 Hz,1 H)7.42(m,J=7.93 Hz,2 H)7.35(m,J=8.24 Hz,2 H)6.87(d,J=8.70 Hz,2 H)6.47(s,1 H)5.70-5.77(m,1 H)4.52(t,J=7.17 Hz,1 H)4.03(t,J=6.10 Hz,2 H)3.38-3.46(m,2 H)2.63(t,J=6.94 Hz,2 H)2.57(br.s.,1 H)2.54(s,4 H)2.47(br.s.,1 H)2.29(s,1 H)2.11(t,J=7.40 Hz,1 H)2.01-2.08(m,2 H)1.96(t,J=6.33 Hz,2 H)0.79(t,J=6.71 Hz,1 H)

[0264] Example C-8: Synthesis of 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-00001410) Step 1) 3-(6-(4-(4-aminophenyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Ethylbis(propan-2-yl)amine (670 mg, 5.19 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and 4-(piperazin-1-yl)aniline (306 mg, 1.73 mmol) in DMA (2 ml) at room temperature. The reaction was stirred at 160 °C for 16 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (621 mg). MS (ESI, m / z): [M+H] + =447.6.

[0265] Step 2) Synthesis of 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-00001410) [ka] HATU (36.8 mg, 0.1 mmol) was added to (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][-1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50 mg, 0.1 mmol) and 3-(6-(4-(4-aminophenyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (45 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.1 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =830.2

[0266] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)10.07(s,1 H)7.98-8.06(m,1 H)7.51(dd,J=9.16,2.14 Hz,1 H)7.39-7.49(m,5 H)7.36(d,J=8.55 Hz,2 H)7.10(d,J=1.98 Hz,1 H)6.93(d,J=9.00 Hz,2 H)5.62(d,J=7.48 Hz,1 H)4.52(t,J=7.10 Hz,1 H)3.54(br.s.,4 H)3.38-3.47(m,2 H)3.21(br.s.,4 H)2.77-2.90(m,1 H)2.49-2.59(m,5 H)2.35(s,3 H)1.57(s,3 H)

[0267] Example C-9: Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pentyl}oxy)phenyl)acetamide (ICT-00001411) Step 1) Synthesis of 3-[6-(5-hydroxypentyl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione [ka] CuI (85 mg, 446 μmol) and Pd(PPh3)2Cl2 (313 mg, 446 μmol) were added to a solution of 3-(6-bromo-1-oxo-1,2-dihydrohoptalazin-2-yl)piperidine-2,6-dione (1.5 g, 4.46 mmol) and pent-4-yn-1-ol (488 mg, 5.8 mmol) in DMF (5 mL), followed by the addition of TEA (1.35 g, 13.4 mmol). The mixture was irradiated in a microwave reactor at 100 °C for 2 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The residue was purified by MPLC with EA / hexane (0-10%) to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =[340.4].

[0268] Step 2) Synthesis of 3-[6-(5-hydroxypentyl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione [ka] A mixture of 3-[6-(5-hydroxypentyl)-1-oxo-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (504 mg, 1.60 mmol) and palladium (15.4 mg, 0.142 mmol) in MeOH (10 ml) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was evaporated and the residue was dried under vacuum (403 mg). MS (ESI, m / z): [M+H] + =344.3

[0269] Step 3) Synthesis of 5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pentyl methanesulfonate [ka] Ethylbis(propan-2-yl)amine (3 equivalents) was added to a solution of 3-[6-(5-hydroxypentyl)-1-oxo-1,2-dihydroptalazin-2-yl]piperidine-2,6-dione (403 mg, 0.79 mmol) and methanesulfonyl chloride (403 mg, 2.12 mmol) in DCM (30 ml). The reaction was stirred at 0° C. for 1 hour. The mixture was stirred at room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (530 mg). MS (ESI, m / z): [M+H] + =422.3

[0270] Step 4) Synthesis of tert-butyl N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl]pentyl}oxy)phenyl]carbamate [ka] Cesium carbonate (182 mg, 1.10 mmol) and potassium iodide (9.1 mg, 55 μmol) were added to a solution of 5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl]pentyl methanesulfonate (116 mg, 275 μmol) and tert-butyl N-(4-hydroxyphenyl)carbamate (57.6 mg, 275 μmol) in 1 mL of DMF at room temperature. Cesium carbonate (182 mg, 1.10 mmol) and potassium iodide (9.1 mg, 55 μmol) were added at room temperature. The reaction was stirred at 65° C. for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The mixture was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the Boc-protected compound, which was dissolved in 1 ml of DCM, followed by 0.2 ml of TFA and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. (42 mg) MS (ESI, m / z): [M+H] + =[435.5].

[0271] Step 5) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pentyl}oxy)phenylamide (ICT-0001411) [ka] HATU (73.1 mg, 0.2 mmol) was added to 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (50 mg, 0.1 mmol) and 3-{6-[5-(4-aminophenoxy)pentyl]-1-oxo-1,2-dihydrobutalazin-2-yl}piperidine-2,6-dione (42 mg, 0.1 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (67.4 mg, 0.2 mmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-20%) to give the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =818.4

[0272] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)10.09(s,1 H)8.33-8.38(m,1 H)8.13(d,J=8.24 Hz,1 H)7.68-7.75(m,2 H)7.39-7.48(m,5 H)7.33-7.36(m,2 H)6.80(d,J=9.00 Hz,2 H)4.52(t,J=7.17 Hz,1 H)3.86(t,J=6.33 Hz,2 H)3.39(d,J=6.71 Hz,2 H)2.77(t,J=7.78 Hz,2 H)2.56-2.58(m,1 H)2.54(s,4 H)2.35(s,3 H)2.30(s,1 H)1.91(br.s.,1 H)1.87(br.s.,1 H)1.63-1.70(m,4 H)1.39(d,J=7.17 Hz,2 H)1.17(s,2 H)

[0273] Example C-10: Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}methyl)phenyl]acetamide (ICT-0001423) Step 1) Synthesis of 3-(4-methyl-6-{4-[(4-nitrophenyl)methyl]piperazin-1-yl}-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione [ka] 3-(6-Fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (654 mg, 2.3 mmol) and ethylbis(propan-2-yl)amine (1.5 g, 11.3 mmol) were added to a solution of 1-[(4-nitrophenyl)methyl]piperazine (0.5 g, 2.3 mmol) in NMP (3 mL). The reaction was stirred at 135 °C overnight. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography with MeOH / DCM (0-10%) to give the title compound (0.38 g).

[0274] Step 2) Synthesis of 3-(6-{4-[(4-aminophenyl)methyl]piperazin-1-yl}-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl)piperidine-2,6-dione [ka] 10 mL of saturated NH4Cl was added to a solution of 3-(4-methyl-6-{4-[(4-nitrophenyl)methyl]piperazin-1-yl}-1-oxo-1,2-dihydroptarazin-2-yl) and iron (865 mg, 15.5 mmol) in THF (10 mL). The reaction was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The compound was then purified by column chromatography with MeOH / DCM (0-10%) to give the title compound (0.31 g).

[0275] Step 3) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}methyl)phenyl]acetamide (ICT-0001423) [ka] HATU (82.6 mg, 217 μmol) and ethylbis (70.2 mg, 543 μmol) were added to a solution of 2-[(9S)-7-(4-chlorophenyl)methyl-4,5,13-trimethyl-3-thia-1,8,11,12-tetraaztricyclo[8.3.0.02,6,6]trideca-2(6),4-oxo-1,2-dihydroptarazin-2-yl]piperidine (50 mg, 109 μmol) in DMF (2.0 ml). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-10%) column chromatography to give the title compound (51 mg). MS (ESI, m / z): [M+H] + =844.4

[0276] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.90(s,1 H)10.26(s,1 H)7.99(d,J=9.16 Hz,1 H)7.54(m,J=8.39 Hz,2 H)7.42(d,J=8.55 Hz,3 H)7.36(d,J=8.39 Hz,2 H)7.17-7.24(m,2 H)7.01(s,1 H)5.53-5.68(m,1 H)4.53(t,J=7.10 Hz,1 H)3.41-3.48(m,4 H)3.38(br.s.,3 H)2.80-2.89(m,1 H)2.46-2.55(m,8 H)2.34-2.37(m,3 H)1.84-2.03(m,2 H)1.57(s,3 H)1.15-1.22(m,4 H)

[0277] Example C-11: Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{[(2S)-4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]morpholin-2-yl]methoxy}phenyl)acetamide (ICT-0001430) Step 1) Synthesis of tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]morpholine-4-carboxylate [ka] Triethylamine (2.1 g, 1.5 mmol) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (3 g, 13.8 mmol) in DCM (120 mL) at room temperature. The reaction mixture was stirred for 15 minutes. Diluted methanesulfonyl chloride (1.9 g, 16.6 mmol) in 15 mL of DCM was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 30 hours. After the reaction was complete, the reaction mixture was poured into water, extracted with DCM, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-10%) to give the title compound (4.1 g).

[0278] Step 2) Synthesis of tert-butyl (2S)-2-[(4-{[(tert-butoxy)carbonyl]amino}penoxy)methyl]morpholine-4-carboxylate [ka] tert-Butyl N-(4-hydroxyphenyl)carbamate (3.05 g, 14.6 mmol), disium(1+) carbonate (9.5 g, 29.1 mmol), and potassium iodide (121 mg, 728 μmol) were added to a solution of tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]morpholine-4-carboxylate (4.3 g, 14.6 mmol) in DMF (10 mL).

[0279] Step 3) Synthesis of 4-[(morpholin-2-yl)methoxy]aniline [ka] 4.0 M HCl in dioxane (140 mL) was added to a solution of tert-butyl 2-[(4-{{(tert-butoxy)carbonyl]amino}penoxy)methyl]morpholine-4-carboxylate (6.3 g, 15.4 mmol) in dioxane (20 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was concentrated in vacuo and used in the next step without further purification (6.2 g).

[0280] Step 4) Synthesis of 3-(6-{2-[(4-aminophenoxy)methyl]morpholin-4-yl}-4-methyl-1-oxo-2λ4-phthalazin-2-yl)piperidine-2,6-dione [ka] To a solution of 4-[(morpholin-2-yl)methoxy]aniline (3.21 g, 15.4 mmol) in NMP (20 mL), 3-(6-fluoro-4-methyl-1-oxo-2λ4-phthalazin-2-yl) piperidine-2,6-dione (4.46 g, 15.4 mmol), and ethyl bis(propan-2-yl)amine (9.96 g, 77.1 mmol) was added. The reaction was stirred at 120 °C overnight. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-10%) to give the title compound (6.3 g).

[0281] Step 5) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{[(2S)-4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]morpholin-2-yl]methoxy}phenyl)acetamide (ICT-0001430) [ka] HATU (82.6 mg, 217 μmol) and ethylbis(propan-2-yl)amine (70.2 mg, 543 μmol) were added to a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6(6),4,7,10,12-pentaen-9-yl]acetic acid (43.5 mg, 109 μmol) and 3-{6-[(2S)-2-[(4-aminophenoxy)methyl]morpholin-4-yl]-4-methyl-1-oxo-1,2-dihydroptaradin-2-yl}piperidine-2,6-dione (51.8 mg, 109 μmol) in DMF (2.0 mL). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-10%) to give the title compound (57 mg). MS (ESI, m / z): [M+H] + =861.4

[0282] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)10.13(s,1 H)8.04(d,J=9.00 Hz,1 H)7.45-7.52(m,3 H)7.42(d,J=8.70 Hz,3 H)7.35(d,J=8.39 Hz,2 H)7.05-7.09(m,1 H)6.90(d,J=9.00 Hz,2 H)5.63(dd,J=11.52,4.35 Hz,1 H)4.53(t,J=7.10 Hz,1 H)3.93-4.17(m,4 H)3.76-3.93(m,3 H)3.62-3.69(m,1 H)3.40(d,J=6.87 Hz,2 H)2.76-2.92(m,3 H)2.45-2.61(m,6 H)2.35(s,4 H)1.96-2.03(m,1 H)1.90-1.96(m,1 H)1.14-1.26(m,1 H)

[0283] Example C-12: Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)methyl]phenyl}acetamide (ICT-00001441) Step 1) Synthesis of tert-butyl 4-[(4-nitrophenyl)methyl]piperazine-1-carboxylate [ka] 1-[(4-nitrophenyl)methyl]piperazine (0.5 g, 2.26 mmol) was dissolved in THF (15 mL). Di-tert-butyl dicarbonate (740 mg, 3.39 mmol) dissolved in THF (15 mL) was added to the THF solution of 1-[(4-nitrophenyl)methyl]piperazine. The resulting mixture was stirred at room temperature for 2 hours. The colorless solution was evaporated to remove THF. The colorless oil was poured into water (100 ml). The colorless oil was extracted three times with 50 mL of CHCl. ​​The organic layer was washed with water and brine solution. The organic layer was dried over anhydrous NaSO. After filtration, the solvent was evaporated. The residue, without the tablets (380 mg), was used in the subsequent reaction. MS (ESI, m / z): [M+H] + =[322.3],

[0284] Step 2) Synthesis of tert-butyl 4-[(4-aminophenyl)methyl]piperazine-1-carboxylate [ka] 10 mL of saturated NH4Cl was added to a solution of tert-butyl 4-[(4-nitrophenyl)methyl]piperazine-1-carboxylate (270 mg, 840 μmol) and iron (938 mg, 16.8 mmol) in THF (10 ml). The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (158 mg). MS (ESI, m / z): [M+H] + =[292.4].

[0285] Step 3) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[(piperazin-1-yl)methyl]phenyl}acetamide [ka] HATU (300 mg, 789 μmol) was added to 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (158 mg, 395 μmol) and tert-butyl 4-[(4-aminophenyl)methyl]piperazine-1-carboxylate (115 mg, 395 μmol) in DMF (5 mL) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (255 mg, 1.97 mmol). The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the Boc-protected compound, which was treated with 50% TFA in DCM (5 mL) and stirred for 5 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through an NH-DM 1020 Chromatrex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =575.2

[0286] Step 4) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]methyl}phenyl)acetamide [ka] K2CO3 (50.6 mg, 366 μmol) was added to a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]N-{4-[(piperazin-1-yl)methyl]phenyl}acetamide (42 mg, 73.2 μmol) and 1,2-difluoro-4-nitrobenzene (11.6 mg, 73.2 μmol) in acetonitrile (10 ml). The reaction was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. Subsequent purification by column chromatography afforded the title compound (52.2 mg). MS (ESI, m / z): [M+H] + =[714.2]

[0287] Step 5) Synthesis of N-(4-{[4-(4-amino-2-fluorophenyl)piperazin-1-yl]methyl}phenyl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide [ka] 10 mL of saturated NH4Cl was added to a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]methyl}phenyl)acetamide (52.2 mg, 73.2 μmol) and iron (81.7 mg, 1.46 mmol) in THF (10 mL). The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =[684.4].

[0288] Step 6) Synthesis of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)methyl]phenyl}acetamide (ICT-00001441) [ka] NaHCO (14.8 mg, 176 μmol) was added to N-(4-{[4-(4-amino-2-fluorophenyl)piperazin-1-yl]methyl}phenyl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (20 mg, 29.3 μmol) and 3-bromorphidine-2,6-dione (16.9 g, 87.8 μmol) in 10 ml of DMF at room temperature. The reaction was stirred at 80 °C for 3 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over MgSO, and then concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =795.4

[0289] 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.24(s,1 H)7.53(s,3 H)7.42(s,4 H)7.36(s,1 H)7.19(s,3 H)4.53(t,J=7.02 Hz,2 H)2.57(s,7 H)2.54(s,7 H)2.47(s,1 H)2.29(s,6 H)2.02(s,5 H)1.16(s,1 H) [Table 2-1] [Table 2-2] A:IC 50 or DC 50 <100nM, B: 100nM <IC 50 or DC 50 <1uM, C:1uM <IC 50 or DC 50

[0290] Example 1: Cell line culture and compound treatment Human breast cancer cell line [MDA-MB-231] was cultured in RPMI medium supplemented with 10% fetal bovine serum, penicillin [100 U / ml], and streptomycin [100 mg / ml]. Synthesized compounds were prepared as 10 mM or 50 mM stock solutions dissolved in DMSO [dimethyl sulfoxide], serially diluted, and treated. [RPMI2650] and [SNU2972] were cultured under the specified conditions.

[0291] Example 2: Evaluation of the antiproliferative activity of BRD4 targeting ligand compounds in cancer cells To observe cell growth inhibition, cells were plated into 96-well plates at 5,000 cells / well and treated with various concentrations of the samples for 72 hours. The IC50 value (the compound concentration that achieves 50% cell inhibition) is the average of three independent measurements.

[0292] Experimental Example 3: Evaluation of the BRD4 protein degradation ability of PROTACs targeting BRD4 protein To evaluate the ability of PROTACs to degrade BRD4 expressed in cells, cells were plated in 6-well plates at 5 x 10 5The cells were distributed at a concentration of 1000 cells / well, and the samples were treated for 24 hours. To perform Western blotting assays to confirm protein expression, the protease inhibitor-treated cells were treated for 30 minutes in 70 μL of RIPA buffer containing protease inhibitors. The cell lysates were then collected using a scraper on ice and centrifuged at 15,000 rpm for 30 minutes at 4°C to obtain the protein-containing supernatant. SDS-PAGE and membrane transfer of the proteins were performed using 10 μg of protein from each sample. Anti-BRD4, anti-beta-tubulin, and anti-GAPDH antibodies were incubated for 16 hours at 4°C, followed by secondary antibodies for 1 hour at room temperature. Protein expression was confirmed using the SuperSignal™ West Pico PLUS chemiluminescent substrate and an image analyzer. Protein expression was normalized based on the expression values ​​of beta or GAPDH, and protein expression in each sample was measured as a percentage relative to 100% for the sample treated with 0.1% DMSO vehicle. Protein expression was quantified using the ImageJ program. The change in protein expression level due to compound treatment (DC50: the concentration of compound that achieves 50% protein expression inhibition) was calculated using GraphicPad Prism 8.0 software. The results are shown in Tables 1 and 2 above. [Industrial Applicability]

[0293] The present invention can be used for anti-cancer purposes.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] BRD4 target protein binding portion (P)-{linker (L)}p-E3 ligase binding portion (E) During the ceremony, The E3 ligase binding moiety (E) has a structure represented by the following chemical formula 2 or 3: The BRD4 target protein binding moiety (P) has a structure represented by the following formula 4 or 5: p is an integer of 0 or 1; 【Chemistry 1】 During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 linear or branched alkyloxy, or an oxygen- or nitrogen-containing heterocycle of 4 to 8 rings; Q １ ~Q ４ are each independently C—F, C—Cl, C—H, C—X, or N, and Q １ ~Q ４ At least one of the following is C—X; Y is H, halogen, or C1-C6 straight or branched chain alkyl that is unsubstituted or optionally substituted with halogen or cyclic alkyloxy; Z is the moiety to which one end of the linker is attached, R １ is hydrogen, nitro, amino, carbonyl, C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain alkyl substituted with halogen, or cycloalkyl, or a pharmaceutically acceptable salt thereof.

2. One end of the linker (L) is (i) replacing X in the structure of Chemical Formula 2 and connecting to the structure of Chemical Formula 1; or (ii) The compound according to claim 1, which is bonded to the nitrogen atom or oxygen atom of X in the structure of Chemical Formula 2 and connected to the structure of Chemical Formula 2.

3. The linker (L) is 【Chemistry 2】 or is selected from the following structural formulas: 【Transformation 6】 In the formula, R ２ and R ３ each independently represents unsubstituted or substituted C1-C4 alkyl, piperidine, piperazine, -(CH ２ ) ｓ -, -(CH ２ ) ｑ -[O(C ２ H ４ )] ｒ -, -O-(CH ２ )-, benzene or morpholine; Q ５ and Q ６ are independently carbon atoms or independently nitrogen atoms; 2. The compound of claim 1, wherein m, n, q, r, s, t, and u are each independently an integer selected from 0 to 7.

4. The following compounds: 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(5-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)pent-4-phospho-1-yl)-3-methoxybenzamide, 3-(6-(4-((4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-((4-(4-(4-(R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, 3-((4-(4-((4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-6-yl)pent-4-rin-1-yl)piperidin-4-yl)-3-methoxybenzamide, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-N-(1-((3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydroptalazin-5-yl)glycyl)-4-methylpiperidin-4-yl)-3-methylpiperidin-4-yl)-3-methoxybenzamide, 3-(6-(4-((S)-4-(4-((R)-5-(cyclohexylmethyl)-4-((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)morpholin-2-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-(2-(2-(2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydroptaladin-5-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl)ethyl)3-methoxybenzamide, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)piperidin-4-yl)-3-methoxybenzamide, 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-({4-[4-(4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-2-methoxybenzoyl)piperazin-1-yl]-3-fluorophenyl}amino)-1-methylpiperidine-2,6-dione, 3-(6-(4-(1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperidin-4-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-((1-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)azetidin-3-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(2-((3-(2,6-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydropetalazin-5-yl)amino)ethyl)-3-methoxybenzamide, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]phteridin-7-yl)amino)N-(1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)-3-methoxybenzamide, 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]-3-methoxybenzamide, 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)3-methoxybenzamide, 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4S)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]phteridin-7-yl]amino}-N-{1-[2-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)ethyl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl}piperazin-1-yl}propyl)piperidin-4-yl]-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-[1-({4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}methyl)piperidin-4-yl]-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[2-(2-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenoxy}ethoxy)ethyl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-dei)propanoyl]piperidin-4-yl}-3-methoxybenzamide, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)propyl]piperidin-4-yl}-3-methoxybenzamide, 3-{6-[4-(4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-4-methyl-1-oxo-1,2-dihydroptaladin-2-yl}piperidine-2,6-dione, 3-{6-[4-(4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-3-methoxybenzoyl)piperazin-1-yl]-1-oxo-1,2-dihydroptaladin-2-yl}piperidine-2,6-dione, 4-{[(4R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4H,5H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino}-N-{1-[3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-dei)propanoyl]piperidin-4-yl}-3-methoxybenzamide, 3-(8-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(8-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)N-(1-(1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidine-4-carbonyl)piperidin-4-yl)piperidin-4-yl)-3-methoxybenzamide, 3-(6-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(7-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(8-((2-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(5-((2-(4-((((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-((2-(4-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(7-((2-(4-(((R)-5-(cyclohexylmethyl)-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-(1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(7-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-6-yl]pent-4-phospho-1-yl}oxy)phenylamide, 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)phenyl)acetamide, 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]pentyl}oxy)phenylamide, 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl]piperazin-1-yl}methyl)phenylamide (ICT-0001423), 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{[(2S)-4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]morpholin-2-yl]methoxy}phenylamide, and 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)methyl]phenyl}acetamide, or a pharmaceutically acceptable salt thereof.

5. An anti-cancer composition comprising a compound according to any one of claims 1 to 4.

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