Degrading agent for degrading CMET protein and pharmaceutical composition containing same

Abstract

TPD compounds are disclosed. The present invention relates to novel PROTAC compounds that bind to cMET protein and pharmaceutical compositions containing the same. The present invention relates to PROTAC compounds that bind to cMET protein, and since PROTAC compounds can bind to and degrade cMET protein, they can be useful for treating or preventing diseases associated with cMET protein. The compounds of the present invention have excellent anti-cancer effects and can also induce degradation of cMET protein, which can exhibit therapeutic effects against cMET 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 that binds to the cMET protein and the E3 ligase binding moiety is prepared, and the E3 ligase binding moiety and the cMET protein target binding moiety are connected via a linker to complete a PROTAC compound. 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 and pharmaceutical composition thereof, in which a novel E3 ligase binding moiety and a cMET protein target binding moiety are connected via a linker. [Means for solving the problem]

[0005] In order to achieve the technical task, the present invention provides a TPD compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] cMET target protein binding domain (P)-{linker (L)}p-E3 ligase binding domain (E) During the ceremony, The E3 ligase binding moiety (E) is a compound represented by the following chemical formulas 2 to 6: The cMET target protein binding moiety (P) is a compound represented by any one of the following chemical formulas 7 to 10: p is an integer of 0 or 1 (if p is 0, P and E are directly connected); [Chemical formula 2] [ka] [Chemical formula 3] [ka] [Chemical formula 4] [ka] [Chemical formula 5] [ka] [Chemical formula 6] [ka] [Chemical formula 7] [ka] [Chemical formula 8] [ka] [Chemical formula 9] [ka] [Chemical formula 10] [ka] During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 straight or branched chain alkyl, or an oxygen- or nitrogen-containing heterocycle of 4-8 atoms; 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 hydrogen, halogen, or C1-C6 linear, branched, or cyclic alkyloxy unsubstituted or substituted with halogen; one of Q5 and Q6 is a carbon atom and the other is a nitrogen atom; Z is a carbon atom or a nitrogen atom, R 1 is hydrogen, nitro, amino, carbonyl, C1-C6 straight, branched or cyclic alkyl, or C1-C6 straight, branched or cyclic alkyl substituted with halogen.

[0006] In the present invention, the end of the linker (L) is (i) can be connected to the structure of formula 1 by replacing X in the structure of formula 2; (ii) can be connected to the structure of formula 1 by bonding to the nitrogen atom or oxygen atom of X in the structure of formula 2; (iii) may be directly attached to the benzene ring of the structure of formula 3, (iv) It can be directly connected to the amino group located at the end of the structure of Formula 4, (v) may be directly attached to the triazole ring of the structure of Formula 5; or (vi) It is directly connected to the pyridine ring of the structure of Chemical Formula 6, and the other end of the linker (L) can be connected to a compound bound to piperidine or piperazine located at any end of the structures of Chemical Formulas 7 to 10.

[0007] In the present invention, the end of the linker (L) is [ka] It may have a structure selected from the group of formulas: [ka] In the formula, R2 and R3 are each independently -(CH2) s -, -(CH2) t -[O(C2H4)] u -, -O-(CH2)-, -CH(OH)-piperazine, piperidine, azetidine, -(CH2) v -Piperidine, -(CH2) v -Piperazine, piperazine-(CH2) v -Piperidine, piperazine-(CH2) v -morpholine, piperidine-(CH2) v -Morpholine, Azetidine-(CH2) v -Piperazine, Azetidine-(CH2) v -piperidine, benzene-piperidine, benzene-piperazine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-piperazine, benzene, triazole or pyrrolidine, m, n, q, r, s, t, u, v, and w are each independently an integer selected from 0 to 7.

[0008] The present invention also provides anti-cancer compositions comprising any of the compounds described above. [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-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 represented by Chemical Formula 1. [Chemical formula 1] cMET target protein binding domain (P)-{linker (L)}-E3 ligase binding domain (E) The basic structure of the E3 ligase binding moiety according to the present invention can be prepared according to the following reaction scheme 1 or reaction scheme 2. [Reaction Scheme 1] [ka] [Reaction Scheme 2] [ka]

[0014] In the above reaction formula 1 or 2, X is hydrogen, halogen, amino, nitro, hydroxy, piperazine group, or C1-C4 alkoxy. However, for the sake of convenience, the above formula does not show the substituents that can be bonded to carbons at Q1-Q4 of the compound of formula 1, and R 1Among the substituents, only simple substituents such as hydrogen or methyl are shown as examples.

[0015] Below, embodiments are used to prepare specific examples of E3 ligase binding moiety compounds.

[0016] Example A: Preparation of E3 Ligase Ligating Moiety Compounds Example A-1: ​​Compound [ka] Preparation of (prepared according to Equation 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].

[0017] 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 benzoylbenzenecarboperoxoate (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 complete when the red color disappeared. After cooling, the reaction was washed with water, dried over magnesium sulfate, 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].

[0018] 1-3) Preparation of methyl 2-formyl-6-nitrobenzoate [ka] At room temperature, NMO (N-methylmorpholine N-oxide) (561 mg, 4.87 mmol) and 4 Å molecular sieves 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 magnesium sulfate, 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].

[0019] 1-4) Preparation of 2-formyl-6-nitrobenzoic acid [ka] At room temperature, an aqueous solution of lithium hydroxide (1.15 g, 47.8 mmol) 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0020] 1-5) Preparation of 8-nitrobutalazin-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 magnesium sulfate and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0021] 1-6) Preparation of 3-(8-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 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 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 magnesium sulfate 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].

[0022] 1-7) Preparation of 3-(8-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(8-nitro-1-oxo-1,2-dihydrohoptalazin-2-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

[0023] 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].

[0024] 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 benzoylbenzenecarboperoxoate (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 magnesium sulfate, 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].

[0025] 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 magnesium sulfate, 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].

[0026] 2-4) Preparation of 2-formyl-3-nitrobenzoic acid [ka] At room temperature, an aqueous solution of lithium hydroxide (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 remove the THF. After cooling to 0°C, the residue 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0027] 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0028] 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-nitrobutalazine-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 magnesium sulfate 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].

[0029] 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) was added to a solution of 3-(5-nitro-1-oxoptalazine-2(1H)-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 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

[0030] 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 reduced pressure. The product was used in the next reaction without further purification. (11.2 g, 103%) MS (ESI, m / z): [M+1] + =[168.3].

[0031] 3-2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (24.7 g, 139 mmol) and benzoylbenzenecarboperoxoate (1.53 g, 6.30 mmol) were added sequentially to a solution of methyl 2-fluoro-6-methylbenzoate (21.2 g, 126 mmol) in ClCHCHCl (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 magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the following reaction without further purification. (35 g, 112% yield) MS (ESI, m / z): [M+1] + =[245.9].

[0032] 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 magnesium sulfate, 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% yield) MS (ESI, m / z): [M+1] + =[183.1].

[0033] 3-4) Preparation of 2-fluoro-6-formylbenzoic acid [ka] At room temperature, an aqueous solution (41 ml) of lithium hydroxide (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 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 (100 ml). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure to give white crystals (10.4 g, 97.8%). MS (ESI, m / z): [M+1] + =[168.8].

[0034] 3-5) Preparation of 8-fluorobutalazin-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 titrated with 100 ml of ethyl acetate (EA) and filtered to give white crystals (3.05 g, 30%). MS (ESI, m / z): [M+1] + =[164.8].

[0035] 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-fluorobutalazine-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 solution was dried over magnesium sulfate 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

[0036] Example A-4: Compound [ka] Preparation of 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 and extracted with NaHCO3 and ethyl acetate (EA). It was dried over magnesium sulfate. 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].

[0037] 4-2) Preparation of methyl 2-(bromomethyl)-3-fluorobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (15.9 g, 89.2 mmol) and benzoylbenzenecarboperoxoate (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 complete when the red color disappeared. After cooling, the reaction was washed with water, dried over magnesium sulfate, 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].

[0038] 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 was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 ml), dried over magnesium sulfate, 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].

[0039] 4-4) Preparation of 3-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution (41 ml) of lithium hydroxide monohydrate (2.88 g, 68.6 mmol) in water was added to a solution of methyl 3-fluoro-2-formylbenzoate (2.5 g, 13.7 mmol) in THF (68 ml). After stirring for 4 hours, the reaction was concentrated under reduced pressure to remove 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 (100 ml). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure to give white crystals (2.5 g, 108%). MS (ESI, m / z): [M+1] + =[168.8].

[0040] 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 and washed with hexane. Vacuum drying afforded the title compound (1.3 g, 53%). MS (ESI, m / z): [M+1] + =[165.3]

[0041] 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-fluoropreptalazin-1-one (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 magnesium sulfate, 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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[0042] Example A-5: Compound [ka] Preparation of 5-1) Preparation of methyl 4-fluoro-6-methylbenzoate [ka] Methyl 4-fluoro-2-methylbenzoate was prepared from 4-fluoro-2-methylbenzoate according to the preparation method of Example 4-1.

[0043] 5-2) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate [ka] At room temperature, 1-bromophillolidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzenecarboperoxoate (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 magnesium sulfate, 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].

[0044] 5-3) Preparation of methyl 3-fluoro-2-formylbenzoate [ka] NMO (15.6 mg, 134 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22 g, 89 mmol) in DCM (100 ml) at room temperature. 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 magnesium sulfate, 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].

[0045] 5-4) Preparation of 4-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution (50 ml) of lithium hydroxide (13.8 g, 329 mmol) in water 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (10 g, 90.3%). MS (ESI, m / z): [M+1] + =[169.2].

[0046] 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (5.5 g, 83.07%). MS (ESI, m / z): [M+1] + =[165.3].

[0047] 5-6) Preparation of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluorophthalazin-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 solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound as white crystals (110 mg, 65.5%). MS (ESI, m / z): [M+1] + =[276.6]

number

[0048] 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-methylbenzoate according to the preparation method of Example 4-1.

[0049] 6-2) Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate [ka] At room temperature, 1-bromophilidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzenecarboperoxoate (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 complete when the red color disappeared. After cooling, the reaction was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by MPLC (HX / EA EA 0->5%) (29 g, 98.8% yield). MS (ESI, m / z): [M+1] + =[248.4].

[0050] 6-3) Preparation of methyl 5-fluoro-2-formylbenzoate [ka] 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) at room temperature. 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 magnesium sulfate, 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].

[0051] 6-4) Preparation of 5-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution of lithium hydroxide (17.3 g, 412 mmol) in water (50 ml) 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (12 g, 86.67%). MS (ESI, m / z): [M+1] + =[169.2].

[0052] 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 magnesium sulfate and concentrated under reduced pressure to give white crystals (6.5 g, 81.59%). MS (ESI, m / z): [M+1] + =[165.3].

[0053] 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-fluorine-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 then 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 solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (300 mg, 35.78%). MS (ESI, m / z): [M+1] + =[276.6].

number

[0054] 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 the mixture was stirred at 100° C. for 16 hours. After cooling, 5 ml of 1N HCl was added, and the mixture was stirred for 1 hour. The organic layer was dried over magnesium sulfate 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].

[0055] 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, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound. (810 mg, 108% yield) MS (ESI, m / z): [M+1] + =[183.1].

[0056] 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].

[0057] 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 mixture was concentrated under reduced pressure and dried. Water (10 ml) was added, stirred for 1 hour, and 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].

number

[0058] 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-oxothalamin-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]

[0059] 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-oxoptalazine-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] [NMR]1H NMR(400 MHz,DMSO-d6)δ10.98(s,1H),7.54(t,J=8.0 Hz,1H),7.37(brs,2H),6.95(d,J=8.2 Hz,1H),6.88(d,J=7.6 Hz,1H),5.62(br dd,J=5.3,12.0 Hz,1H),3.0-2.82(m,1H),2.66-2.52(m,2H),2.39(s,3H),2.11-2.02(m,1H)

[0060] 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 magnesium sulfate. 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).

[0061] 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-dihydrobutalazin-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 magnesium sulfate and evaporated. The reaction mixture was purified by MPLC (MC / ME Me 0->10%). White solid product (40 mg, 86% yield). MS (ESI, m / f): [M+1] + =[342.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ 8.24(s,1 H)8.02(d,J=9.05 Hz,1 H)7.47(dd,J=8.93,2.57 Hz,1 H)7.31(s,0.5 H)7.23(d,J=2.45 Hz,1 H)7.13(s,0.5 H)5.34(dd,J=8.93,4.52 Hz,1 H)3.28-3.44(m,6 H)2.85-2.95(m,4 H)2.30-2.40(m,1 H)2.16-2.30(m,2 H)

[0062] Example A-10: Compound [ka] Preparation of 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 NH4Cl and brine. The organic layer was dried over magnesium sulfate, 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%).

[0063] 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-dihydrobutalazin-6-yl]piperazine-1-carboxylate (60 mg, 0.14 mmol) was dissolved in 20% TFA 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 magnesium sulfate and evaporated. The reaction mixture was purified by MPLC (MC / ME Me 0->10%) to give a white solid as the product (yield: 40 mg / 86%). MS (ESI, m / f): [M+1] +=[342.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ 8.21-8.29(m,1 H)7.76(d,J=8.80 Hz,1 H)7.58(dd,J=8.93,2.57 Hz,1 H)7.47(d,J=2.45 Hz,1 H)7.28(s,0.5 H)7.13(s,0.5 H)5.34-5.44(m,1 H)3.26-3.33(m,4 H)2.81-2.91(m,3 H)2.62-2.69(m,1 H)2.55-2.62(m,1 H)2.31-2.44(m,1 H)2.15-2.31(m,2 H)

[0064] 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-dihydroptarazin-2-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 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 / f): [M+1] + =[288.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ 11.04(br.s.,1 H)8.40(s,1 H)8.14-8.25(m,1 H)7.42-7.49(m,2 H)5.80(dd,J=12.23,5.38 Hz,1 H)3.94(s,3 H)2.86-2.99(m,1 H)2.52-2.67(m,2 H)2.07-2.17(m,1 H)

[0065] 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 reaction mixture was stirred 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 / f): [M+1] + =[288.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ 11.01-11.11(m,1 H)8.38-8.45(m,1 H)7.90-7.96(m,1 H)7.65(d,J=2.69 Hz,1 H)7.56(dd,J=8.68,2.57 Hz,1 H)5.77-5.85(m,1 H)3.93-3.98(m,3 H)2.87-3.00(m,1 H)2.53-2.70(m,2 H)2.06-2.18(m,1 H)

[0066] 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 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 / f): [M+1] + =[288.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1 H)8.32(s,1 H)7.88(t,J=8.01 Hz,1 H)7.40(d,J=8.31 ​​Hz,1 H)7.44(d,J=7.70 Hz,1 H)5.64(dd,J=11.49,4.52 Hz,1 H)3.90(s,3 H)2.83-2.96(m,1 H)2.52-2.66(m,2 H)2.03-2.13(m,1 H)

[0067] 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 magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (16.5 g, 98.2%) MS (ESI, m / z): [M+1] + =[259.4].

[0068] 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 magnesium sulfate, 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 / f): [M+1] + =[195.0].

[0069] 14-3) Preparation of 2-formyl-3-methoxybenzoic acid [ka] Lithium hydroxide (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 magnesium sulfate and concentrated under reduced pressure to give white crystals. (11.2 g, 82.6%) MS (ESI, m / f): [M+1] + =[199.2].

[0070] 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 magnesium sulfate and concentrated under reduced pressure to give white crystals. (9.2 g, 76.35%) MS (ESI, m / f): [M+1] + =[176.9].

[0071] 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 magnesium sulfate, 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 / f): [M+1] + =[288.3]. [NMR]1H NMR(400 MHz,DMSO-d6)δ11.06(s,1H),8.51(s,1H),7.87-7.77(m,2H),7.54-7.51(m,1H), 5.85(m,1H),4.0(s,3H),2.98-2.90(m,1H),2.65-2.55(m,2H),2.14-2.09(m,1H).

[0072] 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 completion of 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 and refluxed for 4 hours, 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]

[0073] 15-2) Preparation of 6-bromophthalazin-1(2H)-one [ka] NH2NH2H2O (315 mg, 9.82 mmol) was added 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) at room temperature and stirred for 30 minutes. 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 / f): [M+1] + =[226.3].

[0074] 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 magnesium sulfate, 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 / f): [M+1] + =[337.2]. [NMR]1H NMR(400 MHz,DMSO-d6)δ11.08(s,1H),8.45(s,1H),8.28(s,1H),8.18-8.16(m,1H),8.06-8.0 4(m,1H),5.84-5.80(m,1H),2.93-2.90(m,1H),2.65-2.54(m,2H),2.15-2.12(m,1H).

[0075] Example A-16: Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione dihydrochloride 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-dihydrohoptalazin-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 Na2SO4, and concentrated. The residue was purified by column chromatography to give a pale yellow-white oil. (415 mg, 86.2%) MS (ESI, m / f): [M+1] + =[442.4]

[0076] 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 solution was extracted with magnesium sulfate 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 / f): [M+1] + =[342.6]. [NMR]1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),8.35(s,1H),7.87-7.83(m,1H),7.53-7.51(m,1H),7.39-7.41(m,1H),5. 55(m,1H),3.31-3.27(br,8H),2.88-2.80(m,1H),2.64-2.57(m,2H),2.50(br,1H),2.13-2.08(m,1H).

[0077] Example B: Preparation of CMET PROTACs based on ABN derivatives Example B-1: Preparation of 3-{6-[(4-{4-[(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}phenyl)methyl]piperazin-1-yl}-4-oxobutyl)amino]-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0000922) Step 1) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate [ka] 1-Bromomeloridine-2,5-dione (31.8 g, 178.0 mmol) was added to a solution of methyl 4-fluoro-2-methylbenzoate (20.0 g, 119.0 mmol) in ClCH2CHCl (100 ml) at room temperature, followed by the addition of benzoylbenzenecarboperoxoate (1.92 g, 5.95 mmol). The reaction was heated at reflux for 3 hours. Upon completion of the reaction, the red color disappeared. After cooling, the reaction was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by MPLC. (HX / EA 0-5%). (Yield: 22.0 g). MS (ESI, m / z): [M+H] + =248.4.

[0078] Step 2) Preparation of 4-fluoro-2-formyl benzoate [ka] NMO (15.6 mg, 134 mmol) was added to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22.0 g, 89 mmol) in DCM (100 mL) at room temperature, followed by the addition of molecular sieves 4A. 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 magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (12.0 g) as a white solid. MS (ESI, m / z): [M+H] + =183.2.

[0079] Step 3) Preparation of 4-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution of methyl 4-fluoro-2-formylbenzoate (12.0 g, 65.9 mmol) in THF (50 mL) and a solution of lithium hydroxide (1+) (13.8 g, 329 mmol) in HO (50 mL) were added. 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 1 M HCl to adjust the pH to 4. The reaction was extracted with ethyl acetate (50 mL × 2). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure to give white crystals (10.0 g). MS (ESI, m / z): [M+H] + =169.2.

[0080] Step 4) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one [ka] NH2NH2 monohydrate (2.02 mg, 40.3 mmol) was added to a solution of 4-fluoro-2-formylbenzoic acid (6.78 g, 40.3 mmol) in MeOH (50 mL) at room temperature. 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 with ethyl acetate (150 mL x 2). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure to give white crystals (5.5 g). MS (ESI, m / z): [M+H] + =165.3.

[0081] Step 5) Preparation of 3-(6-fluoro-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluoro-1,2-dihydroptaladin-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. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined ethyl acetate solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (110.0 mg) as white crystals. MS (ESI, m / z): [M+H] + =276.6. 1H NMR(400 MHz,DMSO-d6)δ 11.11(s,1H),8.50(s,1H),8.38(dd,J=8.86,5.44 Hz,1H),7.72-7.89(m,2H),5.70-5.90(m,11H),2.56-2.70(m,2H),2.11-2.25(m,1H)

[0082] Step 6) Preparation of 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)amino)butanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 4-aminobutanoic acid (225 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =359.4

[0083] Step 7) Preparation of 3-{6-[(4-{4-[(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-dei]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-4-oxobutyl)amino]-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0000922) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (17 mg, 0.03 mmol) and 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl}amino}butanoic acid (13.2 mg, 0.04 mmol) in DMF (2.0 ml) followed by ethylbis(propan-2-yl)amine (5.0 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into the reaction mixture. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (17 mg). MS (ESI, m / z): [M+H] + =894.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)9.14(s,1 H)8.65-8.70(m,2 H)8.58(s,1 H)8.21-8.29(m,1 H)8.11(s,1 H)7.82-7.87(m,1 H)7.54(m,J=8.09 Hz,2 H)7.27-7.34(m,2 H)7.01(dd,J=8.93,2.06 Hz,1 H)6.86(t,J=5.26 Hz,1 H)6.69(d,J=1.98 Hz,1 H)5.65(dd,J=12.05,5.04 Hz,1 H)4.79-4.91(m,2 H)4.66(d,J=12.36 Hz,1 H)4.31(d,J=13.28 Hz,1 H)4.12-4.19(m,1 H)3.82-3.90(m,4 H)3.34-3.47(m,6 H)2.99-3.13(m,4 H)2.78-2.88(m,1 H)2.46-2.59(m,2 H)2.36(t,J=7.02 Hz,1 H)2.26(d,J=14.19 Hz,4 H)1.94-2.03(m,1 H)1.83-1.94(m,1 H)1.75(t,J=6.87 Hz,1 H)1.30(t,J=6.71 Hz,1 H) 1.14-1.21(m,1 H)

[0084] Example B-2: Synthesis of 3-{6-[(6-{4-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine-4-dei]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-6-oxohexyl)amino]-1-oxo-1,2-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000923) Step 1) Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}hexanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 6-aminohexanoic acid (286 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =387.4 Step 2) Preparation of 3-{6-[(6-{4-[(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}phenyl)methyl]piperazin-1-yl}-6-oxohexyl)amino]-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}hexanoic acid (23.1 mg, 0.06 mmol) in DMF (2.0 ml) were added, followed by the addition of ethylbis(propan-2-yl)amine (5.0 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =922.6. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.98(s,1 H)9.21(s,1 H)8.74(s,2 H)8.65(s,1 H)8.31(s,1 H)8.18(s,1 H)7.91(d,J=8.68 Hz,1 H)7.61(d,J=8.19 Hz,2 H)7.37(d,J=8.07 Hz,2 H)7.07(dd,J=8.74,2.26 Hz,1 H)6.84-6.92(m,1 H)6.75(d,J=2.20 Hz,1 H)5.66-5.77(m,1 H)4.85-5.00(m,2 H)4.73(d,J=12.23 Hz,1 H)4.38(d,J=13.45 Hz,1 H)4.22(d,J=4.28 Hz,1 H)3.88-3.99(m,4 H)3.49(s,2 H)3.36-3.47(m,4 H)3.05-3.18(m,2 H)2.83-2.98(m,1 H)2.61(br.s.,1 H)2.55(d,J=8.07 Hz,1 H)2.25-2.40(m,4 H)2.01-2.10(m,2 H)1.88-2.01(m,2 H)1.74(br.s.,2 H)1.47-1.66(m,2 H)1.31-1.47(m,2 H)1.14-1.31(m,2 H)

[0085] Example B-3: Preparation of 3-(6-((5-(4-(4-(2-(((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)5-oxopentyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000924) Step 1) Preparation of 5-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)amino)pentanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl) and 5-aminopentanoic acid (245 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =373.4

[0086] Step 2) Preparation of 3-(6-((5-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)5-oxobutyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000924) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 5-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl)amino)phenyl)phenyl)pyrimidin-2-yl)morpholine A solution of benzoic acid (28.1 mg, 0.06 mmol) in DMF (2.0 ml) followed by ethylbis(propan-2-yl)amine (5 equivalents) was added. The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (23 mg). MS (ESI, m / z): [M+H] + =908.1. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.98(s,1 H)9.21(s,1 H)8.74(s,2 H)8.64(s,1 H)8.31(s,1 H)8.18(s,1 H)7.91(d,J=8.93 Hz,1 H)7.61(m,J=8.19 Hz,2 H)7.38(m,J=8.19 Hz,2 H)7.04-7.11(m,1 H)6.87-6.93(m,1 H)6.76(d,J=2.08 Hz,1 H)5.74(dd,J=11.55,7.15 Hz,1 H)4.85-5.00(m,2 H)4.73(d,J=11.98 Hz,1 H)4.38(d,J=12.72 Hz,1 H)4.22(br.s.,1 H)3.87-3.98(m,4 H)3.50(s,2 H)3.44(br.s.,4 H)3.05-3.19(m,2 H)2.85-2.97(m,2 H)2.59(d,J=19.93 Hz,1 H)2.35(br.s.,4 H)2.30(br.s.,3 H)2.07(dd,J=11.92,4.22 Hz,1 H)1.89-2.01(m,2 H)1.61(br.s.,2 H)1.37(t,J=5.93 Hz,2 H)

[0087] Example B-4: Preparation of 3-(6-((7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)7-oxoheptyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000925) synthesis Step 1) Preparation of 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)amino)heptanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydropetalazin-2-yl) and 7-aminoheptanoic acid (260 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =401.4

[0088] Step 2) Preparation of 3-(6-((7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)7-oxoheptyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000925) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 7-((2-(2-(2-(2-(2-(dioxopiperidin-3-yl)1-oxo-1,2-dihydroptarazin-6-yl)amino)heptanoic acid (32.1 mg, 0.05 mmol) mg, 0.06 mmol) HATU (41.3 mg, 0.11 mmol) in DMF (2.0 ml), followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into the reaction mixture, which was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (19 mg). MS (ESI, m / z): [M+H] + =936.8. 1H NMR(400 MHz,DMSO-d6)δ ppm10.98(s,1 H)9.21(s,1 H)8.74(s,2 H)8.64(s,1 H)8.31(s,1 H)8.18(s,1 H)7.91(d,J=8.93 Hz,1 H)7.61(m,J=8.07 Hz,2 H)7.38(m,J=8.07 Hz,2 H)7.07(dd,J=8.86,2.14 Hz,1 H)6.88(t,J=4.77 Hz,1 H)6.75(d,J=1.83 Hz,1 H)5.72(dd,J=11.92,5.32 Hz,1 H)4.85-4.99(m,2 H)4.73(d,J=12.84 Hz,1 H)4.38(d,J=13.45 Hz,1 H)4.22(d,J=4.77 Hz,1 H)3.88-3.97(m,4 H)3.50(s,2 H)3.44(br.s.,4 H)3.05-3.17(m,2 H)2.84-2.96(m,2 H)2.61(br.s.,1 H)2.56(br.s.,1 H)2.36(br.s.,2 H)2.24-2.33(m,4 H)2.01-2.10(m,1 H)1.90-2.01(m,2 H)1.55-1.65(m,2 H)1.45-1.55(m,2 H) 1.31-1.43(m,4 H)

[0089] Example B-5: Preparation of 3-(6-((2-(2-(2-(2-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000935) Step 1) Synthesis of 2-(2-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 2-(2-(2-aminoethoxy)ethoxy-acetic acid (285 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (240 mg). MS (ESI, m / z): [M+H] + =419.4

[0090] Step 2) Preparation of 3-(6-((2-(2-(2-(2-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000935) [ka] HATU (41.3 mg, 0.11 mmol) was dissolved in (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropropanediol)-2-methylpropanediol). To a solution of (butalazin-6-yl)amino)ethoxy)ethoxy)acetic acid (43.1 mg, 0.06 mmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (35 mg). MS (ESI, m / z): [M+H] + =954.1. 1H NMR(400 MHz,DMSO-d6)δ ppm10.99(s,1 H)9.21(s,1 H)8.79(br.s.,2 H)8.65(s,1 H)8.31(s,1 H)8.17(s,1 H)7.92(d,J=8.93 Hz,1 H)7.78(br.s.,2 H)7.57(br.s.,2 H)7.12(dd,J=8.93,2.20 Hz,1 H)6.93(br.s.,1 H)6.82(s,1 H)5.73(d,J=10.88 Hz,1 H)4.86-5.00(m,2 H)4.73(d,J=12.23 Hz,1 H)4.39(d,J=12.59 Hz,3 H)4.21(br.s.,3 H)3.88-3.98(m,4 H)3.56-3.66(m,6 H)3.13(br.s.,2 H)2.84-2.98(m,2 H)2.59(d,J=18.10 Hz,2 H)2.08(d,J=4.28 Hz,2 H)1.91-2.02(m,2 H)1.75(s,2 H)1.46(br.s.,2 H)1.34-1.42(m,3 H)

[0091] Example B-6: Preparation of 3-[6-(12-{4-[(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-dei]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione (ICT-0000938) Step 1) Preparation of 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl]amino}ethoxy)ethoxy]ethoxy]ethoxy}acetic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetic acid (410 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. The title compound (250 mg) was obtained. MS (ESI, m / z): [M+H] + =463.4

[0092] Step 2) Preparation of 3-[6-(12-{4-[(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}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione (ICT-0000938) [ka] HATU (41.3 mg, 0.11 mmol) was added to a solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 2-{2-[2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrohoptalazin-6-yl]amino}ethoxy)ethoxy]ethoxy}acetic acid (27.1 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =998.2. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.99(s,1 H)9.21(s,1 H)8.79(br.s.,2 H)8.65(s,1 H)8.31(s,1 H)8.16(s,1 H)7.91(d,J=8.80 Hz,1 H)7.78(br.s.,2 H)7.57(br.s.,2 H)7.08-7.14(m,1 H)6.92(br.s.,1 H)6.80(s,1 H)5.72(dd,J=11.37,4.89 Hz,1 H)4.85-5.00(m,2 H)4.73(d,J=12.10 Hz,1 H)4.39(d,J=11.62 Hz,3 H)4.15-4.21(m,3 H)3.88-3.97(m,4 H)3.44-3.67(m,15 H)3.10(d,J=12.84 Hz,3 H)2.78-2.98(m,2 H)2.59(d,J=17.97 Hz,2 H)1.88-2.09(m,2 H)1.33-1.41(m,3 H)

[0093] Example B-7: Preparation of 3-[6-(15-{4-[(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}phenyl)methyl]piperazin-1-yl}-15-oxo-4,7,10,13-tetraoxa-1-azpentadecan-1-yl)-1-oxo-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (ICT-0000939) synthesis Step 1) Preparation of 14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}-3,6,9,12-tetratetradecanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 14-amino-3,6,9,12-tetratetradecanoic acid (548 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =507.4

[0094] Step 2) Preparation of 3-[6-(15-{4-[(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}phenyl)methyl]piperazin-1-yl}-15-oxo-4,7,10,13-tetraoxa-1-azpentadecan-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (ICT-0000939) [ka] A solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]amino}-3,6,9,12-tetraoxatetradecanoic acid (20.5 mg, 0.06 mmol) in DMF (2.0 ml) was added, followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =1042.8. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.99(s,1 H)9.21(s,1 H)8.79(br.s.,2 H)8.65(s,1 H)8.31(s,1 H)8.17(s,1 H)7.91(d,J=8.93 Hz,1 H)7.78(br.s.,2 H)7.58(br.s.,2 H)7.11(dd,J=8.93,2.20 Hz,1 H)6.93(br.s.,1 H)6.80(d,J=2.08 Hz,1 H)5.67-5.77(m,1 H)4.85-5.00(m,2 H)4.73(d,J=12.84 Hz,2 H)4.39(d,J=12.59 Hz,3 H)4.09-4.21(m,3 H)3.86-4.00(m,4 H)3.44-3.66(m,12 H)3.12(dd,J=17.97,12.59 Hz,3 H)2.83-3.00(m,2 H)2.56-2.62(m,2 H)1.88-2.11(m,6 H)1.45(br.s.,2 H)1.37(t,J=5.87 Hz,3 H)

[0095] Example B-8: Preparation of 3-(8-((2-(2-(3-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl})benzyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2-(1H)-yl]piperidine-2,6-dione (ICT-0000940) Step 1) Preparation of methyl 2-fluoro-6-methylbenzoate [ka] 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) at room temperature. After stirring for 30 minutes, the reaction was treated with iodomethane (46 g, 324 mmol) and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product (11.2 g) was used in the next reaction without further purification. MS (ESI, m / z): [M+H] + =168.3.

[0096] Step 2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate [ka] To a solution of methyl 2-fluoro-6-methylbenzoate (21.2 g, 126 mmol) in ClCH2CHCl (250 ml), 1-bromophillolidine-2,5-dione (24.7 g, 139 mmol) was added, followed by benzoylbenzenecarboperoxoate (1.53 g, 6.30 mmol) at room temperature. The reaction was heated at reflux for 16 hours. Upon completion of the reaction, the red color disappeared. After cooling, the reaction was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product (35 g, 112%) was used in the next reaction without further purification. MS (ESI, m / z): [M+H] +=247.9.

[0097] Step 3) Synthesis of methyl 2-fluoro-6-formylbenzoate [ka] 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) at room temperature. The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (11.52 g) as a white solid. MS (ESI, m / z): [M+H] + =183.1.

[0098] Step 4) Preparation of 2-fluoro-6-formylbenzoic acid [ka] A solution of methyl 2-fluoro-6-formylbenzoate (11.5 g, 63.2 mmol) in THF (82 mL) and a solution of lithium hydroxide (1+) (7.57 g, 180 mmol) in HO (41 mL) were added to the THF solution at room temperature. 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 1 M HCl and the pH was adjusted to 4. The reaction was extracted with ethyl acetate (100 mL × 2). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure to give white crystals (10.4 g). MS (ESI, m / z): [M+H] + =168.8

[0099] Step 5) Preparation of 8-fluoroptaladin-1(2H)-one [ka] 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 MeOH (120 mL) at room temperature and stirred for 16 hours. The white precipitate was filtered and washed with MeOH. The resulting white solid was titrated in 100 mL of EA and filtered to give white crystals (3.05 g, 30%). MS (ESI, m / z): [M+H] + =165.1.

[0100] Step 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-fluorobutalazine-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 at room temperature for 6 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL×2). The combined ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography. The title compound (70.0 mg, 20.8%) was obtained as white crystals. MS (ESI, m / z): [M+H] + =276.1. 1H NMR(400 MHz,DMSO-d6)δppm 11.06(s,1H),8.48(s,1H),7.99(ddd,J=4.6,7.2,8.2 Hz,1H),7.80(d,J=7.2 Hz,1H),7.67(dd,J=8.2,11.4 Hz,1H),5.77(dd,J=5.3,12.0 Hz,1H),2.99-2.77(m,1H),2.68-2.51(m,2H),2.23-2.02(m,1H)

[0101] Step 7) Preparation of 3-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-5-yl]amino}ethoxy)ethoxy]propanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 3-[2-(2-aminoethoxy)ethoxy]propanoic acid (257 mg, 1.45 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography with MeOH / DCM (0-20%) to give the title compound (290 mg). MS (ESI, m / z): [M+H] + =433.4

[0102] Step 8) Preparation of 3-(8-((2-(2-(3-(4-(4-(2-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl})benzyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)1-oxoptalazine-2-(1H)-yl]piperidine-2,6-dione (ICT-0000940) [ka] HATU (38.0 mg, 0.10 mmol) was added to a solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (27.6 mg, 0.05 mmol) and 3-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-5-yl]amino}ethoxy)ethoxy]propanoic acid (25.9 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =968.1. 1H NMR(400 MHz,DMSO-d6)δppm 10.96(s,1 H)9.14(s,1 H)8.71-8.79(m,1 H)8.67(s,2 H)8.57(s,1 H)8.24(s,1 H)8.15(s,1 H)7.51-7.61(m,2 H)7.29(d,J=7.93 Hz,2 H)6.84(d,J=7.48 Hz,2 H)5.64(d,J=7.32 Hz,1 H)4.79-4.93(m,2 H)4.66(d,J=12.36 Hz,1 H)4.31(d,J=12.97 Hz,1 H)4.15(br.s.,1 H)3.52-3.62(m,4 H)3.39-3.52(m,4 H)3.36(br.s.,4 H)2.98-3.11(m,3 H)2.78-2.88(m,1 H)2.39-2.58(m,5 H)2.25(d,J=16.63 Hz,2 H)1.98-2.05(m,1 H)1.83-1.93(m,1 H)1.12-1.24(m,6 H)

[0103] Example B-9: Preparation of 3-[8-(12-{4-[(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-dei]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione (ICT-0000942) Step 1) Preparation of 2-{2-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl}amino}ethoxy)ethoxy]ethoxy}ethoxy}acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to 3-(8-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (399 mg, 1.45 mmol) and 2-{2-[2-(2-(2-aminoethoxy)ethoxy}acetic acid (300 mg, 1.45 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (290 mg). MS (ESI, m / z): [M+H] + =463.5

[0104] Step 2) Preparation of 3-[8-(12-{4-[(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}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione (ICT-0000942) [ka] HATU (38.0 mg, 0.10 mmol) was added to a solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (27.6 mg, 0.05 mmol) and 2-{2-[2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-5-yl]amino}ethoxy)ethoxy]ethoxy}acetic acid (27.7 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (26 mg). MS (ESI, m / z): [M+H] + =998.1. 1H NMR(400 MHz,DMSO-d6)δppm 10.96(s,1 H)9.14(s,1 H)8.72-8.78(m,1 H)8.64-8.69(m,2 H)8.58(s,1 H)8.24(s,1 H)8.13-8.16(m,1 H)7.51-7.60(m,2 H)7.29(d,J=7.93 Hz,2 H)6.80-6.87(m,2 H)4.79-4.91(m,2 H)4.65(d,J=12.97 Hz,1 H)4.31(d,J=13.12 Hz,1 H)4.04(s,2 H)3.97-4.02(m,1 H)3.82- 3.90(m,4 H)3.52-3.63(m,4 H)3.44-3.52(m,4 H)3.29-3.36(m,4 H)2.99-3.09(m,2 H)2.78-2.88(m,1 H)2.56(br.s.,1 H)2.52(br.s.,1 H)2.29(br.s.,2 H)2.24(br.s.,1 H)1.82-1.94(m,2 H)1.30(t,J=6.56 Hz,2 H)1.11-1.25(m,6 H)

[0105] Example B-10: Preparation of 3-[8-(16-{4-[(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-dei]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (ICT-0000946) Step 1) Preparation of 2-{2-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl}amino}ethoxy)ethoxy]ethoxy}ethoxy}acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to 3-(8-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (399 mg, 1.45 mmol) and 2-{2-[2-(2-(2-aminoethoxy)ethoxy}acetic acid (300 mg, 1.45 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (290 mg). MS (ESI, m / z): [M+H] + =463.5

[0106] Step 2) Preparation of 3-[8-(16-{4-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine-4-dei]pyrimidine-5-dei}phenyl)methyl]piperazin-1-yl}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-1-oxo-1,2-dihydroptarazin-2-yl]piperidine-2,6-dione (ICT-0000946) [ka] HATU (38.0 mg, 0.10 mmol) was added to a solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (27.6 mg, 0.05 mmol) and 2-{2-[2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydropetalazin-5-yl]amino}ethoxy)ethoxy]ethoxy}acetic acid (27.7 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (26 mg). MS (ESI, m / z): [M+H] + =998.1.1H NMR(400MHz,DMSO-d6)

[0107] Example B-11: Preparation of 3-{8-[(5-{4-[(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}phenyl)methyl]piperazin-1-yl}-5-oxopentyl)amino]-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0000959) Step 1) Preparation of 5-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl]amino}pentanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazin-2(1H)-yl) and 5-aminopentanoic acid (255 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (300 mg). MS (ESI, m / z): [M+H] + =373.4

[0108] Step 2) Preparation of 3-{8-[(5-{4-[(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}phenyl)methyl]piperazin-1-yl}-5-oxopentyl)amino]-1-oxo-1,2-dihydroptarazin-2-yl}piperidine-2,6-dione (ICT-0000959) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 5-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl}amino}pentanoic acid (22.2 mg, 0.06 mmol) in DMF (2.0 ml) followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =908.8. 1H NMR(400 MHz,DMSO-d6)δppm 11.04(s,1 H)9.21(s,1 H)8.81(s,2 H)8.72(br.s.,1 H)8.65(s,1 H)8.31(s,1 H)8.24(s,1 H)7.79(d,J=7.46 Hz,2 H)7.66(t,J=7.95 Hz,1 H)7.56(d,J=8.44 Hz,2 H)6.92(d,J=7.21 Hz,1 H)6.89(d,J=8.80 Hz,1 H)5.69(br.s.,1 H)4.82-4.99(m,2 H)4.73(d,J=12.96 Hz,1 H)4.42(br.s.,2 H)4.38(br.s.,2 H)4.22(br.s.,1 H)4.07(br.s.,1 H)3.87-4.00(m,4 H)3.23(m,4 H)3.02-3.20(m,4 H)2.77-3.01(m,2 H)2.52-2.68(m,2 H)2.33(br.s.,4 H)2.09(s,1 H)1.64(br.s.,2 H)1.23(s,2 H)

[0109] Example B-12: Preparation of 3-{8-[(7-{4-[(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}phenyl)methyl]piperazin-1-yl}-7-oxoheptyl)amino]-1-oxo-1,2-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000960) Step 1) Preparation of 7-[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl]amino}heptanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl) and 4-aminobutanoic acid (317 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (300 mg). MS (ESI, m / z): [M+H] + =401.4

[0110] Step 2) Preparation of 3-{8-[(7-{4-[(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}phenyl)methyl]piperazin-1-yl}-7-oxoheptyl)amino]-1-oxo-1,2-dihydroptalazin-2-yl}piperidine-2,6-dione (ICT-0000960) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and 7-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-5-yl]amino}amino} in DMF (2.0 ml), followed by ethylbis(propan-2-yl)amine (5 equiv.). The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =936.1 1H NMR(400 MHz,DMSO-d6)δppm 11.03(s,1 H)9.21(s,1 H)8.71(s,1 H)8.75(s,2 H)8.65(s,1 H)8.31(s,1 H)8.23(s,1 H)7.79(br.s.,1 H)7.54-7.70(m,3 H)7.39(br.s.,1 H)6.87(d,J=8.56 Hz,1 H)6.91(d,J=7.46 Hz,1 H)5.69(br.s.,1 H)4.85-4.99(m,2 H)4.73(d,J=12.23 Hz,1 H)4.38(d,J=14.06 Hz,2 H)4.21(br.s.,1 H)3.88-3.98(m,4 H)3.50(br.s.,2 H)3.43(br.s.,4 H)3.04-3.23(m,4 H)2.80-2.96(m,2 H)2.55-2.69(m,2 H)2.33(s,2 H)1.62(br.s.,2 H)1.50(br.s.,2H)1.40(br.s.,2 H)1.34(br.s.,2 H)1.14-1.28(m,4 H)

[0111] Example B-13: Preparation of 3-[8-({2-[2-(3-{4-[(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}phenyl)methyl]piperazin-1-yl}-3-oxoproxy)ethoxy}ethyl}amino)1-oxo-1,2-dihydroptaladin-2-yl]piperidine-2,6-dione (ICT-0000967) Step 2) Preparation of 17-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl)amino)-3,6,9,12,15-pentaoxaheptadecanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 17-amino-3,6,9,12,15-pentaheptadecanoic acid (327 mg, 1.45 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (310 mg). MS (ESI, m / z): [M+H] + =551.1

[0112] Step 2) Preparation of 3-(8-((17-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)17-oxo-3,6,9,12,15-pentaheptacyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000967) [ka] A solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (30.1 mg, 0.05 mmol) and 17-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl]amino}-3,6,9,12,15-pentaheptaceanoic acid (30.0 mg, 0.05 mmol) in DMF (2.0 mL) was added, followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =1086.1. 1H NMR(400 MHz,DMSO-d6)δppm 10.97(s,1 H)9.14(s,1 H)8.69(s,2 H)8.64(t,J=4.88 Hz,1 H)8.58(s,1 H)8.24(s,1 H)8.16(s,1 H)7.52-7.61(m,2 H)7.29(d,J=7.93 Hz,2 H)6.84(d,J=7.32 Hz,1 H)6.81(d,J=8.54 Hz,1 H)5.63(d,J=7.48 Hz,1 H)4.79-4.92(m,2 H)4.66(d,J=12.66 Hz,1 H)4.31(d,J=13.12 Hz,1 H)4.06-4.19(m,1 H)3.82-3.90(m,4 H)3.51-3.61(m,1 H)3.38-3.50(m,3 H)3.36(br.s.,2 H)2.98-3.18(m,5 H)2.76-2.88(m,1 H)2.45-2.59(m,4 H)2.29(br.s.,1 H)2.25(br.s.,3 H)1.98-2.07(m,1 H)1.82-1.94(m,1 H)1.57(quin,J=6.98 Hz,2 H)1.48(quin,J=7.36 Hz,2 H)1.29-1.40(m,2 H)1.13-1.24(m,11 H)

[0113] Example B-14: Preparation of 3-(8-((21-(4-(4-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)21-oxo-3,6,9,12,15,18-hexaoxahenicosyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000968) Step 1) Preparation of 1-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydroptaladin-5-yl)amino)-3,6,9,12,15,18-hexaoxahenicoinic acid-21-oic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 1-amino-3,6,9,12,15,18-hexaoxaheniconic acid-21-arsenic acid (327 mg, 1.45 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%). The title compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =609.6

[0114] Step 2) Preparation of 3-(8-((21-(4-(4-(2-(2-((S)-2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-21-oxo-3,6,9,12,15,18-hexaoxahenicosyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000968) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (31.8 mg, 0.05 mmol) and 1-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydrophthalazin-5-yl)amino)3,6,9,12,15,18-hexaoxaheniconic acid-21-arsenic acid (35.0 mg, 0.05 mmol) were added to HATU (43.7 mg, 0.10 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =1144.1. 1H NMR(400 MHz,DMSO-d6)δppm 10.97(s,1 H)9.14(s,1 H)8.64-8.70(m,2 H)8.57(s,1 H)8.24(s,1 H)8.13-8.17(m,1 H)7.52-7.60(m,3 H)7.31(d,J=8.09 Hz,2 H)6.81-6.88(m,2 H)5.62(br.s.,1 H)4.79-4.92(m,2 H)4.66(d,J=13.43 Hz,2 H)4.31(d,J=12.36 Hz,1 H)4.15(br.s.,2 H)3.81-3.90(m,4 H)3.59(t,J=5.19 Hz,2 H)3.32-3.55(m,8 H)2.99-3.09(m,2 H)2.77-2.88(m,2 H)2.57(br.s.,1 H)2.46-2.55(m,6 H)2.30(br.s.,2 H)2.24(br.s.,1 H)1.81-1.93(m,5 H)1.68(br.s.,2 H)1.38(br.s.,3 H)1.17(s,7 H)

[0115] Example B-15: Preparation of 3-(8-((4-(4-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)4-oxobutyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000969) Step 1) Preparation of 4-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-5-yl)amino)butanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (3-(8-fluoro-1-oxoptalazine-2(1H)-dei) and 4-aminobutanoic acid (127 mg, 1.45 mmol) in NMP (2.0 ml). Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione (3-(8-fluoro-1-oxoptalazine-2(1H)-dei). The title compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =359.6 Step 2) Preparation of 3-(8-((4-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)4-oxobutyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000969) [ka] (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (31.8 mg, 0.05 mmol) and 4-((3-(2,6-dioxopiperidin-3-yl-4-oxo-3,4-dihydropyrazole) (Diazin-5-yl)amino)butanoic acid (25.0 mg, 0.10 mmol) in DMF (2.0 ml) followed by ethyl bis(propan-2-yl)amine (5 equivalents). It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =893.9 1H NMR(400 MHz,DMSO-d6)δppm 10.97(s,1 H)9.14(s,1 H)8.64-8.70(m,2 H)8.57(s,1 H)8.24(s,1 H)8.13-8.17(m,1 H)7.52-7.60(m,3 H)7.31(d,J=8.09 Hz,2 H)6.81-6.88(m,2 H)5.62(br.s.,1 H)4.79-4.92(m,2 H)4.66(d,J=13.43 Hz,2 H)4.31(d,J=12.36 Hz,1 H)4.15(br.s.,2 H)3.81-3.90(m,4 H)3.59(t,J=5.19 Hz,2 H)3.32-3.55(m,8 H)2.99-3.09(m,2 H)2.77-2.88(m,2 H)2.57(br.s.,1 H)2.46-2.55(m,6 H)2.30(br.s.,2 H)2.24(br.s.,1 H)1.81-1.93(m,5 H)1.68(br.s.,2 H)1.38(br.s.,3 H)1.17(s,7 H)

[0116] Example B-16: Preparation of 3-(8-((6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)6-oxohexyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000970) Step 1) Preparation of 6-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl)amino)hexanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (8-fluoro-1-oxoptalazine-2(1H)-dei) and 6-aminohexanoic acid (153 mg, 1.45 mmol) in NMP (2.0 ml). Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione (3-(8-fluoro-1-oxoptalazine-2(1H)-dei). The title compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =387.6

[0117] Step 2) Preparation of 3-(8-((6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)6-oxohexyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000970) [ka] A solution of (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (31.8 mg, 0.05 mmol) and 6-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydrobutalazin-5-yl)amino)hexanoic acid (29.0 mg, 0.05 mmol) in DMF (2.0 ml) was added, followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =922.3. 1H NMR(400 MHz,DMSO-d6)δppm 10.97(s,1 H)9.14(s,1 H)8.64-8.70(m,2 H)8.57(s,1 H)8.24(s,1 H)8.13-8.17(m,1 H)7.52-7.60(m,3 H)7.31(d,J=8.09 Hz,2 H)6.81-6.88(m,2 H)5.62(br.s.,1 H)4.79-4.92(m,2 H)4.66(d,J=13.43 Hz,2 H)4.31(d,J=12.36 Hz,1 H)4.15(br.s.,2 H)3.81-3.90(m,4 H)3.59(t,J=5.19 Hz,2 H)3.32-3.55(m,8 H)2.99-3.09(m,2 H)2.77-2.88(m,2 H)2.57(br.s.,1 H)2.46-2.55(m,10 H)2.30(br.s.,2 H)2.24(br.s.,1 H)1.81-1.93(m,5 H)1.68(br.s.,2 H)1.38(br.s.,3 H)1.17(s,7 H)

[0118] Example B-17: Preparation of 3-(6-(4-((1-(4-(1-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000978) Step 1) Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and tert-butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (600 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (400 mg). MS (ESI, m / z): [M+H] + =539.4

[0119] Step 2) Preparation of 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (400 mg, 1.52 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (400 mg). MS (ESI, m / z): [M+H] + =439.4

[0120] Step 3) Preparation of 3-(6-(4-((1-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000978) [ka] Potassium carbonate (6 mg, 0.02 mmol) was dissolved in a solution of (S)-4-(2-(2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl methanesulfonate (12 mg, 0.02 mmol) and 3-(1-oxo-6-(4-(piperidin-4-yl)piperazine)-2-yl)benzyl methanesulfonate (12 mg, 0.02 mmol) in DMF (2.0 ml). To the resulting solution was added (9.5 mg, 0.02 mmol) of benzo-1-ylphthalazine-2(1H)-ylpiperidine-2,6-dione. The reaction was stirred at 60° C. for 2 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (5 mg). MS (ESI, m / z): [M+H] + =906.8. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.98(s,1 H)9.21(s,1 H)8.74(s,2 H)8.64(s,1 H)8.31(s,1 H)8.18(s,1 H)7.91(d,J=8.93 Hz,1 H)7.61(m,J=8.19 Hz,2 H)7.38(m,J=8.19 Hz,2 H)7.04-7.11(m,1 H)6.87-6.93(m,1 H)5.74(dd,J=11.55,7.15 Hz,1 H)4.85-5.00(m,2 H)4.73(d,J=11.98 Hz,1 H)4.38(d,J=12.72 Hz,1 H)4.22(br.s.,1 H)3.87-3.98(m,4 H)3.50(s,2 H)3.44(br.s.,4 H)3.05-3.19(m,2 H)2.85-2.97(m,2 H)2.59(d,J=19.93 Hz,1 H)2.35(br.s.,4 H)2.30(br.s.,4 H)2.07(dd,J=11.92,4.22 Hz,1 H)1.89-2.01(m,2 H)1.61(br.s.,2 H)1.37(t,J=5.93 Hz,2 H)

[0121] Example B-18: Preparation of 3-(4-methyl-8-((2-(4-(4-(4-(2-((S)-2-((5-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpho)pyrimidin-5-yl)benzyl)piperazin-1-yl)2-oxoethyl)amino)1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000983) synthesis Step 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 magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography to give the title compound (820 mg). MS (ESI, m / z): [M+H] + =196.8

[0122] Step 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 until the pH was approximately 3. 100 ml of EA was added, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. MS (ESI, m / z): [M+H] + =183.8

[0123] Step 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. MS (ESI, m / z): [M+H] + =179.1

[0124] Step 4) Preparation of 3-(8-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] t-BuONa (17.9 mg, 0.185 mmol) was added to a solution of 8-fluoro-4-methylphthalazin-1(2H)-one (30 mg, 0.168 mmol) in DMF (1 mL) at 0 °C and stirred at 0 °C for 20 min. 3-Bromoperidine-2,6-dione (32.3 mg, 0.168 mmol) was added to the solution and stirred at room temperature for 1 h. The title compound (2 mg) was obtained as a solid. MS (ESI, m / z): [M+H] + =289.8 1H NMR(400 MHz,DMSO-d6)δ11.05(s,1H),8.04-7.94(m,1H),7.79(d,J=7.9 Hz,1H),7.69(dd,J=7.9,11.3 Hz,1H),5.71(br dd,J=4.9,12.1 Hz,1H),3.0-2.83(m,1H),2.64-2.56(m,2H),2.55(s,3H),2.17-2.05(m,1H).

[0125] Step 5) Preparation of (3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-5-yl)glycine [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-4-methyl-1-oxoptalazin-2(1H)-yl) and glycine (125 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =345.4

[0126] Step 6) Preparation of 3-(4-methyl-8-((2-(4-(4-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)2-oxoethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0000983) [ka] HATU (41.3 mg, 0.11 mmol) was added to (S)-2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)methyl)4-(5-(4-(piperazin-1-yl)phenyl)pyrimidin-2-yl)morpholine (30 mg, 0.05 mmol) and (3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-5-yl)glycine (20.6 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (17 mg). MS (ESI, m / z): [M+H] + =879.8 1H NMR(400 MHz,DMSO-d6)δppm 10.94(s,1 H)9.36(br.s.,1 H)1 9.14(s,1 H)8.73(br.s.,2 H)8.58(s,1 H)8.24(s,1 H)7.65-7.77(m,2 H)7.62(t,J=7.78 Hz,1 H)7.42-7.56(m,2 H)6.78-6.93(m,1 H)4.80-4.92(m,2 H)4.67(d,J=12.51 Hz,1 H)4.33(d,J=12.97 Hz,2 H)4.15(br.s.,1 H)3.82-3.90(m,4 H)3.55(dq,J=10.59,6.54 Hz,2 H)3.43(t,J=10.45 Hz,2 H)3.00-3.12(m,4 H)2.78-2.89(m,1 H)2.47-2.59(m,3 H)2.01(d,J=5.04 Hz,1 H)1.89(d,J=17.09 Hz,2 H)1.38(d,J=6.87 Hz,2 H)1.09-1.23(m,6 H)

[0127] Example B-19: Preparation of 3-(6-(4-(2-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethyl)piperazine-1-dei)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001109) Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and tert-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =442.4

[0128] Step 2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =342.4

[0129] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 2-bromoacetate (121 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =456.4

[0130] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] TFA (1 ml) was added to tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)acetate (30 mg, 0.06 mmol) in DCM (3 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (15 mg). MS (ESI, m / z): [M+H] + =400.4

[0131] Step 5) Preparation of 3-(6-(4-(2-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (ICT-0001109) [ka] 2.HATU (20.6 mg, 0.06 mmol) was dissolved in (S)-2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)methyl) 4-(5-(4-(piperazin-1-yl)phenyl-pyrimidin-2-yl)morpholine (15 mg, 0.03 mmol) and 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydropyrazine-3-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)methyl) 4-(5-(4-(piperazin-1-yl)phenyl-pyrimidin-2-yl)morpholine) (15 mg, 0.03 mmol) and 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydropyrazine-3-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl) 4-(5-(4-(piperazin-1-yl)phenyl-pyrimidin-2-yl)morpholine) (15 mg, 0.03 mmol). To the resulting solution was added (6-yl)piperazin-1-yl)piperazin-1-yl)acetic acid (12.3 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (8 mg). MS (ESI, m / z): [M+H] + =935.1. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.98(s,1 H)9.21(s,1 H)8.74(s,2 H)8.64(s,1 H)8.31(s,1 H)8.18(s,1 H)7.91(d,J=8.93 Hz,1 H)7.61(m,J=8.19 Hz,2 H)7.38(m,J=8.19 Hz,2 H)7.04-7.11(m,1 H)6.87-6.93(m,1 H)6.76(d,J=2.08 Hz,1 H)4.85-5.00(m,2 H)4.73(d,J=11.98 Hz,1 H)4.38(d,J=12.72 Hz,1 H)4.22(br.s.,1 H)3.87-3.98(m,4 H)3.50(s,2 H)3.44(br.s.,4 H)3.05-3.19(m,2 H)2.85-2.97(m,2 H)2.59(d,J=19.93 Hz,2 H)2.35(br.s.,4 H)2.30(br.s.,4 H)2.07(dd,J=11.92,4.22 Hz,1 H)1.89-2.01(m,2 H)1.61(br.s.,2 H)1.37(t,J=5.93 Hz,2 H)

[0132] Example B-20: Preparation of 3-((3-fluoro-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (ICT-0001403) Step 1) Preparation of (S)-4-(5-(4-((4-(2-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine [ka] Ethylbis(propan-2-yl)amine (35.1 mg, 0.27 mmol) was added to (S)-2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)methyl)-4-(5-(4-(piperazin-1-yl)phenyl-2-yl)pyrimidin-2-yl)morpholine (87.5 mg, 0.18 mmol) and 2,4-difluoro-1-nitrobenzene (57.6 mg, 0.36 mmol) in DMF (2 ml). The reaction was stirred at 120° C. for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (95 mg). MS (ESI, m / z): [M+H] + =692.6.

[0133] Step 2) Preparation of (S)-3-fluoro-4-(4-(4-(2-(2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)aniline [ka] 2 mL of saturated NH4Cl was added to a solution of (S)-4-(5-(4-((4-(4-(2-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)-2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (85 mg, 0.12 mmol) and iron (34.3 mg, 0.62 μmol). 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. The ethyl acetate organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (69 mg). MS (ESI, m / z): [M+H] + =662.6.

[0134] Step 3) Preparation of 3-((3-fluoro-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (ICT-0001403) [ka] Sodium bicarbonate (27.9 mg, 0.33 mmol) was added to a solution of 3-fluoro-4-{(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}phenyl)methyl]piperazin-1-yl}aniline (120 mg, 0.18 mmol) and 3-bromorphidine-2,6-dione (69.6 mg, 0.36 mmol). The reaction was stirred at 60° C. for 12 hours. The reaction was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (121 mg). MS (ESI, m / z): [M+H] + =773.9. 1H NMR(400 MHz,DMSO-d6)δppm 10.71(s,1 H)9.14(s,1 H)8.68(s,2 H)8.58(s,1 H)8.25(s,1 H)7.55(m,J=8.09 Hz,2 H)7.33(m,J=8.09 Hz,2 H)6.76(t,J=9.31 Hz,1 H)6.43(dd,J=14.95,2.29 Hz,1 H)6.35(d,J=8.54 Hz,1 H)5.74(d,J=7.78 Hz,1 H)4.79-4.93(m,2 H)4.66(d,J=12.36 Hz,1 H)4.31(d,J=12.97 Hz,1 H)4.09-4.25(m,1 H)3.79-3.89(m,4 H)3.37-3.55(m,3 H)3.00-3.10(m,2 H)2.80(br.s.,2 H)2.61-2.71(m,1 H)2.51(d,J=4.43 Hz,1 H)2.47(s,2 H)1.97-2.05(m,1 H)1.77(dd,J=12.13,4.50 Hz,1 H)

[0135] Example B-21: Preparation of 3-(((2-fluoro-4-(4-(2-(2-(2-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (ICT-0001439) Step 1) Preparation of tert-butyl (S)-2-(4-(4-(2-(2-(2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetate [ka] tert-Butyl 2-bromoacetate (150 mg, 0.62 mmol), ethyl bis(propan-2-yl)amine (2.0 equiv.) were dissolved in ACN (10.0 ml) to prepare (S)-2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)methyl)4-(5-(4-(piperazin-1-yl)phenyl-pyrimidin-2-yl)morpholino) To a solution of (S)-2-(5-(1-(1-methyl-1-yl)phenyl-pyridin-2-yl)morpholine (300 mg, 0.62 mmol) was added tert-butyl 2-bromoacetate (150 mg, 0.62 mmol) and ethyl bis(propan-2-yl)amine (2.0 equiv.) was added. The title compound (210 mg) was obtained. MS (ESI, m / z): [M+H] + =667.7

[0136] Step 2) Preparation of (S)-2-(4-(4-(2-(2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetic acid [ka] TFA (1 ml) was added to a solution of tert-butyl (S)-2-(4-(4-(2-(2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetate (200 mg, 0.45 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =611.4

[0137] Step 3) Preparation of 3-((3-fluoro-4-(4-(2-(4-(4-(2-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (ICT-0001439) [ka] HATU (74.4 mg, 0.16 mmol) was added to (S)-2-(4-(2-(2-((5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetic acid (100 mg, 0.16 mmol) and 3,3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (50.2 mg, 0.16 mmol), followed by the addition of ethylbis(propan-2-yl)amine (31.7 mg, 0.22 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (79 mg). MS (ESI, m / z): [M+H] + =900.1. 1H NMR(400 MHz,DMSO-d6)δ ppm 10.80(s,1 H)9.21(s,1 H)8.75(s,2 H)8.65(s,1 H)8.32(s,1 H)7.60(m,J=7.93 Hz,2 H)7.37(m,J=8.09 Hz,2 H)6.78-6.88(m,1 H)6.53(dd,J=14.80,2.29 Hz,1 H)6.44(d,J=8.70 Hz,1 H)5.88(d,J=7.78 Hz,1 H)4.86-4.99(m,2 H)4.73(d,J=12.21 Hz,1 H)4.38(d,J=13.12 Hz,1 H)3.89-3.97(m,4 H)3.66(br.s.,1 H)3.56(br.s.,2 H)3.45-3.54(m,3 H)3.17(br.s.,1 H)3.04-3.14(m,2 H)2.86(br.s.,2 H)2.78(br.s.,2 H)2.74(s,1 H)2.59(br.s.,1 H)2.42(br.s.,4 H)2.37(br.s.,2 H)

[0138] Example B-22: Preparation of 3-((3-fluoro-4-(4-(2-(4-(4-(4-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (ICT-0001379) [ka] (S)-2-(4-(2-(2-(2-((5-(1-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetic acid (100 mg, 0.16 mmol) and (2R,4S)-1-((R)-2-amino-3,3 HATU (74.4 mg, 0.16 mmol) in N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80.2 mg, 0.16 mmol) followed by ethylbis(propan-2-yl)amine (31.7 mg, 0.22 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =1038.1. 1H NMR(400 MHz,DMSO-d6)δppm 9.14(s,1 H)8.92(s,1 H)8.65-8.74(m,2 H)8.58(s,1 H)8.24(s,1 H)7.54(d,J=7.93 Hz,2 H)7.35-7.40(m,2 H)7.22-7.35(m,4 H)5.05(d,J=3.20 Hz,1 H)4.79-4.94(m,3 H)4.66(d,J=12.66 Hz,1 H)4.40-4.49(m,1 H)4.26-4.40(m,2 H)4.21(br.s.,1 H)3.82-3.89(m,4 H)3.37 -3.55(m,4 H)2.95-3.09(m,2 H)2.37-2.40(m,4 H)1.91-2.05(m,1 H)1.31(d,J=7.02 Hz,3 H)0.80-0.94(m,10 H) [Table 1-1] [Table 1-2]

[0139] Example C: Preparation of a tepotinib-based cMET PROTAC Example C-1: Preparation of 3-(1-(3-(5-((1-(1-(1-(1-((1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000907) Step 1) Preparation of tert-butyl 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oate [ka] A solution of 3-(8-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (200 mg, 0.73 mmol), tert-butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-oate (280 mg, 0.87 mmol), and DIPEA (0.38 mL, 2.18 mmol) in NMP (1.5 mL) was stirred at 120° C. for 20 hours. MS (ESI, m / z): [M+H] + =577.2.

[0140] Step 2) Preparation of 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid [ka] 1 ml of TFA solution was added to tert-butyl 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptarazin-5-yl)amino-3,6,9,12-tetraoxapentadecan-15-oate (360 mg, 0.62 mmol) in DCM (5 mL) and stirred at room temperature for 2 h. MS (ESI, m / z): [M+H] + =521.2.

[0141] Step 3) Preparation of 3-(1-(3-(5-((1-(1-(1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydroptaladin-5-yl)amino)3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000907) [ka] To a solution of 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1 at room temperature in DMF (5 ml), HATU (13.5 mmol, 0.06 mmol) was added 6-dihydropyridazin-3-yl}benzonitrile (25 mg, 0.05 mmol) and 1-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydrobutalazin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oxane (27.2 mmol, 0.05 mmol), followed by the addition of ethylbis(propan-2-yl)amine (33.8 mg, 0.26 mmol). The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-20%) to give the title compound (51.3 mg). MS (ESI, m / z): [M+H] + =982.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.67-5.77(m,1 H)4.85-5.00(m,2 H)4.73(d,J=12.84 Hz,2 H)4.39(d,J=12.59 Hz,3 H)4.09-4.21(m,3 H)3.86-4.00(m,4 H)3.44-3.66(m,8 H)3.12(dd,J=17.97,12.59 Hz,3 H)2.83-3.00(m,2 H)2.56-2.62(m,2 H)1.88-2.11(m,6 H)1.45(br.s.,2 H)

[0142] Example C-2: Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(2-(2-(2-(3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-000975) Step 1) Preparation of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate [ka] K2CO3 (1.41 g, 10.2 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (3 g, 10.2 mmol) and benzyl 4-((methylsulfonyl)oxymethyl)piperidine-1-carboxylate (4.5 g, 20.5 mmol) in 30 ml of DMF and stirred at 85 °C for 16 hours. After cooling, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to give benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.95 g). MS (ESI, m / z): [M+H] + =418.2.

[0143] Step 2) Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate [ka] Pd / C (10 wt%, 50 mg) was added to a solution of tert-butyl 4-((1-(benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (0.5 g, 1.2 mmol) in 10 ml of MeOH and stirred at room temperature under a hydrogen atmosphere for 4 hours. The solution was filtered through a pad of Celite 545. The solvent was removed under reduced pressure to give tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.35 g). MS (ESI, m / z): [M+H] + =284.0.

[0144] Step 3) Preparation of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate [ka] A solution of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (1 g, 3.46 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1.96 g, 6.91 mmol), and DIPEA (1.81 mL, 10.4 mmol) in NMP (10 mL) was stirred at 120° C. for 20 hours. The reaction mixture was purified by reverse-phase column chromatography to give tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptalazine-6-yl)piperazin-1-yl)piperazine-1-carboxylate (910 mg). MS (ESI, m / z): [M+H] + =552.3.

[0145] Step 4) Preparation of 3-(1-oxo-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] 2 ml of TFA was added to a solution of tert-butyl 4-((1-(2-(2-(2-(2-(2-(2-(2-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (910 mg, 1.65 mmol) in 10 ml of DCM and stirred at room temperature for 2 hours. MS (ESI, m / z): [M+H] + =453.0.

[0146] Step 5) Preparation of 3-(1-(1-(3-(5-((1-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-000975) [ka] HATU (47.7 mg, 0.13 mmol) was added to 2-(((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (30 mg, 0.06 mmol) and 3-(1-oxo-6-(4-(piperazin-1-yl)piperidin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (24 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =972.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.03(s,1 H)8.65-8.70(m,3 H)8.38(s,3 H)8.22-8.30(m,3 H)8.19(d,J=9.78 Hz,1 H)8.12(d,J=9.29 Hz,1 H)7.94(d,J=7.58 Hz,1 H)7.73(t,J=7.83 Hz,1 H)7.48-7.53(m,2 H)7.17(d,J=9.78 Hz,1 H)5.45(s,2 H)4.10(d,J=5.99 Hz,1 H)

[0147] Example C-3: Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-dei}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-000979) Synthesis Step 1) Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and tert-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =442.4

[0148] Step 2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10.0 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaradin-6-yl) in DCM (30.0 ml). TFA (10.0 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperin-3-yl)-piperazine-1-carboxylate-6-yl) in DCM (30.0 ml). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =342.4

[0149] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 2-bromoacetate (121 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =456.4

[0150] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] TFA (1.0 ml) was added to a solution of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)acetate (30 mg, 0.06 mmol) in DCM (3.0 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (15 mg). MS (ESI, m / z): [M+H] + =400.4

[0151] Step 5) Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazine-1-dei}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-000979) [ka] HATU (47.7 mg, 0.13 mmol) was added to a solution of 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-5-yl}acetic acid (20.6 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =860.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.01(s,1 H)8.65(s,2 H)8.38(s,2 H)8.20-8.27(m,3 H)8.18(d,J=9.77 Hz,1 H)8.04(d,J=9.16 Hz,1 H)7.93(d,J=7.63 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.44-7.53(m,3 H)7.26(s,1 H)7.17(d,J=9.77 Hz,1 H)5.75(dd,J=11.90,4.73 Hz,1 H)5.44(s,2 H)4.42(d,J=12.21 Hz,1 H)4.06-4.16(m,3 H)3.43(br.s.,6 H)3.12(d,J=12.97 Hz,1 H)3.05(t,J=11.98 Hz,1 H)2.86-2.98(m,1 H)2.64(br.s.,1 H)2.60(br.s.,6 H)2.09(d,J=5.04 Hz,1 H)1.96(d,J=16.48 Hz,1 H)1.83(br.s.,2 H)1.32-1.40(m,1 H)

[0152] Example C-4: Preparation of 3-(1-(3-(5-((1-(1-((1-((1-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000980) synthesis Step 1) Preparation of 3-(6-oxo-1-(3-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(2-methyl-2-pyridazin-3-yl)benzonitrile (250 mg, 0.52 mmol) and tert-butyl 4-[(methanesulfonyl)methyl]piperidine-1-carboxylate (184 mg, 0.62 mmol) were added to a solution of 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (250 mg, 0.52 mmol) and tert-butyl 4-[(methanesulfonyl)methyl]piperidine-1-carboxylate (184 mg, 0.62 mmol) in 1 ml of DMF at room temperature. The reaction was stirred at 60° C. for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the Boc-protected compound. The compound was treated with 4.0 M HCl in dioxane and stirred for 4 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and purified by NH-DM 1020 chromatrex pad to give the title compound (205 mg). MS (ESI, m / z): [M+H] = 576.7. 1H NMR(500 MHz,DMSO-d6)δppm 11.02(s,1 H)8.60-8.71(m,2 H)8.37(s,2 H)8.13-8.28(m,4 H)8.04(d,J=9.05 Hz,1 H)7.93(d,J=7.70 Hz,1 H)7.71(t,J=7.89 Hz,1 H)7.42-7.54(m,3 H)7.25(d,J=2.08 Hz,1 H)7.16(d,J=9.78 Hz,1 H)5.75(dd,J=12.10,4.89 Hz,1 H)5.44(s,2 H)3.98-4.13(m,2 H)3.37-3.47(m,4 H)2.99-3.15(m,2 H)2.85-2.98(m,1 H)2.59(br.s.,5 H)1.99(s,1 H)1.29-1.39(m,1 H)1.11-1.25(m,2 H)

[0153] Step 2) Preparation of 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-5-yl]amino}acetic acid [ka] A solution of 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione at room temperature was added followed by ethylbis(propan-2-yl)amine (179 mg, 1.38 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 magnesium sulfate 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 concentrated under reduced pressure to give the target compound (189 mg). MS (ESI, m / z): [M+H]=0.345.2

[0154] Step 3) Preparation of 3-(1-(3-(5-((1-((1-((3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000980) [ka] HATU (3-[6-oxo-1-({3-[5-({1-[(piperidin-4-yl)methyl]piperidin-4-yl}methoxy)pyrimidin-2-yl]phenyl}methyl)-1,6-dihydropyridazin-3-yl]benzonitrile (50 mg, 0.09 mmol) and 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaradin-5-yl]benzonitrile [2-(2-methyl-2-yl)amino}acetic acid (29.2 mg, 0.09 mmol), followed by ethylbis(propan-2-yl)amine (33.7 mmol). The reaction was stirred for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (34.2 mg). MS (ESI, m / z): [M+H] + =903.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.00(s,1 H)9.45(br.s.,1 H)8.65(s,2 H)8.38(s,2 H)8.15-8.29(m,3 H)7.94(d,J=7.70 Hz,1 H)7.61-7.79(m,2 H)7.45-7.53(m,2 H)7.17(d,J=9.78 Hz,1 H)6.94(d,J=7.46 Hz,2 H)5.63(br.s.,1 H)5.45(s,2 H)4.40(d,J=12.35 Hz,1 H)4.08(br.s.,4 H)3.92(d,J=13.82 Hz,1 H)3.02(d,J=12.23 Hz,1 H)2.79-2.97(m,3 H)2.54-2.71(m,4 H)2.42(s,4 H)2.01-2.18(m,3 H)1.82-2.01(m,3 H)1.77(br.s.,6 H)1.31(br.s.,1 H)1.08-1.27(m,4 H)1.04(d,J=6.11 Hz,1 H)0.94(d,J=5.87 Hz,1 H)

[0155] Example C-5: Preparation of 3-(1-(3-(5-((1-(1-((3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-5-yl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000981) [ka] HATU (36.8 mg, 0.1 mmol) was added to 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (41.6 mg, 0.09 mmol) and 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-5-yl}amino}acetic acid (29.3 mg, 0.86 mmol), followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol) in DMF (5 ml) at room temperature. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-20%) to give the title compound (35.6 mg). MS (ESI, m / z): [M+H] + =805.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.01(s,1 H)9.47(br.s.,1 H)8.61-8.71(m,2 H)8.33-8.43(m,2 H)8.20-8.28(m,2 H)8.18(d,J=9.90 Hz,1 H)7.85-7.99(m,1 H)7.72(t,J=7.89 Hz,1 H)7.67(t,J=8.13 Hz,1 H)7.41-7.54(m,2 H)7.17(d,J=9.78 Hz,1 H)6.95(dd,J=8.13,3.12 Hz,2 H)5.45(s,2 H)3.95-4.15(m,3 H)3.10(t,J=12.23 Hz,1H)2.82-2.98(m,1 H)2.52-2.81(m,3 H)2.42(s,3 H)2.02-2.16(m,1 H)1.11-1.29(m,1 H)

[0156] Example C-6: Preparation of 3-(1-{[3-(5-{[1-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}hexanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000984) Step 1) Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}hexanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydroptalazin-2-yl) and 6-aminohexanoic acid (286 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =387.4

[0157] Step 2) Preparation of 3-(1-{[3-(5-{[1-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}hexanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000984) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]amino}hexanoic acid (24.2 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =847.9. 1H NMR(500 MHz,DMSO-d6)δppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.72(dd,J=11.83,4.65 Hz,1 H)5.45(s,2 H)4.44(d,J=14.04 Hz,1 H)4.06(d,J=6.41 Hz,2 H)3.91(d,J=13.89 Hz,2 H)3.62(dq,J=10.49,6.62 Hz,2 H)3.10-3.19(m,4 H)3.02(t,J=12.44 Hz,2 H)2.86-2.96(m,2 H)2.30-2.37(m,2 H)2.02-2.11(m,2 H)1.80(t,J=15.03 Hz,2 H)1.51-1.67(m,4 H)1.36-1.45(m,2 H)

[0158] Example C-7: Preparation of 3-(1-{[3-(5-{[1-(7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}heptanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000985) Step 1) Preparation of 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)amino)heptanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydropetalazin-2-yl)amine and 7-aminoheptanoic acid (260 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =401.4

[0159] Step 2) Preparation of 3-(1-{[3-(5-{[1-(7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}heptanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000985) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 7-((2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)amino)heptanoic acid (25.2 mg, 0.06 mmol), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (30 mg). MS (ESI, m / z): [M+H] + =861.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.99(s,1 H)8.62-8.69(m,2 H)8.39(s,2 H)8.14-8.30(m,2 H)7.86-7.97(m,2 H)7.73(t,J=7.93 Hz,1 H)7.44-7.54(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.93,2.06 Hz,1 H)6.89(br.s.,1 H)6.73-6.80(m,1 H)5.72(dd,J=12.05,5.04 Hz,1 H)5.45(s,2 H))4.43(d,J=12.66 Hz,1 H)4.07(d,J=6.26 Hz,2 H)3.90(d,J=13.12 Hz,1 H)3.62(dq,J=10.47,6.53 Hz,4 H)3.09-3.20(m,6 H)3.02(t,J=11.60 Hz,2 H)2.85-2.97(m,1 H)2.32(t,J=7.40 Hz,2 H)2.02-2.12(m,1 H)1.88-2.01(m,2 H)1.75-1.87(m,2 H)1.57-1.64(m,2 H)1.31-1.55(m,2 H)

[0160] Example C-8: Preparation of 3-{1-[(3-{5-[(1-{2-[2-(2-{2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl}amino}ethoxy)ethoxy]acetyl}piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile (ICT-0000986) Step 1) Synthesis of 2-(2-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 2-(2-(2-aminoethoxy)ethoxy-acetic acid) (285 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (240 mg). MS (ESI, m / z): [M+H] + =419.4

[0161] Step 2) Preparation of 3-{1-[(3-{5-[(1-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}ethoxy)ethoxy]acetyl}piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile (ICT-0000986) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaradin-6-yl)amino) To the reaction mixture was added (ethoxy)ethoxy)acetic acid (26.2 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (30 mg). MS (ESI, m / z): [M+H] + =879.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.73(d,J=10.88 Hz,1 H)4.86-5.00(m,2 H)4.73(d,J=12.23 Hz,1 H)4.39(d,J=12.59 Hz,2 H)4.21(br.s.,2 H)3.88-3.98(m,4 H)3.56-3.66(m,6 H)3.13(br.s.,2 H)2.84-2.98(m,2 H)2.59(d,J=18.10 Hz,2 H)2.08(d,J=4.28 Hz,2 H)1.91-2.02(m,2 H)1.75(s,2 H)

[0162] Example C-9: Preparation of 3-(1-{[3-(5-{1-(2-{2-{2-[2-(2-{2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl}amino}ethoxy)ethoxy}ethoxy}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000987) Step 1) Preparation of 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}ethoxy)ethoxy]ethoxy}ethoxy}ethoxy}acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetic acid (410 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%). Target compound (250 mg) MS (ESI, m / z): [M+H] + =463.4

[0163] Step 2) Preparation of 3-(1-{[3-(5-{[1-(2-{2-{2-(2-{2-{2-{2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}ethoxy)ethoxy}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000987) = [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)amino)ethoxy)ethoxy)ethoxy}acetic acid (29.2 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =823.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.72(dd,J=11.37,4.89 Hz,1 H)4.85-5.00(m,2 H)4.73(d,J=12.10 Hz,1 H)4.39(d,J=11.62 Hz,3 H)4.15-4.21(m,3 H)3.88-3.97(m,4 H)3.44-3.67(m,8 H)3.10(d,J=12.84 Hz,3 H)2.78-2.98(m,2 H)2.59(d,J=17.97 Hz,2 H)1.88-2.09(m,2 H)1.33-1.41(m,3 H)

[0164] Example C-10: Preparation of 3-(1-{[3-(5-{[1-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}-3,6,9,12-tetradecanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000988) Step 1) Preparation of 14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}-3,6,9,12-tetratetradecanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and 14-amino-3,6,9,12-tetratetradecanoic acid (548 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =507.4

[0165] Step 2) Preparation of 3-(1-{[3-(5-{[1-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}-3,6,9,12-tetratetradecanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000988) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl]amino}hexanoic acid (31.8 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =968.3. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.67-5.77(m,1 H)4.85-5.00(m,2 H)4.73(d,J=12.84 Hz,2 H)4.39(d,J=12.59 Hz,3 H)4.09-4.21(m,3 H)3.86-4.00(m,4 H)3.44-3.66(m,8 H)3.12(dd,J=17.97,12.59 Hz,3 H)2.83-3.00(m,2 H)2.56-2.62(m,2 H)1.88-2.11(m,6 H)1.45(br.s.,2 H)

[0166] Example C-11: Synthesis of 3-(1-(3-(5-((1-(1-(4-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000989) Step 1) Preparation of 4-((2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)amino)butanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1 mmol) and 4-aminobutanoic acid (225 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =373.4.

[0167] Step 2) Preparation of 3-(1-(3-(5-((1-(4-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000989) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 4-((2-(2-(2-(2-(2-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butane The acid (30.8 mg, 0.06 mmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =833.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.72(dd,J=11.83,4.65 Hz,1 H)5.45(s,2 H)4.44(d,J=14.04 Hz,1 H)4.06(d,J=6.41 Hz,2 H)3.91(d,J=13.89 Hz,2 H)3.62(dq,J=10.49,6.62 Hz,2 H)3.10-3.19(m,4 H)3.02(t,J=12.44 Hz,2 H)2.86-2.96(m,2 H)2.30-2.37(m,2 H)2.02-2.11(m,3 H)1.80(t,J=15.03 Hz,2 H)1.51-1.67(m,2 H)1.36-1.45(m,2 H)

[0168] Example C-12: Preparation of 3-(1-(3-(5-((1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)hexanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000990) Synthesis Step 1) Preparation of 6-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)hexanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1 mmol) and 6-aminohexanoic acid (325 mg, 2.18 mmol) in NMP (2.0 ml) at room temperature. The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (280 mg). MS (ESI, m / z): [M+H] + =401.4.

[0169] Step 2) Preparation of 3-(1-(3-(5-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)hexanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0000990) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 6-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptarazin-6-yl)amino)hexanoic acid (38.8 mg, 0.13 mmol) was added to the reaction mixture, followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography with MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =861.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.63-8.68(m,2 H)8.39(s,2 H)8.15-8.28(m,2 H)7.89-7.96(m,2 H)7.73(t,J=7.86 Hz,1 H)7.46-7.53(m,2 H)7.17(d,J=9.61 Hz,1 H)7.08(dd,J=8.85,1.98 Hz,1 H)6.89(t,J=5.11 Hz,1 H)6.72-6.78(m,1 H)5.72(dd,J=11.83,4.65 Hz,1 H)5.45(s,2 H)4.44(d,J=14.04 Hz,1 H)4.06(d,J=6.41 Hz,2 H)3.91(d,J=13.89 Hz,2 H)3.62(dq,J=10.49,6.62 Hz,2 H)3.10-3.19(m,4 H)3.02(t,J=12.44 Hz,2 H)2.86-2.96(m,2 H)2.30-2.37(m,2 H)2.02-2.11(m,2 H)1.95-2.00(s,3H)1.80(t,J=15.03 Hz,2 H)1.51-1.67(m,4 H)1.36-1.45(m,2 H)

[0170] Example C-13: Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001087) Step 1) Preparation of 2-(2-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1 mmol) and 2-(2-(2-aminoethoxy)ethoxy)acetic acid (425 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =433.4.

[0171] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001087) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 2-(2-(2-((2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptalazine The resulting mixture was added to 100 ml of 1,000 sucrose (58.8 mg, 0.06 mmol) of 1,000 sucrose (6-yl)aminoethoxyethoxy)acetic acid, followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =893.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.93(s,1 H)8.60-8.66(m,2 H)8.37(d,J=5.34 Hz,2 H)8.20-8.29(m,3 H)8.17(d,J=9.77 Hz,1 H)7.94(t,J=9.46 Hz,2 H)7.71(t,J=7.86 Hz,1 H)7.45-7.52(m,2 H)7.09-7.18(m,2 H)6.88(t,J=5.42 Hz,1 H)6.72-6.79(m,1 H)5.60-5.69(m,1 H)5.44(s,2 H)4.37(d,J=12.36 Hz,1 H)4.10-4.21(m,2 H)4.04(d,J=6.26 Hz,2 H)3.80(d,J=13.43 Hz,1 H)3.55-3.68(m,8 H)3.35-3.44(m,2 H)3.10-3.19(m,2 H)2.82-3.02(m,2 H)2.52-2.63(m,3 H)2.41(s,3 H)1.98-2.09(m,2 H)1.77(br.s.,2 H)1.25(q,J=7.12 Hz,17 H)

[0172] Example C-14: Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001088) Step 1) Preparation of 2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)acetic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.0 mmol) and 2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid (455 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (290 mg). MS (ESI, m / z): [M+H] + =477.4.

[0173] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001088) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophosphatidyl)amino)ethoxy)propan-1-yl)-2-methyl-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol). To the reaction mixture was added bis(ethoxy)ethoxy)acetic acid (63.8 mg, 0.06 mmol), followed by the addition of ethyl bis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =837.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.58-8.65(m,2 H)8.35-8.39(m,2 H)8.20-8.27(m,2 H)8.15-8.19(m,1 H)7.90-7.96(m,2 H)7.71(t,J=7.86 Hz,1 H)7.45-7.52(m,2 H)7.16(d,J=9.77 Hz,1 H)7.10(dd,J=8.77,2.06 Hz,1 H)6.87(t,J=5.42 Hz,1 H)6.68-6.77(m,1 H)5.65(d,J=7.17 Hz,1 H)5.44(s,2 H)4.36(d,J=12.66 Hz,1 H)4.13-4.19(m,1 H)4.07-4.13(m,1 H)4.04(d,J=6.10 Hz,2 H)3.82(d,J=12.51 Hz,1 H)3.62(t,J=5.49 Hz,3 H)3.51-3.58(m,8 H)3.35-3.41(m,2 H)3.11-3.18(m,1 H)2.83-3.05(m,2 H)2.54-2.62(m,2 H)2.38-2.44(s,3 H)1.93-2.07(m,2 H)1.78(d,J=11.60Hz,2H)

[0174] Example C-15: Preparation of 3-(1-(3-(5-((1-(1-(1-(14-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)amino)-3,6,9,12-tetradecanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001089) Step 1) Preparation of 14-((2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)-3,6,9,12-tetratetradecanoic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1 mmol) and 14-amino-3,6,9,12-tetratetradecanoic acid (485 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (290 mg). MS (ESI, m / z): [M+H] + =521.4.

[0175] Step 2) Preparation of 3-(1-(3-(5-((1-(14-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)3,6,9,12-tetratetradecanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001089) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 14-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroproptalazin-6-yl)amino)3,6,9,12-tetrahydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol). To the resulting solution was added oxadenoic acid (68.8 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =837.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.58-8.65(m,2 H)8.35-8.39(m,2 H)8.20-8.27(m,2 H)8.15-8.19(m,1 H)7.90-7.96(m,2 H)7.71(t,J=7.86 Hz,1 H)7.45-7.52(m,2 H)7.16(d,J=9.77 Hz,1 H)7.10(dd,J=8.77,2.06 Hz,1 H)6.87(t,J=5.42 Hz,1 H)6.68-6.77(m,1 H)5.65(d,J=7.17 Hz,1 H)5.44(s,2 H)4.36(d,J=12.66 Hz,1 H)4.13-4.19(m,1 H)4.07-4.13(m,1 H)4.04(d,J=6.10 Hz,2 H)3.82(d,J=12.51 Hz,1 H)3.62(t,J=5.49 Hz,3 H)3.51-3.58(m,8 H)3.35-3.41(m,2 H)3.11-3.18(m,1 H)2.83-3.05(m,2 H)2.54-2.62(m,6 H)2.38-2.44(s,3 H)1.93-2.07(m,2 H)1.78(d,J=11.60Hz,2H)

[0176] Example C-16: Preparation of 3-(1-(3-(5-((1-(1-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001091) Step 1) Preparation of 1-((2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)amino)3,6,9,12-tetraoxapentadecan-15-oic acid [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.0 mmol) and 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid (515 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (300 mg). MS (ESI, m / z): [M+H] + =535.4.

[0177] Step 2) Preparation of 3-(1-(3-(5-((1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001091) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 1-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)amino)-3,6,9,12-tetraoxapenta[3-(2-methyl-4-oxo-1,2-dihydrobutalazin-6-yl)] ... Decane-15-oxane (71.8 mg, 0.06 mmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H]+ = 996.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.61-8.68(m,2 H)8.38(br.s.,2 H)8.23(t,J=8.39 Hz,2 H)8.17(d,J=9.77 Hz,1 H)7.89-7.97(m,2 H)7.71(t,J=7.86 Hz,1 H)7.42-7.53(m,2 H)7.16(d,J=9.77 Hz,1 H)7.07-7.14(m,1 H)6.87(t,J=5.42 Hz,1 H)6.70-6.79(m,1 H)5.65(d,J=6.71 Hz,1 H)5.44(s,2 H)4.36(d,J=12.51 Hz,1 H)4.13-4.19(m,1 H)4.07-4.13(m,1 H)3.98-4.07(m,2 H)3.77-3.89(m,1 H)3.58-3.65(m,2 H)3.45-3.58(m,12 H)3.35-3.41(m,2 H)2.84-3.04(m,2 H)2.52-2.66(m,3 H)2.39-2.44(m,3 H)2.00-2.07(m,2 H)1.96(d,J=17.40 Hz,1 H)1.78(d,J=11.60 Hz,2 H)

[0178] Example C-17: Preparation of 3-(1-(3-(5-((1-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001096) synthesis Step 1) Preparation of benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate [ka] K2CO3 (1.41 g, 10.2 mmol) was added to a solution of tert-butyl 4-(((methylsulfonyl)oxymethyl]piperidine-1-carboxylate (3 g, 10.2 mmol) and benzyl piperazine-1-carboxylate (4.5 g, 20.5 mmol) in 30 ml of DMF and stirred at 85 °C for 16 h. After cooling, the reaction (50 ml) was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to give benzyl 4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.95 g). MS (ESI, m / z): [M+H] + =418.2.

[0179] Step 2) Preparation of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate [ka] Pd / C (10 wt%, 50 mg) was added to a solution of benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (0.5 g, 1.2 mmol) in 10 ml of MeOH and stirred at room temperature under a hydrogen atmosphere for 4 hours. The solution was filtered through a Celite 545 pad. The solvent was removed under reduced pressure to give tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.35 g). MS (ESI, m / z): [M+H] + =284.0.

[0180] Step 3) Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate [ka] A solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (1 g, 3.46 mmol), tert-butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (1.96 g, 6.91 mmol), and DIPEA (1.81 mL, 10.4 mmol) in NMP (10 mL) was stirred at 120° C. for 20 hours. The reaction mixture was purified by reverse-phase column chromatography to give tert-butyl 4-((4-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptalazine-6-yl)piperazin-1-yl)methylperidin-1-carboxylate (910 mg). MS (ESI, m / z): [M+H] + =552.3.

[0181] Step 4) Preparation of 3-(4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] 2 ml of TFA was added to a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (910 mg, 1.65 mmol) in 10 ml of DCM and stirred at room temperature for 2 hours. MS (ESI, m / z): [M+H] + =453.0.

[0182] Step 5) Preparation of 3-(1-(3-(5-((1-(4-((4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl-piperidine-1-carbonyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001096) [ka] HATU (47.7 mg, 0.13 mmol) was added to 2-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (30 mg, 0.06 mmol) and 3-(4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (24 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =972.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.60-8.70(m,2 H)8.39(s,1 H)8.37(s,1 H)8.20-8.26(m,2 H)8.17(d,J=9.77 Hz,1 H)8.06(d,J=9.00 Hz,1 H)7.92(d,J=7.63 Hz,1 H)7.71(t,J=7.86 Hz,1 H)7.46-7.53(m,3 H)7.16(d,J=9.77 Hz,1 H)7.07(s,1 H)5.68(dd,J=11.75,4.73 Hz,1 H)5.44(s,2 H)4.34(d,J=12.21 Hz,1 H)4.00-4.08(m,3 H)3.43(br.s.,5 H)2.80-3.03(m,3 H)2.53-2.67(m,4 H)2.43-2.49(m,4 H)2.19(d,J=6.56 Hz,2 H)1.91-2.13(m,4 H)1.77(br.s.,7 H)1.36-1.45(m,1 H)1.32(d,J=10.68 Hz,2 H)1.23(s,1 H)1.08(d,J=11.44 Hz,1 H)0.92(d,J=10.83 Hz,1 H)

[0183] Example C-18: Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001115) Synthesis Step 1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] A solution of 3-(7-fluoro-4-methyl-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione (1 g, 3.46 mmol), tert-butyl piperazine-1-carboxylate (1.26 g, 6.91 mmol), and DIPEA (1.81 mL, 10.4 mmol) in NMP (10 mL) was stirred at 120° C. for 20 hours. The reaction mixture was purified by reverse-phase column chromatography to give tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methylpiperidine-1-carboxylate (910 mg). MS (ESI, m / z): [M+H] + =456.3.

[0184] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] 2 ml of TFA was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl) in 10 ml of DCM and stirred at room temperature for 2 hours. MS (ESI, m / z): [M+H] + =356.3.

[0185] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001115) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 2-(((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (30 mg, 0.06 mmol) and 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2,6-dione ( To the reaction mixture was added 20 mg of ethyl bis(propan-2-yl)amine (0.06 mmol), followed by the addition of ethyl bis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography with MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =874.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.93(s,1 H)8.53-8.61(m,2 H)8.26-8.35(m,2 H)8.13-8.20(m,2 H)8.08-8.13(m,1 H)7.86(d,J=7.70 Hz,1 H)7.74(d,J=8.93 Hz,1 H)7.64(t,J=7.89 Hz,1 H)7.55(dd,J=8.99,2.51 Hz,1 H)7.48(d,J=2.45 Hz,1 H)7.35-7.45(m,2 H)7.05-7.13(m,1 H)5.60-5.72(m,2 H)5.37(s,2 H)3.97(d,J=5.87 Hz,2 H)3.70(br.s.,1 H)3.57(br.s.,1 H)3.40(br.s.,2 H)3.07-3.19(m,2 H)2.78-2.89(m,2 H)2.46-2.58(m,2 H)2.36-2.42(m,3 H)1.92-2.05(m,2 H)1.71(d,J=9.29 Hz,2 H)1.19-1.32(m,2 H)1.06(d,J=6.60 Hz,1 H)

[0186] Example C-19: Preparation of 3-(1-(4-(5-((1-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001173) Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and tert-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =456.4

[0187] Step 2) Preparation of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10.0 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl) in DCM (30.0 ml). TFA (10.0 ml) was added to a solution of piperazine-1-carboxylate (300 mg, 0.71 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4

[0188] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 2-bromoacetate (131 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =470.4

[0189] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] TFA (1.0 ml) was added to tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)acetate (30 mg, 0.06 mmol) in DCM (3.0 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (15 mg). MS (ESI, m / z): [M+H] + =414.4

[0190] Step 5) Preparation of 3-(1-(4-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001173) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-3-yl)benzonitrile in DMF (2.0 ml). To the resulting solution was added 20.6 mg (0.06 mmol) of ethyl bis(propan-1-yl)acetic acid, followed by the addition of ethyl bis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H]+ = 874.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.54-8.62(m,2 H)8.31(s,2 H)8.13-8.20(m,2 H)8.10(d,J=9.77 Hz,1 H)8.00(d,J=8.85 Hz,1 H)7.86(d,J=7.63 Hz,1 H)7.64(t,J=7.86 Hz,1 H)7.37-7.49(m,3 H)7.09(d,J=9.77 Hz,1 H)7.02(br.s.,1 H)5.61(d,J=6.56 Hz,1 H)5.37(s,2 H)4.35(d,J=12.36 Hz,1 H)3.60-4.24(m,1 H)4.01(d,J=6.10 Hz,2 H)(3.42-3.52(m,2 H)3.39(br.s.,2 H)3.33-3.37(m,1 H)3.12(s,1 H)2.94-3.04(m,1 H)2.79-2.90(m,1 H)2.45-2.64(m,8 H)2.38-2.44(s,3 H)1.94-2.04(m,1 H)1.81-1.94(m,2 H)1.76(br.s.,2 H)

[0191] Example C-20: Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001174) Step 1) Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropanoate (140 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =484.4

[0192] Step 2) Preparation of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoic acid [ka] TFA (1.0 ml) was added to tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =428.4

[0193] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoyl-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001174) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 3-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-3-yl)benzonitrile) in DMF (2.0 ml). To the resulting solution was added 20.6 mg (0.06 mmol) of bis(propan-1-yl)propanoic acid, followed by 3 equivalents of ethyl bis(propan-2-yl)amine. The reaction was stirred at room temperature for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H]+ = 889.1. 1H NMR(500 MHz,DMSO-d6)δ 10.98(s,1 H)8.61-8.68(m,2 H)8.38(s,2 H)8.24(t,J=8.24 Hz,2 H)8.18(d,J=9.77 Hz,1 H)8.07(d,J=9.00 Hz,1 H)7.90-7.97(m,1 H)7.72(t,J=7.86 Hz,1 H)7.44-7.54(m,3 H)7.17(d,J=9.77 Hz,1 H)7.09(s,1 H)5.68(d,J=6.71 Hz,1 H)5.45(s,2 H)4.44(d,J=13.73 Hz,1 H)4.08(d,J=6.10 Hz,2 H)3.98(d,J=13.28 Hz,1 H)3.37-3.48(m,4 H)3.06(t,J=12.74 Hz,1 H)2.85-2.96(m,2 H)2.52-2.67(m,12 H)2.38-2.44(s,3 H)2.03-2.13(m,1 H)1.90-2.00(m,1 H)1.84(d,J=12.36 Hz,1 H)1.78(br.s.,1 H)

[0194] Example C-21: Preparation of 3-(1-(3-(5-((1-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001175) Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 4-bromobutanoate (145 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (210 mg). MS (ESI, m / z): [M+H] + =498.4

[0195] Step 2) Preparation of 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoic acid [ka] TFA (1.0 ml) was added to tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (25 mg). MS (ESI, m / z): [M+H] + =442.4

[0196] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001175) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 4-(4-(2-(2-(2-(2-(2-(2-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoic acid ( A solution of 22.6 mg (0.06 mmol) of methyl bis(propan-2-yl)amine (2.0 ml) was added to DMF (2.0 ml), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H]+ = 903.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.54-8.60(m,2 H)8.31(br.s.,2 H)8.13-8.20(m,2 H)8.11(d,J=9.77 Hz,1 H)7.99(d,J=9.00 Hz,1 H)7.86(d,J=7.48 Hz,1 H)7.65(t,J=7.86 Hz,1 H)7.37-7.47(m,3 H)7.10(d,J=9.77 Hz,1 H)7.01(br.s.,1 H)5.61(d,J=6.87 Hz,1 H)5.38(s,2 H)4.38(d,J=12.51 Hz,1 H)4.00(d,J=6.10 Hz,2 H)3.87(d,J=12.36 Hz,1 H)3.37(br.s.,3 H)2.97(t,J=11.98 Hz,1 H)2.76-2.89(m,1 H)2.46-2.59(m,6 H)2.41(s,4 H)2.30(t,J=6.79 Hz,3 H)1.94-2.04(m,3 H)1.83-1.94(m,3 H)1.61-1.79(m,4 H)

[0197] Example C-22: Preparation of 3-(1-(3-(5-((1-(5-(5-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001176) Step 1) Preparation of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)pentanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 5-bromopentanoate (145 mg, 0.62 mmol) in ACN (10.0 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =512.4

[0198] Step 2) Preparation of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)pentanoic acid [ka] TFA (1.0 ml) was added to tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)pentanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (28 mg). MS (ESI, m / z): [M+H] + =456.4

[0199] Step 3) Preparation of 3-(1-(3-(5-((1-(5-(1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001176) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 5-(4-(4-(2-(2-(2-(2-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-3-yl)benzonitrile) in solution. To the resulting solution was added 23 mg (0.06 mmol) of bis(propan-1-yl)pentanoic acid, followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (35 mg). MS (ESI, m / z): [M+H] + =917.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.53-8.61(m,2 H)8.31(br.s.,2 H)8.17(t,J=8.93 Hz,2 H)8.11(d,J=9.77 Hz,1 H)8.02(d,J=8.70 Hz,1 H)7.86(d,J=7.78 Hz,1 H)7.65(t,J=7.86 Hz,1 H)7.37-7.50(m,3 H)7.01-7.11(m,2 H)5.62(d,J=7.32 Hz,1 H)5.37(s,2 H)4.37(d,J=12.82 Hz,1 H)4.00(d,J=6.26 Hz,2 H)3.86(d,J=12.97 Hz,1 H)3.49-3.58(m,1 H)3.44(br.s.,1 H)3.31-3.39(m,2 H)3.06(dd,J=7.25,4.20 Hz,1 H)2.97(t,J=12.21 Hz,1 H)2.77-2.90(m,1 H)2.46-2.58(m,6 H)2.42(br.s.,5 H)2.30(br.s.,2 H)1.95-2.05(m,2 H)1.67-1.80(m,2 H)1.48(br.s.,2 H)1.11-1.26(m,4 H)

[0200] Example C-23: Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}-2-oxoethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001177) Step 1) Preparation of tert-butyl 2-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 2-bromoacetate (82.0 mg, 0.42 mmol) in ACN (5 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Target compound (210 mg) MS (ESI, m / z): [M+H] + =593.7

[0201] Step 2) Preparation of 2-[4-({[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid [ka] TFA (3 ml) was added to tert-butyl 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetate (200 mg, 0.38 mmol) in DCM (9 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (130 mg). MS (ESI, m / z): [M+H] + =537.6

[0202] Step 3) Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl]piperazin-1-yl}-2-oxoethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001177) [ka] HATU (42.5 mg, 0.12 mmol) was added to 2-[4-({[2-(3-{3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (30 mg, 0.056 mmol) and 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (19.9 mg, 0.05 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =874.9. 1H NMR(500 MHz,DMSO-d6)δppm 10.91(s,1 H)8.57(s,2 H)8.31(s,2 H)8.13-8.20(m,2 H)8.11(d,J=9.77 Hz,1 H)8.02(d,J=9.00 Hz,1 H)7.86(d,J=7.63 Hz,1 H)7.65(t,J=7.86 Hz,1 H)7.36-7.48(m,3 H)7.09(d,J=9.77 Hz,1 H)7.05(d,J=1.98 Hz,1 H)5.62(d,J=7.17 Hz,1 H)5.37(s,2 H)3.98(d,J=5.80 Hz,2 H)3.70(br.s.,2 H)3.57(br.s.,2 H)3.46(br.s.,2 H)3.39(br.s.,2 H)2.77-2.89(m,3 H)2.48-2.56(m,2 H)1.94-2.04(m,4 H)1.71(d,J=9.77 Hz,4 H)1.26(d,J=10.68 Hz,2 H)1.16(s,3 H)

[0203] Example C-24: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)methyl-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001195) Step 1) Preparation 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(propan-2-yl)amine (1.34 g, 10.4 mmol) was added to 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 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%). The protected compound was obtained and treated with (5 mL) 50% TFA in DCM and stirred for 5 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 a chromatrex pad containing NH-DM 1020 (550 mg) to give the title compound. MS (ESI, m / z): [M+H] + =453.6.

[0204] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3-yl)piperazin-1-yl)methyl-1-yl)methyl)piperidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001195) [ka] KCO (68.1 mg, 0.5 mmol) was added to 5-chloro-N-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-oxy)phenyl]-N-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine (47.2 mg, 0.1 mmol) and 3-{7-[4-(2-chloroacetyl)piperazin-1-yl]-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl}piperidine-2,6-dione (42.6 mg, 0.1 mmol) in DMF (5 ml). The reaction was stirred at room temperature for 4 hours. The reaction was poured into water. The ethyl acetate organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (38.2 mg). MS (ESI, m / z): [M+H] + =[972.2], 1H NMR(500 MHz,DMSO-d6)δ ppm 11.02(s,1 H)8.67(s,1 H)8.50(s,2 H)8.38(s,1 H)8.11-8.29(m,2 H)7.83-7.99(m,1 H)7.73(t,J=7.95 Hz,1 H)7.46-7.56(m,1 H)7.38-7.45(m,4 H)7.31(d,J=8.07 Hz,1 H)7.17(d,J=9.66 Hz,1 H)5.71(br.s.,1 H)5.45(s,1 H)4.37(d,J=13.20 Hz,1 H)4.19-4.29(m,1 H)4.05-4.19(m,2 H)3.71(d,J=12.96 Hz,2 H)3.44(br.s.,1 H)2.86-3.13(m,3 H)2.78(br.s.,2 H)2.56-2.72(m,1 H)2.53(s,1 H)2.43(d,J=6.85 Hz,1 H)2.06-2.12(m,1 H)1.96(d,J=10.27 Hz,2 H)1.84(d,J=11.25 Hz,1 H)1.67(d,J=11.49 Hz,1 H)

[0205] Example C-25: Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001199) Step 1) Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equivalents) was added to a solution of 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropanoate (153 mg, 0.73 mmol) in CAN (10 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =484.4

[0206] Step 2) Preparation of 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoic acid [ka] TFA (5 ml) was added to a solution of tert-butyl tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate (150 mg, 0.32 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =414.4

[0207] Step 3) Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptarazin-6-yl]piperazine-1-dei}propanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001199) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.063 mmol) and 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}piperazin-1-yl}propanoic acid (26.0 mg, 0.13 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (43 mg). MS (ESI, m / z): [M+H] + =875.1. 1H NMR(500 MHz,DMSO-d6)δppm 11.01(s,1 H)8.66(s,2 H)8.39(s,2 H)8.21-8.29(m,3 H)8.18(d,J=9.92 Hz,1 H)8.05(d,J=8.39 Hz,1 H)7.94(d,J=7.93 Hz,1 H)7.73(t,J=7.86 Hz,1 H)7.44-7.56(m,3 H)7.28(br.s.,1 H)7.17(d,J=9.77 Hz,1 H)5.72-5.79(m,1 H)5.45(s,2 H)4.44(d,J=12.97 Hz,1 H)4.08(d,J=6.10 Hz,2 H)3.97(d,J=12.97 Hz,1 H)3.62(dq,J=10.49,6.52 Hz,8 H)3.07-3.19(m,8 H)2.83-2.97(m,2 H)2.04-2.11(m,3 H)1.84(d,J=12.82 Hz,1 H)1.78(br.s.,1 H)

[0208] Example C-26: Preparation of 3-(1-{[3-(5-{1-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazine-1-dei}butanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001200) Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 4-bromobutanoate (188 mg, 0.84 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =484.6

[0209] Step 2) Preparation of 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-di)butanoic acid [ka] TFA (5 ml) was added to a solution of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate (200 mg, 0.41 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =428.4

[0210] Step 3) Preparation of 3-(1-{[3-(5-{[1-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazine-1-dei}butanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001200) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}piperazin-1-yl}butanoic acid (26.8 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (40 mg). MS (ESI, m / z): [M+H] + =889.1. 1H NMR(500 MHz,DMSO-d6)δppm 10.94(s,1 H)8.55-8.61(m,2 H)8.31(s,2 H)8.13-8.21(m,3 H)8.11(d,J=9.92 Hz,1 H)7.98(d,J=7.93 Hz,1 H)7.86(d,J=7.63 Hz,1 H)7.65(t,J=7.93 Hz,1 H)7.40-7.46(m,3 H)7.21(br.s.,1 H)7.10(d,J=9.77 Hz,1 H)5.63-5.73(m,1 H)5.38(s,2 H)4.37(d,J=12.05 Hz,1 H)4.00(d,J=6.26 Hz,2 H)3.86(d,J=13.89 Hz,1 H)3.54(dd,J=10.45,6.33 Hz,3 H)3.03-3.12(m,3 H)2.97(t,J=12.59 Hz,1 H)2.79-2.90(m,1 H)2.47-2.58(m,4 H)2.29(br.s.,3 H)1.95-2.04(m,4 H)1.68-1.81(m,2 H)1.47(br.s.,4 H)

[0211] Example C-27: Preparation of 3-(1-{[3-(5-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl]piperazin-1-yl}pentanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001201) Step 1) Preparation of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-pentanoate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 5-bromopentanoate (200 mg, 0.84 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =512.6

[0212] Step 2) 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (5 ml) was added to a solution of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl) in DCM (15 ml). TFA (5 ml) was added to a solution of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =442.5

[0213] Step 3) Preparation of 3-(1-{[3-(5-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazine-1-dei}pentanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001201) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (30 mg, 0.06 mmol) and 5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}pentanoic acid (27.7 mg, 0.13 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (42 mg). MS (ESI, m / z): [M+H] + =903.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.01(s,1 H)8.59-8.73(m,2 H)8.38(s,2 H)8.21-8.30(m,3 H)8.18(d,J=9.77 Hz,1 H)8.06(d,J=8.24 Hz,1 H)7.94(d,J=7.63 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.45-7.56(m,3 H)7.29(br.s.,1 H)7.17(d,J=9.77 Hz,1 H)5.76(dd,J=12.21,4.88 Hz,1 H)5.45(s,2 H)4.45(d,J=12.82 Hz,1 H)4.08(d,J=6.26 Hz,2 H)3.93(d,J=12.21 Hz,1 H)3.62(dq,J=10.57,6.55 Hz,4 H)3.09-3.19(m,4 H)3.05(t,J=11.75 Hz,1 H)2.87-2.97(m,1 H)2.54-2.65(m,4 H)2.38(d,J=12.05 Hz,3 H)2.03-2.13(m,3 H)1.84(d,J=12.21 Hz,2 H)1.78(br.s.,2 H)1.26-1.32(m,3 H)

[0214] Example C-28: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001204) Step 1) 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione and Preparation of 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-(piperazin-1-yl)piperidine-1-carboxylate (92 mg, 325 μmol) was added to a solution of 3-(6,7-difluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 325 μmol) in DMA (1 mL) at ambient temperature, followed by the addition of ethyl bis(propan-2-yl)amine (46.3 mg, 358 μmol). The reaction was heated at 120 °C for 16 h. After completion of the reaction, the reaction mixture 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 over magnesium sulfate, and was purified by MPLC (1–5% MeOH in CHCl). The Boc-protected compound was treated with 50% TFA in DCM (5 mL) and stirred for 5 h. 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 a Chromatorex pad with NH-DM1020 to obtain a mixture of regioisomers. This mixture was purified on a C-18 column with 0-80% acetonitrile in HO to give 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

[0215] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)piperidine-1-dei)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001204) [ka] HATU (36.8 mg, 0.09 mmol) was added to 2-[4-({[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (46.6 mg, 0.09 mmol) and 3-(7-fluoro-4-methyl-1-oxo-6-(4-piperidin-4-ylmethyl)piperazin-1-yl)piperazine-2,6-dione (40.8 mg, 0.09 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 magnesium sulfate, and 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] + =990.2. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95-11.03(m,1 H)8.63-8.71(m,2 H)8.38(d,J=5.65 Hz,2 H)8.20-8.27(m,2 H)8.11-8.20(m,1 H)7.93(d,J=7.78 Hz,1 H)7.86(d,J=12.97 Hz,1 H)7.72(t,J=7.93 Hz,1 H)7.45-7.54(m,2 H)7.29(d,J=8.09 Hz,1 H)7.16(d,J=9.77 Hz,1 H)5.68-5.77(m,1 H)5.45(s,2 H)4.36(d,J=11.44 Hz,1 H)4.09(d,J=5.34 Hz,2 H)3.28(br.s.,4 H)2.97-3.05(m,1 H)2.86-2.97(m,1 H)2.60-2.66(m,1 H)2.54-2.60(m,5 H)2.40-2.48(m,1 H)2.23(br.s.,1 H)2.03-2.12(m,1 H)1.87(br.s.,3 H)1.66-1.84(m,3 H)1.53(br.s.,1 H)1.39(s,2 H)1.11(d,J=11.44 Hz,1 H)0.96(d,J=8.54 Hz,1 H)

[0216] Example C-29: Preparation of 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)pent-4-phospho-1-yl)acetamide (ICT-0001205) Step 1) Preparation of 3-(6-(5-aminopent-1-rin-1-yl)-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione [ka] CuI (113 mg, 0.6 mmol) and Pd(PPh3)2Cl2 (418 mg, 0.6 mmol) were added to a solution of 3-(6-bromo-1-oxo-1,2-dihydrohoptalazin-2-ylfolapazin-2yl) and t-butyl pent-4-lin-1-ylcarbamate (1.2 g, 6.54 mmol) in DMF (5 mL), followed by the addition of TEA (1.81 g, 17.8 mmol). The mixture was irradiated in a microwave reactor at 80 °C for 1.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography, treated with 50% TFA in DCM (5 mL), and stirred for 5 h. After the deprotection reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM (5 mL) and passed through a Chromatrex pad containing NH-DM 1020 to give the title compound as an off-white oil (1.59 g). MS (ESI, m / z): [M+H] + =339.1.

[0217] Step 2) Preparation of 2-(4-(((2-(3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)-N-(5-(2-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptaladin-6-yl)pent-4-rin-1-yl)acetamide (ICT-0001205) [ka] HATU (36.3 mg, 0.09 mmol) was added to 2-[4-({[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (46.6 mg, 0.09 mmol) and 3-(6-(5-aminopent-1-rin-1-yl)-1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione (29.4 mg, 0.09 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-20%) to give the title compound (45 mg). MS (ESI, m / z): [M+H] + =857.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.05(s,1 H)8.60-8.74(m,2 H)8.44(s,1 H)8.35-8.42(m,2 H)8.11-8.29(m,4 H)8.01(s,1 H)7.90-7.98(m,1 H)7.84(dd,J=8.32,1.30 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.43-7.54(m,2 H)7.16(d,J=9.77 Hz,1 H)5.80(dd,J=12.13,5.26 Hz,1 H)5.45(s,2 H)4.07(d,J=5.49 Hz,1 H)3.29(br.s.,1 H)2.87-2.98(m,2 H)2.58-2.66(m,1 H)2.52-2.57(m,2 H)2.08-2.17(m,1 H)1.85(br.s.,2 H)1.77(quin,J=6.98 Hz,2 H)1.39(s,1 H)

[0218] Example C-30: Preparation of 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)pentyl)acetamide (ICT-0001206) Step 1) Preparation of 3-(6-(5-aminopentyl)-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] 10% Pd / C (10 mg) was added to a solution of 3-(6-(5-aminopent-1-lin-1-yl)-1-oxothalasin-2(1H)-yl)piperidine-2,6-dione (0.1 g, 0.3 mmol) in MeOH (5 mL) at ambient temperature. The reaction was run by attaching a H2 balloon. After stirring the reaction at room temperature for 5 hours, the reaction was filtered and dried under vacuum to give the target compound (85 mg). MS (ESI, m / z): [M+H] + =343.4.

[0219] Step 2) Preparation of 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(5-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptalazin-6-yl)pentyl)acetamide (ICT-0001206) [ka] HATU (36.3 mg, 0.09 mmol) was dissolved in 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (46.6 mg, 0.09 mmol) and 3-(6-(5-aminopentyl)-1-oxoptalazin-2(1H)-yl)piperidine-2 To the 1,6-dione (28.7 mg, 0.09 mmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (38 mg). MS (ESI, m / z): [M+H] + =861.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.05(s,1 H)8.59-8.72(m,2 H)8.33-8.46(m,3 H)8.12-8.28(m,4 H)7.87-8.00(m,1 H)7.68-7.82(m,3 H)7.43-7.57(m,2 H)7.17(d,J=9.77 Hz,1 H)5.81(dd,J=11.98,5.26 Hz,1 H)5.45(s,2 H)4.07(d,J=4.58 Hz,1 H)3.12(d,J=6.10 Hz,1 H)2.85-2.99(m,1 H)2.80(t,J=7.48 Hz,2 H)2.53-2.67(m,2 H)2.05-2.16(m,1 H)1.68(quin,J=7.48 Hz,2 H)1.48(quin,J=7.13 Hz,2 H)1.39(s,1 H)1.31(d,J=6.56 Hz,2 H)

[0220] Example C-31: Preparation of 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2dihydroptaladin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-0001207) Step 1) Preparation of 3-(6-(4-(4-aminophenyl)piperazin-1-yl)-4-methyl-1-oxoptalazin-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 magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%). Title compound (621 mg). MS (ESI, m / z): [M+H] + =447.6.

[0221] Step 2) 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-0001207) [ka] HATU (39 mg, 0.10 mmol) was added to a solution of 2-[4-({[2-(3-{3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (50 mg, 0.09 mmol) and 3-{6-[4-(4-aminophenyl)piperazin-1-yl]-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl}piperidine-2,6-dione (41.6 mg, 0.09 mmol) in DMF (2 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (21.4 mg, 0.18 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (52 mg). MS (ESI, m / z): [M+H] + =966.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.62-8.67(m,2 H)8.33-8.41(m,2 H)8.21-8.29(m,2 H)8.06-8.21(m,2 H)7.93(d,J=7.78 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.57(d,J=8.39 Hz,1 H)7.45-7.53(m,4 H)7.12-7.20(m,2 H)7.00(d,J=8.54 Hz,2 H)5.69(d,J=7.48 Hz,1 H)5.45(s,2 H)4.01-4.15(m,1 H)3.61(br.s.,3 H)3.28(br.s.,4 H)2.82-3.01(m,1 H)2.52-2.66(m,2 H)1.30-1.43(m,1 H)1.14-1.28(m,1 H)

[0222] Example C-32: Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(2-(2-(1-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001213) Step 1) Preparation of 3-(1-(3-(5-((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1, chloroacetyl chloride (0.784 mmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (0.522 mmol) and DIPEA (1.04 mmol) in DCM (3 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated. The reaction mixture was purified by reverse-phase column chromatography (water (0.1% FA) / ACN (0.1% FA) = 95 / 1 to 0 / 100 gradient). The corresponding fractions were lyophilized to give 143 mg of 3-(1-(3-(5-((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =555.2

[0223] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(4-((1-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001213) [ka] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1 in 0.6 ml of DMSO DIPEA (98 μmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (20 mg, 0.02 mmol) and 3-(4-(4-methyl-1-yl)piperidine-1-(4-(piperazin-1-yl)piperidine-2,6-dione(1H)-yl)piperidine-2,6-dione (15 mg, 0.02 mmol) and stirred at 80° C. for 16 h. The reaction mixture was purified by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The product was purified by column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient), 4 mg of 3-(1-(1-(5-((1-(2-(2-(4-(1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(dioxopiperin-3-yl)4-methyl-1-oxo-1-2-(dihydroptarazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was purified on amino silica. MS (ESI, m / z): [M+H] + =971.8. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1H),8.65(s,2H),8.39(s,1H),8.37(s,1H),8.24(d,J=8.1 Hz,1H),8.23(s,1H),8.17(d,J=8.1 Hz,1H),8.03(m,1H)7.93(d,J=7.8 Hz,1H),7.71(t,J=7.9 Hz,1H),7.49(s,1H),7.46(m,2H),7.16(d,J=9.8 Hz,1H),7.02(s,1H),5.68(m,1H),5.44(s,2H),4.38(d,J=12.5 Hz,1H),4.08(s,2H),4.02(d,J=12.5 Hz,2H),3.28(m,4H),2.98(m,2H),2.90(m,3H),2.59(m,2H),2.47(s,3H),2.3 8(brd,6H),2.10(brd,2H),1.77(m,3H),1.3(m,1H),1.23(m,2H),1.10(m,6H)

[0224] Example C-33: Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001214) Step 1) Preparation of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl)piperazin-1-yl)acetate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 2-bromoacetate (143 mg, 0.73 mmol) in ACN (10 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (150 mg). MS (ESI, m / z): [M+H] + =470.4

[0225] Step 2) Preparation of 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)acetic acid [ka] TFA (5 ml) was added to tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)acetate (150 mg, 0.32 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =414.4

[0226] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001214) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)acetic acid. The acid (26.0 mg, 0.06 mmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (33 mg). MS (ESI, m / z): [M+H]+ = 875.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.65(s,2 H)8.38(br.s.,2 H)8.20-8.28(m,2 H)8.17(d,J=9.77 Hz,1 H)7.93(d,J=7.63 Hz,1 H)7.78(d,J=8.85 Hz,1 H)7.71(t,J=7.86 Hz,1 H)7.59(d,J=8.54 Hz,1 H)7.54(br.s.,1 H)7.45-7.50(m,2 H)7.16(d,J=9.77 Hz,1 H)5.70(br.s.,1 H)5.44(s,2 H)4.41(d,J=12.82 Hz,1 H)4.08(d,J=6.26 Hz,3 H)3.62(dd,J=10.38,6.56 Hz,1 H)3.41(br.s.,4 H)3.09-3.19(m,2 H)3.05(t,J=12.05 Hz,1 H)2.86-2.96(m,1 H)2.54-2.66(m,6 H)2.45(s,3 H)2.07(dd,J=8.85,4.88 Hz,2 H)1.95-2.05(m,2 H)1.81(br.s.,2 H)

[0227] Example C-34: Preparation of 3-(1-(3-(5-((1-(1-(3-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001215) Step 1) Preparation of tert-butyl 3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropanoate (143 mg, 0.73 mmol) in ACN (10 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (160 mg). MS (ESI, m / z): [M+H] + =484.4

[0228] Step 2) Preparation of 3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)propanoic acid [ka] TFA (5 ml) was added to a solution of tert-butyl 3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)propanoate (160 mg, 0.32 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =428.4

[0229] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(3-(4-(3-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)propynoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001215) [ka] HATU (47.7 mg, 0.13 mmol) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 3-(4-(4-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)propanoic acid (28.0 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (33 mg). MS (ESI, m / z): [M+H]+ = 875.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.65(s,2 H)8.38(br.s.,2 H)8.20-8.28(m,2 H)8.17(d,J=9.77 Hz,1 H)7.93(d,J=7.63 Hz,1 H)7.78(d,J=8.85 Hz,1 H)7.71(t,J=7.86 Hz,1 H)7.59(d,J=8.54 Hz,1 H)7.54(br.s.,1 H)7.45-7.50(m,2 H)7.16(d,J=9.77 Hz,1 H)5.70(br.s.,1 H)5.44(s,2 H)4.41(d,J=12.82 Hz,1 H)4.08(d,J=6.26 Hz,3 H)3.62(dd,J=10.38,6.56 Hz,1 H)3.41(br.s.,4 H)3.09-3.19(m,2 H)3.05(t,J=12.05 Hz,1 H)2.86-2.96(m,1 H)2.54-2.66(m,10 H)2.45(s,3 H)2.07(dd,J=8.85,4.88 Hz,2 H)1.95-2.05(m,2 H)1.81(br.s.,2 H)

[0230] Example C-35: Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001216) Step 1) Preparation of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 4-bromobutanoate (153 mg, 0.73 mmol) in ACN (10 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (165 mg). MS (ESI, m / z): [M+H] + =498.4

[0231] Step 2) Preparation of 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoic acid [ka] TFA (5 ml) was added to tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoate (165 mg, 0.32 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =442.4

[0232] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001216) [ka] HATU (47.7 mg, 0.13 mmol) was dissolved in 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazine-1) in DMF (2.0 ml). To the resulting solution was added 20.0 mg of ethyl bis(propan-2-yl)butanoic acid (30.0 mg, 0.06 mmol), followed by the addition of ethyl bis(propan-2-yl)amine (3 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (33 mg). MS (ESI, m / z): [M+H]+ = 889.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.65(s,2 H)8.38(br.s.,2 H)8.20-8.28(m,2 H)8.17(d,J=9.77 Hz,1 H)7.93(d,J=7.63 Hz,1 H)7.78(d,J=8.85 Hz,1 H)7.71(t,J=7.86 Hz,1 H)7.59(d,J=8.54 Hz,1 H)7.54(br.s.,1 H)7.45-7.50(m,2 H)7.16(d,J=9.77 Hz,1 H)5.70(br.s.,1 H)5.44(s,2 H)4.41(d,J=12.82 Hz,1 H)4.08(d,J=6.26 Hz,3 H)3.62(dd,J=10.38,6.56 Hz,1 H)3.41(br.s.,4 H)3.09-3.19(m,2 H)3.05(t,J=12.05 Hz,1 H)2.86-2.94(m,1 H)2.54-2.66(m,8 H)2.45(s,3 H)2.08(dd,J=8.85,4.88 Hz,2 H)1.95-2.02(m,2 H)1.83(br.s.,2 H)

[0233] Example C-36: Preparation of 3-(1-(3-(5-((1-(5-(5-(5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001217) Step 1) Preparation of tert-butyl 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)pentanoate [ka] Ethylbis(propan-2-yl)amine (2.0 equiv.) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 5-bromopentanoate (173 mg, 0.73 mmol) in ACN (10 ml). The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (170 mg). MS (ESI, m / z): [M+H] + =512.4

[0234] Step 2) Preparation of 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)pentanoic acid [ka] TFA (5 ml) was added to tert-butyl 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)pentanoate (165 mg, 0.32 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =456.4

[0235] Step 3) Preparation of 3-(1-(3-(5-((1-(5-(1-(5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001217) [ka] HATU (47.7 mg, 0.13 mmol) was added to a solution of 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (30 mg, 0.06 mmol) and 5-(4-(4-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)piperazin-1-yl)pentanoic acid (32.0 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (33 mg). MS (ESI, m / z): [M+H]+ = 917.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.96(s,1 H)8.58-8.67(m,2 H)8.34-8.41(m,2 H)8.23(t,J=8.62 Hz,2 H)8.17(d,J=9.77 Hz,1 H)7.93(d,J=7.78 Hz,1 H)7.74-7.81(m,1 H)7.71(t,J=7.86 Hz,1 H)7.59(d,J=10.07 Hz,1 H)7.54(br.s.,1 H)7.44-7.51(m,2 H)7.16(d,J=9.77 Hz,1 H)5.69(d,J=5.49 Hz,1 H)5.44(s,2 H)4.44(d,J=12.36 Hz,1 H)4.07(d,J=6.26 Hz,2 H)3.93(d,J=12.66 Hz,1 H)3.42-3.54(m,2 H)3.37(br.s.,2 H)3.04(t,J=12.13 Hz,1 H)2.87-2.96(m,2 H)2.52-2.66(m,6 H)2.41-2.46(m,6 H)2.36(br.s.,3 H)2.01-2.12(m,2 H)1.74-1.88(m,2 H)1.54(br.s.,4 H)

[0236] Example C-37: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carbonyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001218) [ka] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-one in 0.6 ml of DMSO DIPEA (123 μmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (24.7 μmol) and 3-(4-methyl-1-oxo-6-(4-(piperidine-4-carbonyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (24.7 μmol) and stirred at 80° C. for 16 hours. The reaction mixture was analyzed by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The resulting product was purified by a 200 sachets column (DCM / MeOH, 100 / 0 to 97 / 3 gradient) and the corresponding fractions were lyophilized. The resulting product was purified by aminosilica column chromatography (DCM / MeOH, 100 / 0 to 97 / 3 gradient) to give 13 mg of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carbonyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =985.8 1H NMR(500 MHz,DMSO-d6)δ ppm 10.96(s,1H),8.64(s,2H),8.38(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8 Hz,1H),8.08(d,J=9 Hz,1H),7.93(d,J=7.6 Hz,1H),7.71(t,J=7.9 Hz,1H),7.48(m,3H),7.16(d,J=7.9 Hz,1H),7.09(s,1H),5.68(m,1H),5.44(s,2H),4.38(d,J=12.5 Hz,1H),4.14(d,J=12.5 Hz,1H),4.08(d,J=6.6 Hz,2H),3.7(brd,2H),3.63(brd,2H),3.49(brd,2H),3.45(brd,2H),3.37(m,2H),2.99(m,2H) ,2.88(m,3H),2.63(brd,2H),2.58(m,2H),2.48(s,3H),2.07(m,5H),1.81(m,2H),1.62(m,4H)

[0237] Example C-38: Preparation of 3-(1-(3-(5-((1-(2-(4-((1-(2-(1-(2-(2-6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)amino)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001219) [ka] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-one in 0.6 ml of DMSO DIPEA (123 μmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (24.7 μmol) and 3-(4-methyl-1-oxo-6-(4-(piperidin-4-ylamino)piperidin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (24.7 μmol) and stirred at 80° C. for 16 hours. The reaction mixture was analyzed by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The resulting product was purified by column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) and purified with 15 mg of 3-(1-(3-(5-((1-(2-(4-((1-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptaradin-6-yl)piperidin-4-yl)amino)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =971.8 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1H),8.65(s,2H),8.39(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8 Hz,1H),8.03(d,J=9 Hz,1H),7.93(d,J=7.6 Hz,1H),7.71(t,J=7.9 Hz,1H),7.48(m,3H),7.16(d,J=9.8 Hz,1H),7.03(s,1H),5.68(m,1H),5.44(s,2H),4.38(d,J=12.5 Hz,1H),4.12(d,J=12.5 Hz,1H),4.07(d,J=6.6 Hz,2H),3.97(d,J=12.7 Hz,2H),3.36(m,2H),3.26(d,J=13 Hz,2H),2.97(m,5H),2.88(m,2H),2.80(brd,2H),2.58(m,3H),2.46(s,3H),2.05(m,4H),1.89(m,2H),1.80(brd,3H)1.28(m,6H).

[0238] Example C-39: Preparation of 3-(1-(3-(5-((1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001221) Step 1) Preparation of tert-butyl 2-(4-(((2-(3-((3-(3-cyanopronyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)acetate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 2-bromoacetate (160 mg, 0.84 mmol) in a solution of NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%). Title compound (150 mg) MS (ESI, m / z): [M+H] + =593.7

[0239] Step 2) Preparation of 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)acetic acid [ka] TFA (5 ml) was added to tert-butyl 2-(((2-(3-((3-(3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetate (150 mg, 0.31 mmol) in DCM (15 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =537.6

[0240] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001221) [ka] HATU (56.7 mg, 0.15 mmol) was added to 2-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (40 mg, 0.08 mmol) and 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2,6-dione(1H)-yl)piperidine-2,6-dione (25.4 mg, 0.08 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (30 mg). MS (ESI, m / z): [M+H] + =860.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.02(s,1 H)8.66(s,2 H)8.39(s,2 H)8.13-8.30(m,4 H)8.08(d,J=8.85 Hz,1 H)7.94(d,J=7.63 Hz,1 H)7.73(t,J=7.86 Hz,1 H)7.45-7.58(m,3 H)7.29(d,J=1.83 Hz,1 H)7.17(d,J=9.77 Hz,1 H)5.76(dd,J=11.75,5.04 Hz,1 H)5.45(s,2 H)4.08(br.s.,2 H)3.57-3.75(m,6 H)3.54(br.s.,2 H)3.42-3.51(m,2 H)3.10-3.20(m,6 H)2.86-2.97(m,2 H)2.55-2.65(m,2 H)1.26-1.31(m,3 H)

[0241] Example C-40: Preparation of 3-(1-(3-(5-((1-(1-(3-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001223) Step 1) Preparation of tert-butyl 3-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 3-bromopropanoate (131 mg, 0.63 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Title compound (100 mg) MS (ESI, m / z): [M+H] + =607.7

[0242] Step 2) Preparation of 3-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)propanoic acid [ka] TFA (5 ml) was added to tert-butyl 3-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoate (150 mg, 0.25 mmol) in DCM. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =551.6

[0243] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001223) [ka] HATU (55.2 mg, 0.15 mmol) was added to 3-(4-((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid (40 mg, 0.07 mmol) and 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2,6-dione(1H)-yl)piperidine-2,6-dione (24.8 mg, 0.07 mmol) in DMF (2 ml), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (35 mg). MS (ESI, m / z): [M+H] + =875.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.58(s,2 H)8.32(s,2 H)8.14-8.23(m,3 H)8.11(d,J=9.77 Hz,1 H)8.00(d,J=9.00 Hz,1 H)7.87(d,J=7.63 Hz,1 H)7.66(t,J=7.86 Hz,1 H)7.39-7.48(m,3 H)7.21(s,1 H)7.10(d,J=9.61 Hz,1 H)5.69(dd,J=11.60,5.04 Hz,1 H)5.38(s,2 H)4.00(br.s.,2 H)3.59(br.s.,4 H)3.45(br.s.,2 H)3.38(br.s.,3 H)2.80-2.89(m,2 H)2.47-2.59(m,3 H)2.00-2.06(m,2 H)1.82-1.93(m,2 H)1.80(br.s.,1 H)1.40(d,J=6.87 Hz,2H)1.17(s,4H)

[0244] Example C-41: Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}-3-oxopropyl-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001224) Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and tert-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =456.4

[0245] Step 2) Preparation of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4

[0246] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001224) [ka] HATU (55.2 mg, 0.15 mmol) was added to 3-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid (30 mg, 0.06 mmol) and 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (25.8 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (20 mg). MS (ESI, m / z): [M+H] + =889.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.66(s,2 H)8.39(s,2 H)8.21-8.29(m,2 H)8.19(d,J=9.77 Hz,1 H)8.06-8.14(m,1 H)7.94(d,J=7.78 Hz,1 H)7.73(t,J=7.86 Hz,1 H)7.44-7.58(m,3 H)7.17(d,J=9.77 Hz,1 H)7.11(s,1 H)5.67-5.73(m,1 H)5.45(s,2 H)4.08(br.s.,1 H)3.67(br.s.,4 H)3.44-3.58(m,4 H)3.12(br.s.,1 H)3.08(s,1 H)2.87-2.98(m,2 H)2.75(br.s.,1 H)2.70(br.s.,1 H)2.54-2.67(m,11 H)2.03-2.09(m,1 H)1.90-2.00(m,1 H)1.24(s,2 H)

[0247] Example C-42: Preparation of 3-(1-(3-(5-((1-(3-(1-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001225) Step 1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and tert-butyl piperazine-1-carboxylate (400 mg, 2.07 mmol) in NMP (3 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =456.4

[0248] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl) in DCM (30 ml). TFA (10 ml) was added to tert-butyl 4-(3,6-dioxopiperidin-3-yl)-piperazine-1-carboxylate-6-yl. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4

[0249] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(3-(3-(4-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001225) [ka] HATU (55.2 mg, 0.15 mmol) was added to 3-(4-((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid (40 mg, 0.07 mmol) and 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2,6-(1H)-yl)piperidine-2,6-dione (25.8 mg, 0.07 mmol) in DMF (2.0 ml), followed by the addition of ethyl bis(propan-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (30 mg). MS (ESI, m / z): [M+H]+ =889.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.00(s,1 H)8.62-8.67(m,2 H)8.39(s,2 H)8.21-8.28(m,2 H)8.19(d,J=9.77 Hz,1 H)7.94(d,J=7.63 Hz,1 H)7.83(d,J=9.16 Hz,1 H)7.73(t,J=7.86 Hz,1 H)7.63(dd,J=9.00,2.29 Hz,1 H)7.55(d,J=2.29 Hz,1 H)7.47-7.53(m,2 H)7.17(d,J=9.77 Hz,1 H)5.71(d,J=5.95 Hz,1 H)5.45(s,2 H)4.09(d,J=6.10 Hz,2 H)3.67(br.s.,4 H)3.49(br.s.,2 H)3.43(br.s.,1 H)2.87-2.97(m,1 H)2.71-2.81(m,2 H)2.54-2.64(m,8 H)2.47(s,3 H)2.04-2.11(m,1 H)1.89(d,J=12.82 Hz,1 H)1.49(d,J=11.29 Hz,1 H)1.25(br.s.,4 H)

[0250] Example C-43: Preparation of 3-(1-(3-(5-((1-(1-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001226) Step 1) Preparation of tert-butyl 4-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)butanoate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 4-bromobutanoate (280 mg, 1.25 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Title compound (100 mg) MS (ESI, m / z): [M+H] + =621.7

[0251] Step 2) Preparation of 4-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoic acid [ka] TFA (5 ml) was added to a solution of tert-butyl 4-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoate (150 mg, 0.25 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =565.6

[0252] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001226) [ka] HATU (54.0 mg, 0.14 mmol) was added to 4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoic acid (40 mg, 0.07 mmol) and 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2,6-dione(1H)-yl)piperidine-2,6-dione (24.2 mg, 0.07 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3.0 equiv.). The reaction was stirred at room temperature for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =889.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.01(s,1 H)8.65(s,2 H)8.39(s,2 H)8.22-8.29(m,3 H)8.19(d,J=9.77 Hz,1 H)8.06(d,J=8.85 Hz,1 H)7.94(d,J=7.93 Hz,1 H)7.73(t,J=7.86 Hz,1 H)7.45-7.53(m,3 H)7.27(d,J=2.29 Hz,1 H)7.17(d,J=9.77 Hz,1 H)5.70-5.81(m,1 H)5.45(s,2 H)4.05(d,J=5.80 Hz,2 H)3.59-3.69(m,4 H)3.35-3.47(m,6 H)2.85-2.98(m,2 H)2.53-2.65(m,2 H)2.35-2.43(m,5 H)1.90-2.02(m,2 H)1.69-1.82(m,2 H)1.18(br.s.,4 H)

[0253] Example C-44: Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001227) Step 1) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (ICT-0001227) [ka] HATU (54.0 mg, 0.14 mmol) was added to 4-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridase-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoic acid (40 mg, 0.07 mmol) and 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (25.2 mg, 0.07 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3.0 equivalents). The reaction was stirred at room temperature for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =903.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.57(s,2 H)8.31(s,2 H)8.27(d,J=8.24 Hz,1 H)8.14-8.21(m,2 H)8.02(d,J=9.00 Hz,1 H)7.87(d,J=7.78 Hz,1 H)7.65(t,J=7.93 Hz,1 H)7.40-7.46(m,3 H)7.10(d,J=9.77 Hz,1 H)7.02(s,1 H)5.62(d,J=7.02 Hz,1 H)5.38(s,2 H)4.00(d,J=6.10 Hz,2 H)3.57(br.s.,4 H)3.44(br.s.,2 H)3.39(br.s.,2 H)2.78-2.89(m,2 H)2.46-2.60(m,7 H)2.37(t,J=6.94 Hz,2 H)1.97-2.04(m,2 H)1.71-1.93(m,2 H)1.39(d,J=10.99 Hz,1 H)1.16(br.s.,6 H)

[0254] Example C-45: Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-ylpiperazin-1-yl)piperazine-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001228) Step 1) Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001228) [ka] HATU (54.0 mg, 0.14 mmol) was dissolved in 4-(((2-(3-((3-(3-(3-(3-(3-cyanophenyl)6-oxopyridase-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoic acid (40 mg, 0.07 mmol) and 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2,6-dione(1H)-yl)piperidin-1-yl)butanoic acid (2.0 ml) in DMF (2.0 ml). To the mixture was added peridine-2,6-dione (25.2 mg, 0.07 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3.0 equiv.). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography with MeOH / DCM (0-20%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =903.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.92(s,1 H)8.57(s,2 H)8.31(s,2 H)8.14-8.20(m,2 H)8.11(d,J=9.77 Hz,1 H)7.87(d,J=7.78 Hz,1 H)7.74(d,J=9.00 Hz,1 H)7.65(t,J=7.78 Hz,1 H)7.51-7.56(m,1 H)7.45-7.49(m,1 H)7.39-7.45(m,2 H)7.10(d,J=9.77 Hz,1 H)5.63(d,J=6.87 Hz,1 H)5.38(s,2 H)3.99(d,J=5.80 Hz,2 H)3.58(br.s.,4 H)3.39(br.s.,3 H)3.34(br.s.,3 H)2.78-2.90(m,1 H)2.45-2.59(m,4 H)2.33-2.41(m,10 H)1.95-2.05(m,2 H)1.84-1.95(m,1 H)1.66-1.80(m,2 H)

[0255] Example C-46: Preparation of 3-(1-(3-(5-((1-(2-(4-(((2R)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001229) [ka] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1-one in 0.6 ml of DMSO DIPEA (98 μmol) was added to 6-dihydropyridazin-3-yl)benzonitrile (18 μmol) and 3-(4-methyl-1-oxo-6-((R)-2-(piperazin-1-ylmethyl)morpholino)phthalazine-2(1H)-yl)piperidine-2,6-dione (18 μmol) and stirred at 80° C. for 16 h. The reaction mixture was purified by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The resulting product was purified by a 100 / 0 to 97 / 3 gradient (DCM / MeOH, 100 / 0 to 97 / 3 gradient). The corresponding fractions were lyophilized. The resulting product was purified by aminosilica column chromatography (DCM / MeOH, 100 / 0 to 97 / 3 gradient) to give 5.6 mg of 3-(1-(3-(5-((1-(2-(2-(4-((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =973.8 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1H),8.65(s,2H),8.38(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8 Hz,1H),8.08(d,J=9 Hz,1H),7.93(d,J=7.6 Hz,1H),7.71(t,J=7.9 Hz,1H),7.48(m,3H),7.16(d,J=9.8 Hz,1H),7.07(s,1H),5.68(m,1H),5.44(s,2H),5.32(s,2H),4.38(d,J=12.5 Hz,1H),4.09-4.03(m,2H),3.97(m,1H),3.87(m,2H),3.71(m,2H),3.60(m,2H)3.53-3.47(m,2H),3.40-3.35(m,2H),2 .98(m,2H),2.88(m,2H),2.65-2.55(m,3H),2.48(s,3H),2.45(brd,2H),2.06(m,2H),1.80(m,2H),1.38-1.10(brd,4H)

[0256] Example C-47: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001231) [ka] HATU (34.0 mg, 0.12 mmol) was dissolved in DMF (2 ml) to prepare a solution of 2-(4-(((2-(3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (46.6 mg, 0.09 mmol) and 3-(6-fluoro-4-methyl-1-oxo-7-(4-(piperidin-4-yl)piperazin-1-(4-(1H)-yl) A solution of piperazine-2,6-dione (40.9 mg, 0.09 mmol) was added at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (43 mg). MS (ESI, m / z): [M+H] + =990.0 1H NMR(500 MHz,DMSO-d6)δ ppm 11.02(s,1 H)9.43(br.s.,1 H)8.58-8.80(m,2 H)8.34-8.46(m,2 H)8.11-8.28(m,3 H)7.94(d,J=7.63 Hz,1 H)7.73(t,J=7.86 Hz,2 H)7.46-7.54(m,2 H)7.17(d,J=9.77 Hz,1 H)5.70(br.s.,1 H)5.45(s,2 H)4.38(d,J=12.66 Hz,1 H)4.30(br.s.,1 H)4.25(br.s.,1 H)4.06-4.14(m,2 H)3.76(br.s.,1 H)3.65(br.s.,1 H)3.54(br.s.,2 H)2.99-3.14(m,3 H)2.83-2.99(m,2 H)2.73(s,1 H)2.54-2.66(m,3 H)2.48(br.s.,3 H)2.22(br.s.,1 H)2.04-2.16(m,2 H)1.89-2.04(m,2 H)1.84(br.s.,2 H)1.70(br.s.,2 H)1.07-1.31(m,2 H)1.01(br.s.,1 H)

[0257] Example C-48: Preparation of 3-(1-(3-(5-((1-(2-(3-(1-(2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)azetidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001232) Step 1) Preparation 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 magnesium sulfate, and 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.

[0258] Step 2) Preparation of tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate [ka] Pd / C (10% by weight, 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 a hydrogen 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.

[0259] Step 3) Preparation 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.

[0260] Step 4) Preparation of 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)-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)-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, NH-DM 1020 and passed through a Chromatorex pad to give the title compound (140 mg), which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =397.3.

[0261] Step 5) Preparation of 3-(1-(1-(3-(5-((1-(2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-dei)azetidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001232) [ka] HATU (36.6 mg, 0.09 mmol) and 3-{6-{4-({[2-(3-{3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (46.6 mg, 0.09 mmol) and 3-{6-[4-(azetidin-3-yl)piperazin-1-yl]-1-oxo-1,2-dihydrobutalazin-2-yl}piperidine-2,6-dione (34.4 mg, 0.09 mmol) in DMF (2 ml) at room temperature, followed by ethylbis(propan-2-yl)amine (33.7 mg, 0.261 μmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (30 mg). MS (ESI, m / z): [M+H] + =916.0. 1H NMR(500 MHz,DMSO-d6)δ ppm 11.01(s,1 H)8.66(s,2 H)8.38(s,2 H)8.21-8.28(m,3 H)8.11-8.21(m,1 H)8.06(d,J=9.00 Hz,1 H)7.88-7.96(m,1 H)7.72(t,J=7.86 Hz,1 H)7.46-7.57(m,3 H)7.28(s,1 H)7.17(d,J=9.77 Hz,1 H)5.75(dd,J=11.44,5.19 Hz,1 H)5.45(s,2 H)4.18-4.26(m,1 H)4.09(br.s.,2 H)4.04(t,J=8.77 Hz,1 H)3.88(br.s.,1 H)3.50(s,1 H)3.45(br.s.,4 H)3.27(br.s.,1 H)2.86-2.97(m,1 H)2.61(d,J=17.85 Hz,1 H)2.54(br.s.,3 H)1.39(s,1 H)

[0262] Example C-49: Preparation of 3-(1-(3-(5-((1-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidin-4-yl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridin-3-yl)benzonitrile (ICT-0001233) Step 1) Preparation of benzyl 4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-4-yl)piperazine-1-carboxylate [ka] Ethyl bis (670 mg, 5.12 mmol) was added to a solution of 3-(7-fluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (0.53 g, 1.73 mmol) in solvent DMF (3 ml) at room temperature. The reaction was stirred at 130° C. for 16 hours. After cooling, the reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC with 100% ethyl acetate. The title compound (678 mg) was obtained as a white foam. MS (ESI, m / z): [M+H] + =573.2.

[0263] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(4-(piperazin-1-yl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Pd / C 10% (100 mg) was added to a solution of 4-(1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperidin-4-yl)piperazin-4-yl)piperazine-1-carboxylate (1 g, 1.75 mmol) at room temperature. The reaction was quenched by attaching a H2 balloon and stirred at room temperature for 16 hours. After cooling, the reaction was filtered and the filtrate was concentrated to give the title compound as a white solid (590 mg). MS (ESI, m / z): [M+H] + =439.5.

[0264] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(1-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidin-4-yl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001233) [ka] 2-[4-({[2-(3-{3-(3-cyanophenyl)-6-oxo-1,{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (46.6 mg, 0.086 mmol) and 3-{4-methyl-1-oxo-7-[4-(piperazin-1-yl)piperidin-1-yl]-1,2- To a solution of {dihydroptalazin-2-yl}piperidine-2,6-dione (31.8 mg, 0.086 mmol) was added, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (53.2 mg). MS (ESI, m / z): [M+H] + =958.2 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.66(s,2 H)8.38(d,J=1.68 Hz,2 H)8.21-8.28(m,2 H)8.12-8.21(m,1 H)7.90-7.97(m,1 H)7.78(d,J=9.00 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.61(d,J=8.70 Hz,1 H)7.55(br.s.,1 H)7.46-7.53(m,2 H)7.17(d,J=9.77 Hz,1 H)5.68(d,J=5.95 Hz,1 H)5.45(s,2 H)4.10(br.s.,1 H)3.47-3.56(m,2 H)2.85-3.02(m,3 H)2.52-2.66(m,4 H)2.46(s,4 H)2.02-2.12(m,1 H)1.39(s,1 H)

[0265] Example C-50: Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001234) Step 1) Preparation of 3-(4-methyl-1-oxo-7-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Ethylbis(propan-2-yl)amine (1.34 g, 10.4 mmol) was added to a solution of 3-(7-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol) and benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (1.1 g, 3.46 mmol) in DMA (5 mL) at room temperature. The reaction was heated at 120 °C for 16 h. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the protected compound. The CBZ-protected compound was dissolved in MeOH (0.5 mL), 10% Pd / C (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 h. The reaction was filtered and concentrated under reduced pressure to give the target compound (1.21 g). MS (ESI, m / z): [M+H] + =453.6.

[0266] Step 2) Preparation of 3-(1-(1-(3-(5-((1-(2-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl)piperidin-4-yl)methyl)piperazine-1-di)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001234) [ka] HATU (36.3 mg, 0.09 mmol) was dissolved in 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yloxy)methylpiperidin-1-yl)acetic acid (46 mg, 0.09 mmol) and 3-(4-(4-methyl-1-oxo-7-(4-(piperazin-1-yl)piperidin-1-yl)phthalazine-2(1H)- To the resulting solution was added 2,6-dione (39 mg, 0.09 mmol) at room temperature, followed by the addition of ethyl bis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (43.2 mg). MS (ESI, m / z): [M+H] + =972.2. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.65(s,2 H)8.36-8.40(m,2 H)8.24(s,1 H)8.19(s,1 H)8.12-8.14(m,1 H)7.96(d,J=6.56 Hz,1 H)7.93(d,J=7.93 Hz,1 H)7.74(s,1 H)7.56(d,J=6.10 Hz,1 H)7.50(s,2 H)7.17-7.19(m,1 H)7.07(br.s.,1 H)6.52(s,2 H)5.45(s,2 H)5.34(br.s.,1 H)4.08(br.s.,1 H)3.94-4.01(m,1 H)2.88-2.96(m,2 H)2.53-2.66(m,3 H)2.42-2.47(m,6 H)2.20(br.s.,1 H)1.77-1.88(m,1 H)1.34-1.42(m,1 H)1.17-1.23(m,10 H)

[0267] Example C-51: Preparation of 3-(1-(3-(5-((1-(1-(2-(3-(1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001235) Step 1) Preparation of tert-butyl 3-((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate [ka] Methanesulfonyl chloride (2.69 g, 23.5 mmol) was slowly added to a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (4 g, 21.4 mmol) and DIPEA (5.58 ml, 32 mmol) in DCM (20 ml) at 0° C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in EA (150 ml) and washed with 150 ml of water and 150 ml of brine solution. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (5.8 g, red oil). MS (ESI, m / z): [M+H] + =266.1.

[0268] Step 2) Preparation of benzyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperazine-1-carboxylate [ka] Potassium carbonate (6.04 g, 43.7 mmol) was slowly added to a solution of tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (5.8 g, 21.9 mmol) and benzylpiperazine-1-carboxylate (7.22 g, 32.8 mmol) in DMF (50 ml) and stirred at 85° C. for 17 hours. The reaction mixture was diluted with 200 ml of EA and washed with water and brine solution. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by reverse-phase column chromatography to give the title compound (3.87 g). MS (ESI, m / z): [M+H] + =390.1

[0269] Step 3) Preparation of tert-butyl 3-(piperazine-1-monomethyl)azetidine-1-carboxylate [ka] A solution of benzyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperazine-1-carboxylate (2.45 g, 6.29 mmol) in MeOH (60 ml) was added to Pd / C (300 mg, 10 wt%) and stirred under a hydrogen atmosphere at room temperature for 17 hours. The solution was filtered through Celite 545 and the solvent was removed under reduced pressure to give the title compound (1.56 g). MS (ESI, m / z): [M+H] + =256.0.

[0270] Step 4) Preparation of tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)azetidine-1-carboxylate [ka] A solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.69 mmol), tert-butyl 3-(piperazine-1-monomethyl)azetidine-1-carboxylate (265 mg, 1.04 mmol), and DIPEA (0.241 ml, 1.38 mmol) was stirred at 120° C. for 20 hours. MS (ESI, m / z): [M+H] + =525.1

[0271] Step 5) Preparation of 3-(6-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-4-methyl-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (0.2 ml) was added to 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 (20 mg, 0.038 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 NH-DM 1020, Chromatorex pad to give the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =425.1.

[0272] Step 6) Preparation of 3-(1-(1-(3-(5-((1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001235) [ka] HATU (36.3 mg, 0.1 mmol) was dissolved in DMF (2 ml) to prepare a solution of 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (46.6 mg, 0.08 mmol) and 3-(6-(4-azetidin-3-yl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)- To the resulting solution was added 2,6-dione (36.9 mg, 0.08 μmol) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (37 mg). MS (ESI, m / z): [M+H] + =944.1. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.65(s,2 H)8.36-8.40(m,2 H)8.24(s,1 H)8.19(s,1 H)8.12-8.14(m,1 H)7.96(d,J=6.56 Hz,1 H)7.93(d,J=7.93 Hz,1 H)7.74(s,1 H)7.56(d,J=6.10 Hz,1 H)7.50(s,2 H)7.17-7.19(m,1 H)7.07(br.s.,1 H)6.52(s,2 H)5.45(s,2 H)5.34(br.s.,1 H)4.08(br.s.,1 H)3.94-4.01(m,1 H)2.88-2.96(m,2 H)2.53-2.66(m,3 H)2.42-2.47(m,2 H)2.20(br.s.,1 H)1.77-1.88(m,1 H)1.34-1.42(m,1 H)1.17-1.23(m,10 H)

[0273] Example C-52: Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(2-(2-(2-(3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001236) Step 1) Preparation of 3-(4-methyl-1-oxo-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Ethyl bis(2-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol) and benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (1.1 g, 3.46 mmol) were added to DMA (5 mL) at room temperature. The reaction was heated at 120 °C for 16 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the protected compound. The CBZ-protected compound was dissolved in MeOH (0.5 mL), 10% Pd / C (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction was filtered and concentrated under reduced pressure to give the target compound (1.1 g). MS (ESI, m / z): [M+H] + =453.6.

[0274] Step 2) Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(2-(2-(dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperidin-4-yl)methylperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001236) [ka] HATU (36.3 mg, 0.09 mmol) was treated with 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yloxy)methyl)piperidin-1-yl)acetic acid (46 mg, 0.09 mmol) and 3-(4-methyl-1-oxo-6-(4-(piperazin-1-yl)piperidin-1-yl)phthalazine-2(1H)-yl) in DMF (2 ml). To the resulting solution was added 2,6-dione (39 mg, 0.09 mmol) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (40.2 mg). MS (ESI, m / z): [M+H] + =972.2 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.64(s,2 H)8.38(d,J=4.73 Hz,2 H)8.20-8.26(m,3 H)8.17(d,J=9.77 Hz,1 H)8.04(d,J=9.00 Hz,1 H)7.93(d,J=7.78 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.47-7.51(m,2 H)7.16(d,J=9.77 Hz,1 H)7.04(s,1 H)5.44(s,2 H)4.05(d,J=5.80 Hz,2 H)3.55(br.s.,1 H)3.09-3.15(m,2 H)2.77-2.97(m,5 H)2.76(s,1 H)2.52-2.65(m,4 H)2.43-2.49(m,5 H)2.36(br.s.,2 H)2.29(br.s.,1 H)2.16(d,J=6.41 Hz,1 H)1.95-2.06(m,1 H)1.73-1.86(m,4 H)1.39(s,1 H)1.30(d,J=11.14 Hz,1 H)1.15-1.26(m,1 H)

[0275] Example C-53: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2-(2-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperidin-1-yl)piperidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001237) Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (1.34 g, 10.4 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol) and tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate (1.0 g, 3.46 mmol) in DMA (5 ml) at room temperature. The reaction was heated at 120 °C for 16 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =539.6

[0276] Step 2) Preparation of 3-(4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (1 ml) was added to a solution of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate (200 mg, 0.5 mmol) in DCM (3 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 a 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] + =439.1.

[0277] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2-(dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperidin-1-yl)piperidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001237) [ka] HATU (36.3 mg, 0.09 mmol) was added to a solution of 2-(4-(((2-(3-(3-(3-(3-cyanophenyl)-6-oxypyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)acetic acid (46 mg, 0.09 mmol) 3-(4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (38 mg, 0.09 mmol) in DMF (2 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-20%) to give the title compound (40.2 mg). MS (ESI, m / z): [M+H] + =958.2 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.66(s,2 H)8.38(s,2 H)8.11-8.28(m,3 H)8.08(d,J=8.70 Hz,1 H)7.94(d,J=7.78 Hz,1 H)7.72(t,J=7.86 Hz,1 H)7.45-7.55(m,3 H)7.17(d,J=9.77 Hz,1 H)7.09(br.s.,1 H)6.54(s,1 H)5.68(d,J=7.17 Hz,1 H)5.45(s,2 H)4.10(br.s.,1 H)2.69(br.s.,1 H)2.53-2.66(m,1 H)2.36(s,1 H)1.20(d,J=6.41 Hz,1 H)

[0278] Example C-54: Preparation of N-(3-(2-(4-(((2-(2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetamido)propyl)-1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidine-4-carboxamide (ICT-0001238) Step 1) Preparation 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-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.69 mmol), tert-butyl piperidine-4-carboxylate (230 mg, 1.04 mmol), and DIPEA (0.24 mL, 1.38 mmol) in NMP (2 mL) was stirred at 120 °C for 20 h. The reaction mixture was purified by reverse-phase column chromatography to give the protected compound (284 mg), which was dissolved in DCM (4 mL), TFA (1 mL) was added, and stirred at room temperature for 2 h. The reaction was concentrated in vacuo. The residue was purified by MPLC in MeOH / DCM (0-20%). Title compound (250 mg). MS (ESI, m / z): [M+H] + =399.0.

[0279] Step 2) Preparation of N-(3-aminopropyl)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl)piperidine-4-carboxamide [ka] HATU (105 mg, 0.27 mmol) was added to a solution of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl) and tert-butyl(3-aminopropyl)carbamate (43.7 mg, 0.25 mmol) in DMF (1 mL) at room temperature, followed by the addition of ethyl bis(propan-2-yl)amine (97.3 mg, 0.75 mmol). The reaction was stirred for 6 hours. The reaction was poured into water and extracted with ethyl acetate. It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound (102 mg). MS (ESI, m / z): [M+H] + =455.7

[0280] Step 3) Preparation of N-(3-(2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetamido)propyl)-1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidine-4-carboxamide (ICT-0001238) [ka] HATU (36.6 mg, 0.09 mmol) and N-(3-aminopropyl)-1-[3-(2-(3-{3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-yl]acetic acid (46.6 mg, 0.09 mmol) and N-(3-aminopropyl)-1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl]piperidine-4-carboxydamide (39.5 mg, 0.09 mmol) in DMF (2 ml) at room temperature, followed by ethylbis(propan-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-20%) to give the title compound (51 mg). MS (ESI, m / z): [M+H] + =974.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.97(s,1 H)8.63-8.67(m,2 H)8.38(br.s.,2 H)8.13-8.27(m,3 H)8.05(d,J=9.00 Hz,1 H)7.84-7.96(m,2 H)7.72(t,J=7.86 Hz,1 H)7.46-7.52(m,2 H)7.17(d,J=9.77 Hz,1 H)7.03-7.09(m,1 H)5.68(d,J=7.32 Hz,1 H)5.45(s,2 H)4.00-4.14(m,3 H)3.45-3.63(m,2 H)3.03-3.19(m,4 H)2.83-3.03(m,4 H)2.53-2.69(m,2 H)2.34-2.49(m,4 H)1.99-2.11(m,1 H)1.95(br.s.,1 H)1.89(br.s.,1 H)1.74-1.85(m,2 H)1.50-1.71(m,5 H)1.33-1.43(m,1 H)

[0281] Example C-55: Preparation of 3-(1-(3-(5-((1-(2-(4-((1-(3-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001239) Step 1) Preparation of 3-(4-methyl-1-oxo-7-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Ethyl bis(2.68 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 (2.63 g, 8.3 mmol) in DMA (5 ml) 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 magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC. The CBZ-protected compound was obtained. The compound was dissolved in MeOH (10 ml) and 10% Pd / C (100 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 (2.15 g). MS (ESI, m / z): [M+H] + =453.2.

[0282] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(4-((1-(3-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001239) [ka] Triethylamine (18.2 mg, 0.18 mmol) was added to a solution of 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.09 mmol) and 3-(4-methyl-1-iodo-7-(4-(piperazin-1-yl)piperidin-1-(1H)-yl)piperidine-2,6-dione (40.8 mg, 0.09 mmol) in DMF (1 mL). The reaction was stirred at 45° C. for 4 hours. The reaction was poured into water. The ethyl acetate organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (45.2 mg). MS (ESI, m / z): [M+H] + =972.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1 H)8.65(s,2 H)8.39(s,1 H)8.37(s,1 H)8.21-8.26(m,2 H)8.13-8.20(m,2 H)7.93(d,J=7.63 Hz,1 H)7.68-7.77(m,2 H)7.54(d,J=9.00 Hz,1 H)7.45-7.51(m,2 H)7.16(d,J=9.77 Hz,1 H)5.69(d,J=6.10 Hz,1 H)5.44(s,1 H)4.38(d,J=12.21 Hz,1 H)4.08(t,J=5.49 Hz,2 H)3.96(d,J=12.05 Hz,1 H)3.27(d,J=13.12 Hz,1 H)2.98(d,J=12.97 Hz,1 H)2.83-2.94(m,2 H)2.53-2.65(m,3 H)2.39-2.47(m,4 H)2.37(br.s.,1 H)2.02-2.12(m,3 H)1.71-1.84(m,4 H)1.31(d,J=16.17 Hz,1 H)1.06-1.23(m,2 H)-0.03-0.03(m,2 H)

[0283] Example C-56: Preparation of 3-(1-(3-(5-((1-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)phenyl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001240) [ka] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-one in 0.6 ml of DMSO DIPEA (98 μmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (18 μmol) and 3-(6-(4-(4-aminophenyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (18 μmol) and stirred at 90° C. for 16 h. The reaction mixture was analyzed by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The resulting product was purified by elution with a 95 / 1 to 0 / 100 gradient (DCM / MeOH). The corresponding fractions were lyophilized. The resulting product was purified by aminosilica column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) to give 1.8 mg of 3-(1-(3-(5-((1-((4-(4-(2-(2,6-diodexperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)phenyl)glycy)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =965.8 1H NMR(500 MHz,DMSO-d6)δ ppm 10.98(s,1H),8.65(s,2H),8.38(s,2H),8.24(m,2H),8.18(d,J=9.8 Hz,1H),8.08(d,J=9 Hz,1H),7.93(d,J=7.6 Hz,1H),7.71(t,J=7.9 Hz,1H),7.58(m,1H),7.49(brd,2H),7.26(d,J=9.8 Hz,1H),7.1(d,J=9.6 Hz,2H),6.84(d,J=9.6 Hz,2H),6.64(m,1H),6.62(m,1H),5.69(m,1H),5.44(s,2H),5.32(s,2H),4.48-4.31(d,J=12.5 Hz,1H),4.08-4.03(m,2H),3.86(m,1H),3.72(m,1H),3.58-3.47(m,4H),3.40-3.35(m,2H),3.00(m,2) H),2.91(m,1H),2.65-2.55(m,2H),2.48(s,3H),2.08(m,2H),2.00-1.83(m,3H),1.38-1.10(brd,2H)

[0284] Example C-57: Preparation of 3-(1-(3-(5-((1-(5-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperazine-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001250) Step 1) Preparation of tert-butyl 5-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxophilidazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoate [ka] Triethylamine (3 eq.) was added to a solution of 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (100 mg, 2.09 mmol) and tert-butyl 5-bromopentanoate (390 mg, 1.46 mmol) in DCM (25 ml). The reaction was stirred at room temperature overnight. The organic layer was dried, concentrated under reduced pressure, and purified by MeOH / DCM (0-20%) column chromatography to give the title compound (133 mg). MS (ESI, m / z): [M+H] + =635.7

[0285] Step 2) Preparation of 5-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidine-1-dei)pentanoic acid [ka] TFA (2 ml) was added to the solution of tert-butyl 5-(4-(((2-(3-((3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoate (133 mg, 2.10 mmol) and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (121 mg). MS (ESI, m / z): [M+H] + =579.6

[0286] Step 3) Preparation of 3-(1-(3-(5-((1-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (ICT-0001250) [ka] Ethylbis(propan-2-yl)amine (3 eq.) was dissolved in 5-(4-(((2-(3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoic acid (23 mg, 0.04 mmol) and 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)) in DCM (1 ml). To a solution of 14.1 mg (0.04 mmol) of 2,6-dione (-yl)piperidine-2,6-dione and 22.7 mg (0.06 mmol) of HATU was added. The reaction was stirred at room temperature overnight. It was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (24.5 mg). MS (ESI, m / z): [M+H] + =917.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.91(s,1 H)8.56(s,2 H)8.31(s,2 H)8.19(d,J=8.39 Hz,2 H)8.11(d,J=9.77 Hz,1 H)8.00-8.07(m,1 H)7.86(d,J=7.48 Hz,1 H)7.65(t,J=7.93 Hz,1 H)7.39-7.44(m,3 H)7.09(d,J=9.77 Hz,1 H)7.01(s,1 H)5.56-5.68(m,1 H)5.38(s,2 H)3.97(d,J=5.95 Hz,2 H)3.43(br.s.,4 H)3.38(br.s.,2 H)3.14-3.26(m,2 H)3.00(br.s.,2 H)2.83(d,J=13.43 Hz,2 H)2.70(br.s.,2 H)2.47-2.59(m,4 H)2.40-2.44(m,2 H)2.30(t,J=7.02 Hz,2 H)1.96-2.04(m,4 H)1.78-1.93(m,2 H)1.68(br.s.,2 H)1.54(br.s.,2 H)

[0287] Example C-58: Preparation of 3-(1-(3-(5-((1-(5-(5-(5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)piperazine-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001251) [ka] Ethylbis(propan-2-yl)amine (3 eq.) was dissolved in 5-(4-(((2-(3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoic acid (23 mg, 0.04 mmol) and 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2(1H)) in DCM (1 ml). To a solution of 14.1 mg (0.04 mmol) of 2,6-dione (-yl)piperidine-2,6-dione and 22.7 mg (0.06 mmol) of HATU was added. The reaction was stirred at room temperature overnight. It was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (25.9 mg). MS (ESI, m / z): [M+H] + =917.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.93(s,1 H)8.54-8.58(m,2 H)8.29-8.33(m,2 H)8.14-8.19(m,2 H)8.11(d,J=9.77 Hz,1 H)7.86(d,J=7.78 Hz,1 H)7.73(d,J=9.00 Hz,1 H)7.65(t,J=7.86 Hz,1 H)7.53(dd,J=9.00,2.59 Hz,1 H)7.46(d,J=2.44 Hz,1 H)7.39-7.44(m,2 H)7.09(d,J=9.77 Hz,1 H)5.64(d,J=6.41 Hz,1 H)5.38(s,2 H)3.95-4.05(m,2 H)3.46-3.59(m,4 H)3.37(br.s.,2 H)3.03(q,J=7.22 Hz,2 H)2.80-2.90(m,3 H)2.46-2.58(m,2 H)2.39(s,3 H)2.29(t,J=7.10 Hz,1 H)1.82-1.94(m,5 H)1.67(br.s.,2 H)1.56-1.64(m,2 H)1.33-1.52(m,6 H)

[0288] Example C-59: Preparation of 3-(1-(3-(5-((1-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001252) [ka] Ethylbis(propan-2-yl)amine (3 equivalents) was added to a solution of 5-(4-((2-(3-(3-(3-(3-cyanophenyl)-6-oxypyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoic acid (121 mg, 0.21 mmol), 3-(1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (72 mg, 0.21 mmol) and HATU (160 mg, 0.32 mmol) in DCM (10 ml). It was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and purified by MeOH / DCM (0-20%) column chromatography to give the title compound (60 mg). MS (ESI, m / z): [M+H] + =903.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.96(s,1 H)8.56(s,2 H)8.31(d,J=7.48 Hz,2 H)8.13-8.23(m,3 H)8.10(d,J=9.77 Hz,1 H)7.99(d,J=9.00 Hz,1 H)7.86(d,J=7.78 Hz,1 H)7.64(t,J=7.86 Hz,1 H)7.37-7.46(m,3 H)7.14-7.19(m,1 H)7.09(d,J=9.77 Hz,1 H)5.69(dd,J=11.90,5.04 Hz,1 H)5.38(s,2 H)3.98(d,J=5.95 Hz,2 H)3.41(br.s.,2 H)3.35(br.s.,2 H)3.26(d,J=9.16 Hz,2 H)2.96-3.08(m,2 H)2.80-2.91(m,2 H)2.78(br.s.,2 H)2.46-2.61(m,3 H)2.31(t,J=7.10 Hz,2 H)1.99-2.06(m,2 H)1.80-1.98(m,4 H)1.52-1.61(m,2 H)1.35-1.51(m,4 H)

[0289] Example C-60: Preparation of 3-(1-(3-(5-((1-(2-(3-(1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methylazetidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001253) Step 1) Preparation of 3-(1-(3-(5-((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Triethylamine (0.62 ml, 8.36 mmol) was added to 3-{6-oxo-1-[(3-{5-[(piperidin-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (2 g, 4.18 mmol) and 2-chloroacetyl chloride (0.71 g, 6.28 mmol) in CHCl (50 mL) at 0° C., warmed to room temperature, and stirred for 1 h. After completion of the reaction, the reaction mixture was poured into water, extracted with DCM, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HX / EA (20-90%) MPLC to give the title compound (37 mg). MS (ESI, m / z): [M+H] + =556.1

[0290] Step 2) Preparation of 3-(1-(3-(5-((1-(2-(3-(3-((4-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methylazetidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001253) [ka] Ethyl bis (45ul, 0.26mmol) was added to 3-(1-(3-(5-((1-(1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (50mg, 0.09mmol) and 3-(6-(4-(4-(azetidin-3-yl)piperazin-1-yl)piperazine-1(1H)-yl)piperidine-2,6-dione (40mg, 0.09mmol) in DMF (1ml) at room temperature. The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H] + =944.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.65(s,1 H)8.67(s,1 H)8.33-8.40(m,2 H)8.31(s,1 H)8.23(br.s.,2 H)8.11-8.20(m,1 H)7.97-8.09(m,1 H)7.88-7.94(m,1 H)7.66-7.75(m,1 H)7.45-7.50(m,2 H)7.13-7.18(m,1 H)5.66(br.s.,1 H)5.39-5.46(m,2 H)4.38(br.s.,1 H)4.07(br.s.,3 H)3.76(br.s.,1 H)3.63(br.s.,1 H)3.44 -3.53(m,4 H)3.41(br.s.,6 H)3.02(d,J=13.58 Hz,2 H)2.89(br.s.,1 H)2.73-2.83(m,1 H)2.62(d,J=14.19 Hz,2 H)2.55(d,J=8.85 Hz,4 H)2.15(d,J=12.82 Hz,1 H)2.07(br.s.,2 H)1.95-2.04(m,2 H)1.86-1.95(m,2 H)1.82(br.s.,2 H)

[0291] Example C-61: Preparation of 3-(1-(3-(5-((1-(1-(2-((6R)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)1,3-oxazinan-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001254) Step 1) Preparation of tert-butyl (2S)-2-{[(4-methylbenzenesulfonyl)oxy]methyl}morpholine-4-carboxylate [ka] 4-Methylbenzene-1-sulfonyl chloride (9.65 g, 50.6 mmol), N,N-dimethylpyridin-4-amine (0.84 g, 6.9 mmol), and triethylamine (3.0 equivalents) were added to a solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (10 g, 46 mmol) in DCM (500 ml). Title compound (17 g). MS (ESI, m / z): [M+H] + =372.4.

[0292] Step 2) Synthesis of tert-butyl (2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate [ka] Potassium carbonate (6.04 g, 43.7 mmol) was slowly added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (5.8 g, 21.9 mmol) and tert-butyl (S)-2-((tosyloxy)methyl)morpholine-4-carboxylate (7.22 g, 32.8 mmol) in DMF (50 ml) and stirred at 85° C. for 17 hours. The reaction mixture was diluted with 200 ml of EA and washed with water and brine solution. The organic layer was dried over magnesium sulfate. It was concentrated. The residue was purified by reverse-phase column chromatography to give the title compound (3.87 g). MS (ESI, m / z): [M+H] + =555.6.

[0293] Step 3) Preparation of 3-(4-methyl-6-(4-(((S)-morpholin-2-yl)methyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (1 ml) was added to a solution of tert-butyl (2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate (200 mg, 0.5 mmol) in DCM (3 ml) and stirred at room temperature for 2 hours. 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 a NH-DM 1020 chromatrex pad to obtain the target compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =455.6.

[0294] Step 4) Preparation of 3-(1-(3-(5-((1-(2-((6R)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)methyl)1,3-oxazinan-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001254) [ka] Ethyl bis (45ul, 0.09mmol) was added to 3-(1-(3-(5-((1-(1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50mg, 0.09mmol) and 3-(4-methyl-6-(4-((S)-morpholin-2-yl)methyl)piperazin-1-yl)1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (40mg, 0.09mmol) in DMF (1ml) at room temperature. The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H] + =974.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.65(s,1 H)8.67(s,1 H)8.33-8.40(m,2 H)8.31(s,1 H)8.23(br.s.,2 H)8.11-8.20(m,1 H)7.97-8.09(m,1 H)7.88-7.94(m,1 H)7.66-7.75(m,1 H)7.45-7.50(m,2 H)7.13-7.18(m,1 H)5.66(br.s.,1 H)5.39-5.46(m,2 H)4.38(br.s.,1 H)4.07(br.s.,3 H)3.76(br.s.,1 H)3.63(br.s.,1 H)3.44 -3.53(m,4 H)3.41(br.s.,6 H)3.02(d,J=13.58 Hz,2 H)2.89(br.s.,1 H)2.73-2.83(m,1 H)2.62(d,J=14.19 Hz,4 H)2.55(d,J=8.85 Hz,4 H)2.15(d,J=12.82 Hz,1 H)2.07(br.s.,2 H)1.95-2.04(m,2 H)1.86-1.95(m,2 H)1.82(br.s.,2 H)

[0295] Example C-62: Preparation of 3-(1-(3-(5-((1-(2-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001255) Step 1) Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001255) [ka] Ethyl bis(45µl, 0.26mmol) was dissolved in 3-(1-(3-(5-((1-(1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (50mg, 0.09mmol) and 3-(4-(4-methyl-1-oxo-6-(4-(piperidin-4-yl) To the resulting solution was added 2,6-dione (38 mg, 0.09 mmol) at room temperature. The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H]+ = 958.2 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.62-8.68(m,2 H)8.35(s,1 H)8.39(s,1 H)8.22(d,J=7.17 Hz,2 H)8.11-8.19(m,1 H)8.03(d,J=9.00 Hz,1 H)7.92(d,J=7.93 Hz,1 H)7.65-7.75(m,1 H)7.39-7.52(m,3 H)7.10-7.19(m,1 H)7.00-7.09(m,1 H)5.67(d,J=7.02 Hz,1 H)5.39 -5.47(m,2 H)4.38(d,J=13.58 Hz,1 H)4.09(d,J=6.41 Hz,3 H)2.92-3.05(m,2 H)2.82-2.92(m,6 H)2.55-2.66(m,8 H)2.20(br.s.,2 H)2.07(br.s.,2 H)1.93-2.04(m,2 H)1.80(br.s.,4 H)1.42(br.s.,2 H)1.34(d,J=9.31 Hz,2 H)1.24(br.s.,2 H)

[0296] Example C-63: Preparation of 3-(1-(3-(5-((1-(1-(2-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001256) Step 1) Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001256) [ka] Ethyl bis (45ul, 0.26mmol) was added to 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50mg, 0.09mmol) and 3-(4-(4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazine-1-(1H)-yl)piperidine-2,6-dione (40mg, 0.09mmol) in DMF (1ml) at room temperature. The reaction was stirred for 6 hours. The reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H]+ = 972.2 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.62-8.68(m,2 H)8.35(s,1 H)8.39(s,1 H)8.22(d,J=7.17 Hz,2 H)8.11-8.19(m,1 H)8.03(d,J=9.00 Hz,1 H)7.92(d,J=7.93 Hz,1 H)7.65-7.75(m,1 H)7.39-7.52(m,3 H)7.10-7.19(m,1 H)7.00-7.09(m,1 H)5.67(d,J=7.02 Hz,1 H)5.39 -5.47(m,2 H)4.38(d,J=13.58 Hz,1 H)4.09(d,J=6.41 Hz,3 H)2.92-3.05(m,2 H)2.82-2.92(m,6 H)2.55-2.66(m,8 H)2.20(br.s.,2 H)2.07(br.s.,4 H)1.93-2.04(m,2 H)1.80(br.s.,4 H)1.42(br.s.,2 H)1.34(d,J=9.31 Hz,2 H)1.24(br.s.,2 H)

[0297] Example C-64: Preparation of 3-(1-(3-(5-((1-(2-(1-(1-(1-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carbonyl)azetidin-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001257) Step 1) Preparation of 3-(1-(3-(5-((1-(2-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carbonyl)azetidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001257) [ka] Ethyl bis(45ul, 0.26mmol) was added to 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (50mg, 0.09mmol) and 3-(6-(4-(azetidine-3-carbonyl)piperazin-1-yl)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (40mg, 0.09mmol) in DMF (1ml) at room temperature. The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H]+ = 958.2. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.62-8.68(m,2 H)8.35(s,1 H)8.39(s,1 H)8.22(d,J=7.17 Hz,2 H)8.11-8.19(m,1 H)8.03(d,J=9.00 Hz,1 H)7.92(d,J=7.93 Hz,1 H)7.65-7.75(m,1 H)7.39-7.52(m,3 H)7.10-7.19(m,1 H)7.00-7.09(m,1 H)5.67(d,J=7.02 Hz,1 H)5.39 -5.47(m,2 H)4.38(d,J=13.58 Hz,1 H)4.09(d,J=6.41 Hz,3 H)2.92-3.05(m,2 H)2.82-2.92(m,6 H)2.55-2.66(m,8 H)2.20(br.s.,2 H)2.07(br.s.,2 H)1.93-2.04(m,2 H)1.80(br.s.,4 H)1.42(br.s.,2 H)1.34(d,J=9.31 Hz,2 H)1.24(br.s.,2 H)

[0298] Example C-65: Preparation of 3-(1-(3-(5-((1-(1-(2-((2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)morpholino)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001258) [ka] Ethylbis(propan-2-yl)amine (3 eq.) was dissolved in DCM (10 ml) to prepare a solution of 2-(4-((2-(3-(3-(3-(3-(3-(3-(3-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (121 mg, 0.21 mmol) and 3-(4-methyl-6-(4-((S)-morpholin-2-yl)methyl)piperazin-1-yl)1-oxopyridine. To a solution of 1,2-diazine-2(1H)-yl)piperidine-2,6-dione (70 mg, 0.21 mmol) and HATU (160 mg, 0.32 mmol) was added. The reaction was stirred at room temperature overnight. It was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (60 mg). MS (ESI, m / z): [M+H] + =974.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(d,J=6.26 Hz,1 H)8.63(d,J=5.65 Hz,2 H)8.32-8.42(m,2 H)8.12-8.30(m,2 H)8.05(dd,J=14.57,8.62 Hz,1 H)7.86-7.98(m,1 H)7.67-7.76(m,1 H)7.60-7.67(m,1 H)7.55(br.s.,1 H)7.39-7.52(m,2 H)7.15(dd,J=9.92,5.49 Hz,1 H)7.06(d,J=19.68 Hz,1 H)5.67(br.s.,1 H)5.44(br.s.,2 H)4.13(br.s.,1 H)4.05(d,J=4.73 Hz,2 H)3.98(d,J=10.99 Hz,1 H)3.84(br.s.,2 H)2.86(d,J=10.53 Hz,4 H)2.53-2.68(m,6 H)2.01(br.s.,7 H)1.93-2.04(m,2 H)1.80(br.s.,4 H)1.77(br.s.,3 H)1.42(br.s.,2 H)

[0299] Example C-66: Preparation of 3-(1-(3-(5-((1-((4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)phenyl)glycy)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001262) [ka] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-one in 0.6 ml of DMSO DIPEA (200 μmol) was added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (36 μmol) and 3-(7-(4-(4-aminophenyl)piperazin-1-yl)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (36 μmol) and stirred at 90° C. for 16 hours. The reaction mixture was analyzed by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The resulting product was purified by column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) and 4.5 mg of 3-(1-(3-(5-((1-(4-(4-(4-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)phenyl)glycy)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was used. MS (ESI, m / z): [M+H] + =965.8 1H NMR(500 MHz,DMSO-d6)δ ppm 10.99(s,1H),8.65(s,2H),8.38(m,2H),8.24(m,2H),8.17(d,J=9.8 Hz,1H),7.94(d,J=9 Hz,1H),7.80(d,J=7.6 Hz,1H),7.72(t,J=7.9 Hz,1H),7.58(m,1H),7.49(brd,2H),7.26(d,J=9.8 Hz,1H),7.17(d,J=9.6 Hz,2H),6.84(d,J=9.6 Hz,2H),6.64(m,1H),6.54(s,1H),5.71(m,1H),5.44(s,2H),5.32(s,2H),4.5 8(m,1H),4.45(m,1H),4.10-4.03(m,2H),3.86(m,1H),3.72(m,1H),3.58-3.4 7(m,2H),3.40-3.35(m,2H),3.40-3.37(m,2H),3.00(brd,2H),2.91(m,1H),2 .65-2.55(m,2H),2.47(s,3H),2.08(m,2H),1.63(m,2H),1.38-1.10(brd,2H)

[0300] Example C-67: Preparation of 3-(1-(3-(5-((1-(2-(4-(1-(3-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidin-4-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001270) Step 1) Preparation of benzyl 4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-4-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (670 mg, 5.19 mmol) was added to a solution of 3-(7-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (524 mg, 1.73 mmol) in DMA (3 mL) at room temperature. The reaction was stirred at 130° C. for 16 hours. After cooling, the reaction was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC with 100% ethyl acetate. The title compound (678 mg) was obtained. MS (ESI, m / z): [M+H] + =573.3.

[0301] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(4-(piperazin-1-yl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] Pd / C 10% (500 mg) was added to a solution of benzyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl]piperidin-4-yl}piperazine-1-carboxylate (1 g, 1.75 mmol) in ethanol (10 mL) at room temperature. The reaction was quenched by attaching a H2 balloon and stirred at room temperature for 16 hours. After cooling, the reaction was filtered and the filtrate was concentrated to give the title compound (780 mg), which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =389.5.

[0302] Step 3) Preparation of 3-(1-(3-(5-((1-(1-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperidin-4-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001270) [ka] Triethylamine was added to 3-(1-{[3-(5-{[1-(2-chloroacetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (50 mg, 90.1 μmol) and 3-{4-methyl-1-oxo-7-[4-(piperazin-1-yl)piperidin-1-yl]-1,2-dihydrobutalazin-2-yl}piperidine-2,6-dione (39.5 mg, 90.1 μmol) in DMF (5 ml). The reaction was stirred at 45° C. for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Concentration under reduced pressure and purification by column chromatography gave the title compound (49 mg). MS (ESI, m / z): [M+H] + =957.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.99(s,1 H)8.61-8.71(m,2 H)8.35-8.41(m,2 H)8.21-8.27(m,2 H)8.12-8.21(m,2 H)7.91-7.96(m,1 H)7.68-7.75(m,2 H)7.46-7.53(m,3 H)7.12-7.19(m,1 H)5.40-5.46(m,2 H)4.38(d,J=12.36 Hz,1 H)4.09(d,J=11.29 Hz,3 H)3.89-3.99(m,1 H)3.47-3.70(m,3 H)3.26(d,J=13.43 Hz,2 H)2.81-3.04(m,6 H)2.54-2.65(m,4 H)2.42-2.47(m,5 H)2.03-2.12(m,2 H)1.75-1.88(m,4 H)1.44(br.s.,1 H)1.39(s,2 H)1.17-1.35(m,3 H)1.14(d,J=7.78 Hz,1 H)

[0303] Example C-68: Preparation of 3-(1-(3-(5-((1-(2-(4-(((2R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001271) Step 1) Preparation of tert-butyl (2R)-2-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-4-carboxylate [ka] Potassium carbonate (6.04 g, 43.7 mmol) was slowly added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (5.8 g, 21.9 mmol) and tert-butyl (S)-2-((tosyloxy)methyl)morpholine-4-carboxylate (7.22 g, 32.8 mmol) in DMF (50 ml) and stirred at 85° C. for 17 hours. The reaction mixture was diluted with 200 ml of EA and washed with water and brine solution. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by reverse phase column chromatography to give the title compound (3.87 g). MS (ESI, m / z): [M+H] + =555.6.

[0304] Step 2) Preparation of 3-(4-methyl-7-(4-(((S)-morpholin-2-yl)methyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (1 ml) was added to a solution of tert-butyl (2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate (200 mg, 0.5 mmol) in DCM (3 ml) and stirred at room temperature for 2 hours. 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 a NH-DM 1020 chromatrex pad to obtain the target compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =455.6.

[0305] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(2-((2R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001271) [ka] Ethyl bis (45ul, 0.26mmol) was added to 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50mg, 0.09mmol) and 3-(4-methyl-7-(4-((S)-morpholin-2-yl)methyl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (40mg, 0.09mmol) in DMF (1ml) at room temperature. The reaction was stirred for 6 hours. It was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC in DCM / MeOH (0-10%) to give the title compound. MS (ESI, m / z): [M+H] + =974.1 1H NMR(500 MHz,DMSO-d6)δ ppm 10.95(s,1 H)8.65(s,1 H)8.67(s,1 H)8.33-8.40(m,2 H)8.31(s,1 H)8.23(br.s.,2 H)8.11-8.20(m,1 H)7.97-8.09(m,1 H)7.88-7.94(m,1 H)7.66-7.75(m,1 H)7.45-7.50(m,2 H)7.13-7.18(m,1 H)5.66(br.s.,1 H)5.39-5.46(m,2 H)4.38(br.s.,1 H)4.07(br.s.,3 H)3.76(br.s.,1 H)3.63(br.s.,1 H)3.44 -3.53(m,4 H)3.41(br.s.,6 H)3.02(d,J=13.58 Hz,2 H)2.89(br.s.,1 H)2.73-2.83(m,1 H)2.62(d,J=14.19 Hz,4 H)2.55(d,J=8.85 Hz,4 H)2.15(d,J=12.82 Hz,1 H)2.07(br.s.,2 H)1.95-2.04(m,2 H)1.86-1.95(m,2 H)1.82(br.s.,2 H)

[0306] Example C-69: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001272) [ka] Triethylamine (18.2 mg, 180 μmol) was dissolved in 3-(1-{[3-(5-{[1-(2-chloroacetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (50 mg, 90.1 μmol) and 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidine-4-yl)phenyl)methyl)benzonitrile (40 mg, 10 μmol) in DMF (2 ml). To the resulting solution was added 42.4 mg (90.1 μmol) of 4-(piperidin-4-yl)piperazine-1-(4-(piperidin-4-yl)piperazine-2(1H)-yl)piperidine-2,6-dione. The reaction was stirred at 45° C. for 4 hours. The reaction was poured into water. The ethyl acetate organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the title compound (71 mg). MS (ESI, m / z): [M+H] + =990.1 1H NMR(500 MHz,DMSO-d6)δ ppm 12.04(s,1 H)9.69(s,2 H)9.44(s,1 H)9.40(s,1 H)9.27(d,J=7.17 Hz,2 H)9.20-9.23(m,1 H)8.96(d,J=7.63 Hz,1 H)8.87(d,J=12.97 Hz,1 H)8.75(t,J=7.86 Hz,1 H)8.50-8.56(m,2 H)8.29(d,J=8.09 Hz,1 H)8.19(d,J=9.61 Hz,1 H)6.75(d,J=7.32 Hz,1 H)6.43-6.54(m,2 H)5.43(d,J=12.66 Hz,1 H)5.09-5.19(m,3 H)4.24-4.38(m,4 H)4.01-4.11(m,2 H)3.90-4.01(m,1 H)3.86(br.s.,2 H)3.57-3.70(m,3 H)3.21(d,J=7.02 Hz,2 H)2.98-3.17(m,3 H)2.68-2.89(m,3 H)2.38(d,J=10.68 Hz,1 H)2.08-2.25(m,2 H)1.04(s,2 H)

[0307] Example C-70: Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001276) Step 1) Preparation of 3-(1-{[3-(5-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Cesium carbonate (4.0 equivalents) was added to a solution of 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (2.75 g, 5.75 mmol) and 2-bromoethan-1-ol (7.18 g, 57.5 mmol) in ACN (300 ml). Cesium carbonate (4.0 equivalents) was added to a solution of 3-{6-oxo-1-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1,6-dihydropyridazin-3-yl}benzonitrile (2.75 g, 5.75 mmol) and 2-bromoethan-1-ol (7.18 g, 57.5 mmol). The reaction was stirred at 70°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-5%). Title compound (2.5g) MS (ESI, m / z): [M+H] + =523.6

[0308] Step 2) Preparation of 2-[4-({[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihyd...

Claims

1. A compound represented by the following chemical formula 1: [Chemical formula 1] cMET target protein binding portion (P)-{linker (L)}p-E3 ligase binding portion (E) During the ceremony, The E3 ligase binding moiety (E) is a compound represented by the following chemical formula 2: The cMET target protein binding moiety (P) is a compound represented by any one of formulas 3 to 7: p is an integer of 0 or 1; [Chemical formula 2] 【Chemistry 1】 [Chemical formula 3] 【Chemistry 2】 [Chemical formula 4] 【Transformation 3】 [Chemical formula 5] 【Chemistry 4】 [Chemical formula 6] 【Transformation 5】 [Chemical formula 7] 【Transformation 6】 [Chemical formula 8] 【Transformation 7】 [Chemical formula 9] 【Transformation 8】 [Chemical formula 10] 【Chemistry 9】 During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 straight or branched chain alkyl, or an oxygen- or nitrogen-containing heterocycle of 4-8 atoms; 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 hydrogen, halogen, or C1-C6 straight, branched, or cyclic alkyloxy unsubstituted or substituted with halogen; However, Q ５ and Q ６ When one of the groups is a carbon atom, the other is a nitrogen atom, and f Z is a carbon atom or a nitrogen atom, R １ is hydrogen, nitro, amino, carbonyl, C1-C6 straight, branched or cyclic alkyl, or C1-C6 straight, branched or cyclic alkyl substituted with halogen.

2. One end of the linker (L) is (i) is connected to the structure of formula 1 by replacing X in the structure of formula 2; or (ii) is connected to the structure of formula 1 by bonding to the nitrogen atom or oxygen atom of X in the structure of formula 2; (iii) directly connected to the benzene ring of the structure of Chemical Formula 3; (iv) directly connected to the amino group located at the terminal of the structure of Chemical Formula 4; (v) directly connected to the triazole ring of the structure of Formula 5; or (vi) The compound of claim 1, wherein the compound is directly connected to the pyridine ring of the structure of formula 6.

3. In paragraph 2, the other end of the linker (L) is connected to a compound linked to piperidine or piperazine located at the end of any one of the structures of formulas 7 to 10.

4. In paragraph 1: The linker (L) is 【Chemistry 10】 a structure selected from the group consisting of the following formulas: 【Chemistry 11】 In the formula, R ２ and R ３ are each independently -(CH ２ ) ｓ -, -(CH ２ ) ｔ -[O(C ２ H ４ )] ｕ -, -O-(CH ２ )-, -CH(OH)-piperazine, piperidine, azetidine, -(CH ２ ) ｖ -piperidine, -(CH ２ ) ｖ -piperazine, piperazine-(CH ２ ) ｖ -piperidine, piperazine-(CH ２ ) ｖ -morpholine, piperidine-(CH ２ ) ｖ -morpholine, azetidine-(CH ２ ) ｖ -piperazine, azetidine-(CH ２ ) ｖ -piperidine, benzene-piperidine, benzene-piperazine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-piperazine, benzene, triazole or pyrrolidine, 2. The compound of claim 1, wherein m, n, q, r, s, t, u, v, and w are each independently an integer selected from 0 to 7.

5. The following compounds: 3-{6-[(4-{4-[(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}phenyl)methyl]piperazin-1-yl}-4-oxobutyl)amino]-1-oxo-1,2-dihydroptalazin-2-yl}piperidine-2,6-dione, 3-{6-[(6-{4-[(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}phenyl)methyl]piperazin-1-yl}-6-oxohexyl)amino]-1-oxo-1,2-dihydroptaladin-2-yl}piperidine-2,6-dione, 3-(6-((5-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)5-oxophthyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-((7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)7-oxoheptyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-((2-(2-(2-(2-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-[6-(12-{4-[(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}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptalazin-2-yl]piperidine-2,6-dione, 3-[6-(15-{4-[(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-dei}phenyl)methyl]piperazin-1-yl}-15-oxo-4,7,10,13-tetraoxa-1-azpentadecan-1-yl)-1-oxo-1,2-dihydroptalazin-2-yl]piperidine-2,6-dione, 3-(8-((2-(2-(3-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl})benzyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoptalazine-2-(1H)-yl]piperidine-2,6-dione, 3-[8-(12-{4-[(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}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodecan-1-yl)-1-oxo-1,2-dihydroptalazin-2-yl]piperidine-2,6-dione, 3-[8-(16-{4-[(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}phenyl)methyl]piperazin-1-yl}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-1-oxo-1,2-dihydropetalazin-2-yl]piperidine-2,6-dione, 3-{8-[(5-{4-[(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}phenyl)methyl]piperazin-1-yl}-5-oxopentyl)amino]-1-oxo-1,2-dihydroptalazin-2-yl}piperidine-2,6-dione, 3-{8-[(7-{4-[(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}phenyl)methyl]piperazin-1-yl}-7-oxoheptyl)amino]-1-oxo-1,2-dihydroptalazin-2-yl}piperidine-2,6-dione, 3-[8-({2-[2-(3-{4-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine-4-dei]pyrimidin-5-dei}phenyl)methyl]piperazin-1-yl}-3-oxopropoxy)ethoxy]ethyl}amino)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione, 3-(8-((21-(4-(4-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)21-oxo-3,6,9,12,15,18-hexaoxahenicosyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(8-((4-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)4-oxobutyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(8-((6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)6-oxohexyl)amino)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-((1-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(4-methyl-8-((2-(4-(4-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethyl)amino)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-(2-(4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-((3-fluoro-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-((2-fluoro-4-(4-(2-(4-(4-(2-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-((3-fluoro-4-(4-(2-(4-(4-(2-(2-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazine-1-dei)acetyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-(1-(3-(5-((1-(1-(1-(3-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((1-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-((3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-5-yl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-6-yl]amino}hexanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(7-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}heptanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-{1-[(3-{5-[(1-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}ethoxy)ethoxy]acetyl}piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile, 3-(1-{[3-(5-{[1-(2-{2-{2-(2-{2-{2-{2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl]amino}ethoxy)ethoxy}ethoxy}piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]amino}-3,6,9,12-tetratetradecanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(6-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)amino)hexanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(14-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)3,6,9,12-tetradedecanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)amino)3,6,9,12-tetraoxapentadecan-15-oyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-ylpiperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(4-(5-((1-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(5-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}-2-oxoethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3-yl)piperazin-1-yl)methyl-1-yl)methyl-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazin-1-yl}butanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}pentanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-6-yl)pent-4-rin-1-yl)acetamide, 2-(4-(((2-(3-(3-(3-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)-N-(5-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dihydroptalazin-6-yl)pentyl)acetamide, 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)phenyl)acetamide, 3-(1-(3-(5-((1-(2-(4-((1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(3-(3-(3-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrobutalazin-6-yl)piperazin-1-yl)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(5-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptaladin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazine-1-carbonyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((1-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperidin-4-yl)amino)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}-3-oxopropyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(3-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((2R)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile 6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-methyl-4-oxo-3,4-dihydropetalazin-6-yl)piperazin-1-yl)methylpiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(3-(3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)azetidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(1-(1-(3-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((1-(1-(2-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(3-((4-(2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methylazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)piperidin-1-yl)piperidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, N-(3-(2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetamido)propyl)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidine-4-carboxamide, 3-(1-(3-(5-((1-(2-(4-((1-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)phenyl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(5-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl)piperazin-1-yl)-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methylazetidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-((6R)-6-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methyl)1,3-oxazinan-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile 6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)piperidin-1-yl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(1-(1-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazine-1-carbonyl)azetidin-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-((2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)methyl)morpholino)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-((4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydraptalazin-6-yl)piperazin-1-yl)phenyl)glycy)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(1-(3-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperidin-4-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((2R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)morpholin-2-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile 6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[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]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl]piperazin-1-yl}ethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(4-(5-((1-(5-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-5-yl)pentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(4-(5-((1-(5-(5-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-5-yl)pent-4-yn-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)pentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(5-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)pent-4-phospho-1-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptalazin-5-yl)prop-2-rin-1-yl)oxy)ethoxy)ethoxy)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-((2R)-2-((4-(2-(2-(2-(dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)methyl)morphopolyno)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4,7-dimethyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile 6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile 3-(1-(3-(5-((1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)azetidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-methyl-4-oxo-3,4-dihydroptalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-{1-[(3-{5-[(1-{[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]methyl}piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile, 3-(1-(3-(5-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-((1-(1-((1-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)ethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(3-((4-((2,6-dioxopiperidin-3-yl)amino)2-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(2-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)methyl]piperidin-1-yl}-2-oxoethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(3-((4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(3-((4-((4-((4-(4-((4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)phenyl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-{[3-(5-{[1-(2-{4-[(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)methyl]piperazin-1-yl}-2-oxoethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-((1-(1-(2-(4-((4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(4-((1-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydroptarazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(4-((1-(3-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzonitrile, 3-(1-(3-(5-(4-(3-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)-2-hydroxypropyl)piperazin-1-dei)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, and 3-(1-(3-(5-(4-(3-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)-2-hydroxypropyl)piperazin-1-yl)pyrimidin-2-yl)benzo)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.

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

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