Degradation agent for degrading cMET protein and pharmaceutical composition comprising same

Abstract

The present invention relates to a novel protein degradation targeting chimera (protac) compound that binds to cMET protein, and a pharmaceutical composition comprising the same. The present invention relates to a protein degradation targeting chimera (protac) compound that binds to cMET protein, which can bind to and decompose cMET protein, and thus can be effectively used for treating or preventing diseases associated with cMET protein. The compound of the present invention has an excellent anti-cancer effect, and can exhibit a therapeutic effect on cMET-related diseases by inducing decomposition of cMET protein.

Description

Technical Field

[0001] The present invention relates to a novel PROTAC compound that binds to the cMET protein and a pharmaceutical composition comprising the novel PROTAC compound. Background Art

[0002] PROTAC is a heterodimeric molecule in which the ligand of the target protein and the ligand bound to the E3 ligase are linked together by a linker. PROTAC binds to both proteins simultaneously, bringing the target protein very close 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 in cells, PROTAC can be used as a chemical probe for studying the function of target proteins, and in addition, it has great potential in treating diseases. The term TPD (targeted protein degradation) is sometimes used instead of the term PROTAC.

[0003] In the present invention, a target protein binding portion and an E3 ligase binding portion that bind to the cMET protein are prepared, and the E3 ligase binding portion is linked to the cMET protein target binding portion through a linker to complete the PROTAC compound.

[0004] Detailed description of the invention

[0005] [Technical Challenges]

[0006] The technical challenges to be solved by the present invention relate to PROTAC and its pharmaceutical composition, in which a novel E3 ligase binding portion is connected to a cMET protein target binding portion via a linker.

[0007] [Technical Solution]

[0008] In order to complete the technical task, the present invention provides a TPD compound or a pharmaceutically acceptable salt thereof, which is represented by the following Chemical Formula 1:

[0009] [Chemical Formula 1]

[0010] cMET targeting protein binding portion (P)-{linker (L)}p-E3 ligase binding portion (E)

[0011] in,

[0012] The E3 ligase binding moiety (E) is a compound represented by the following Chemical Formulas 2 to 6; and

[0013] The cMET targeting protein binding portion (P) is a compound represented by any one of the following Chemical Formulas 7 to 10; and

[0014] p is an integer of 0 or 1 (if p is 0, P and E are directly connected):

[0015] [Chemical Formula 2]

[0016]

[0017] [Chemical Formula 3]

[0018]

[0019] [Chemical Formula 4]

[0020]

[0021] [Chemical Formula 5]

[0022]

[0023] [Chemical Formula 6]

[0024]

[0025] [Chemical Formula 7]

[0026]

[0027] [Chemical Formula 8]

[0028]

[0029] [Chemical Formula 9]

[0030]

[0031] [Chemical Formula 10]

[0032]

[0033] in,

[0034] X is hydrogen, halogen, amino, nitro, hydroxy, C1 to C6 straight or branched chain alkyl, or a 4 to 8 atom heterocycle containing oxygen or nitrogen;

[0035] Q1 to Q4 are each independently CF, C—Cl, CH, CX or N, and at least any one of Q1 to Q4 is CX;

[0036] Y is hydrogen, halogen, or unsubstituted or halogen-substituted C1 to C6 linear, branched, or cyclic alkoxy;

[0037] One of Q5 and Q6 is a carbon atom, and the other is a nitrogen atom;

[0038] Z is a carbon atom or a nitrogen atom; and

[0039] R 1 It is hydrogen, nitro, amino, carbonyl, C1 to C6 linear, branched or cyclic alkyl, or C1 to C6 linear, branched or cyclic alkyl substituted by halogen.

[0040] In the present invention, one end of the linker (L) may be

[0041] (i) connecting to the structure in Chemical Formula 1 by substituting X in the structure in Chemical Formula 2;

[0042] (ii) connected to the structure in Chemical Formula 1 by bonding to the nitrogen atom or oxygen atom of X in the structure in Chemical Formula 2;

[0043] (iii) directly connected to the benzene ring of the structure of Chemical Formula 3;

[0044] (iv) directly linked to the amino group located at the terminal of the structure of Chemical Formula 4;

[0045] (v) directly linked to the triazole ring of the structure of Chemical Formula 5; or

[0046] (vi) directly linked to the pyridine ring of the structure of Chemical Formula 6, and the other end of the linker (L) may be linked to a compound linked to piperidine or piperazine located at the end of any structure of Chemical Formulas 7 to 10.

[0047] In the present invention, one end of the linker (L) is

[0048]

[0049] or

[0050] may have a structure selected from the group consisting of:

[0051]

[0052] wherein 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, phenyl-piperidine, phenyl-piperazine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-piperazine, benzene, triazole or pyrrolidine; and

[0053] m, n, q, r, s, t, u, v and w are each independently an integer selected from 0 to 7.

[0054] The present invention also provides an anticancer composition, which comprises any of the above compounds.

[0055] [Effects of the Invention]

[0056] The present invention relates to a PROTAC compound that binds to a cMET protein. Since the PROTAC compound can bind to and degrade the cMET protein, the PROTAC compound can be used to treat or prevent diseases associated with the cMET protein. The compound of the present invention has excellent anti-cancer effects and can also induce the degradation of the cMET protein, which can show therapeutic effects on cMET-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 Schematic diagram of a PROTAC compound consisting of an E3 ligase binding portion, a linker, and a target protein binding portion. DETAILED DESCRIPTION

[0058] The present invention will be described in more detail below. However, the present invention can be implemented in various forms and is not limited to the embodiments described herein.

[0059] The terms used herein are only used to describe specific embodiments and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly implies otherwise. In the specification of the present invention, 'comprising' a certain component means that it may include more other components, rather than excluding other components, unless there is a special statement to the contrary.

[0060] The PROTAC according to the present invention may be a compound represented by Chemical Formula 1:

[0061] [Chemical Formula 1]

[0062] cMET target protein binding part (P) - linker (L) - E3 ligase binding part (E)

[0063] The basic structure of the E3 ligase binding portion according to the present invention can be prepared by the following reaction formula 1 or reaction formula 2.

[0064] [Reaction Equation 1]

[0065]

[0066] [Reaction Equation 2]

[0067]

[0068] In the above reaction formula 1 or 2, X is hydrogen, halogen, amino, nitro, hydroxyl, piperazine group or C1 to C4 alkoxy group. However, for the sake of convenience of explanation, in the above formula, the substituents that can be bonded to carbon in Q1 to Q4 of the compound of Chemical Formula 1 are not shown, and R 1 The substituents are shown as examples only of simple substituents such as hydrogen or methyl.

[0069] Hereinafter, specific examples of E3 ligase binding moiety compounds are prepared using Examples.

[0070] Example A: Preparation of E3 ligase conjugated compound

[0071] Example A-1: ​​Compound Preparation (prepared according to formula 1)

[0072] 1-1) Preparation of methyl 2-methyl-6-nitrobenzoate

[0073]

[0074] 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].

[0075] 1-2) Preparation of methyl 2-(bromomethyl)-6-nitrobenzoate

[0076]

[0077] At room temperature, 1-bromomerolidine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carbon peroxyester (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 ClCH2CH2Cl (100 ml). The reactants were heated and refluxed for 3 hours. The time point when the red color disappeared was the time when the reaction was completed. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0078] 1-3) Preparation of methyl 2-formyl-6-nitrobenzoate

[0079]

[0080] At room temperature, NMO (N-methylmorpholine N-oxide) (561 mg, 4.87 mmol) and Molecular sieves were sequentially added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reactant 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, and the title compound was obtained as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0081] 1-4) Preparation of 2-formyl-6-nitrobenzoic acid

[0082]

[0083] 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 reactant was concentrated under reduced pressure to dry THF. After cooling to 0 ° C, the reactant was acidified with 1N HCl and the pH was adjusted to 4. The reactant was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M + 1] + =[195.2].

[0084] 1-5) Preparation of 8-nitrophthalazin-1(2H)-one

[0085]

[0086] At room temperature, NH2NH2 monohydrate (417mg, 8.33mmol) is added to a solution of 2-formyl-6-nitrobenzoic acid (1.2g, 6.15mmol) in methanol (10ml). After stirring for 30 minutes, the reactant is heated to 80°C for 2 hours. The reactant is cooled to room temperature and concentrated under reduced pressure. The residue is poured into water (50ml) and extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer is dried over magnesium sulfate, concentrated under reduced pressure, and white crystals (1g, 85.07%) are obtained. MS (ESI, m / z): [M+1] + =[191.8].

[0087] 1-6) Preparation of 3-(8-nitro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0088]

[0089] 3-Bromopiperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) are added sequentially to a solution of 8-nitro-1,2-dihydrodroplasine-1-one (60 mg, 0.314 mmol) in DMF (1 ml). The reactant is heated to 85 ° C for 5 hours. After cooling, the reactant is poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography, and the title compound (68 mg, 71.7%) is obtained as white crystals. MS (ESI, m / z): [M+1] + =[302.6].

[0090] 1-7) Preparation of 3-(8-nitro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0091]

[0092] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(8-nitro-1-oxo-1,2-dihydrophthalazin-2-yl) in methanol (5 ml) and stirred under hydrogen for 1 hour under a balloon. The solid was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound in 99% yield. MS (ESI, m / z): [M+1] + =[272.3].

[0093] [NMR] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.10(s,1H),7.46(t,J=7.83Hz,1H),7.22(br s,2H),6.86(d,J=7.83Hz,1H),6.81(d,J=7.34Hz,1H),5.61(brdd,J=5.2,11.92Hz,1H),2.77-2.89(m,1H),2.46-2.57(m,2H),1.95-2.08(m,1H)

[0094] Example A-2: Compound Preparation

[0095] 2-1) Preparation of methyl 2-methyl-3-nitrobenzoate

[0096]

[0097] 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].

[0098] 2-2) Preparation of methyl 2-(bromomethyl)-3-nitrobenzoate

[0099]

[0100] At room temperature, 1-bromophilidine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carbon peroxyester (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 ClCH2CH2Cl (100 ml). The reactants were heated and refluxed for 3 hours. The time point when the red color disappeared was the time when the reaction was completed. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0101] 2-3) Preparation of methyl 2-formyl-3-nitrobenzoate

[0102]

[0103] At room temperature, NMO (561 mg, 4.87 mmol) and Molecular sieves were sequentially added to a solution of methyl 2-(bromomethyl)-3-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reactant 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, and the title compound was obtained as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0104] 2-4) Preparation of 2-formyl-3-nitrobenzoic acid

[0105]

[0106] 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 reactant was concentrated under reduced pressure to remove THF. After cooling to 0 ° C, the residue was acidified with 1N HCl and the pH was adjusted to 4. The reactant was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M + 1] + =[195.2].

[0107] 2-5) Preparation of 5-nitrophthalazin-1(2H)-one

[0108]

[0109] At room temperature, NH2NH2 monohydrate (417mg, 8.33mmol) is added to a solution of 2-formyl-3-nitrobenzoic acid (1.2g, 6.15mmol) in methanol (10ml). After stirring for 30 minutes, the reactant is heated to 80°C for 2 hours. The reactant is cooled to room temperature and concentrated under reduced pressure. The residue is poured into water (50ml) and extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer is dried over magnesium sulfate, concentrated under reduced pressure, and white crystals (1g, 85.07%) are obtained. MS (ESI, m / z): [M+1] + =[191.8].

[0110] 2-6) Preparation of 3-(5-nitro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0111]

[0112] 3-Bromopiperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 5-nitrophthalazine-1 (2H) -one (60 mg, 0.314 mmol) in DMF (1 ml). The reactant was heated to 85 ° C for 5 hours. After cooling, the reactant was poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography, and the title compound (68 mg, 71.7%) was obtained as white crystals. MS (ESI, m / z): [M + 1] + =[302.4].

[0113] 2-7) Preparation of 3-(5-amino-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0114]

[0115] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(5-nitro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (25 mg, 0.82 mmol) in methanol (5 ml) and stirred under hydrogen for 1 hour under a balloon. The solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound in 99% yield. MS (ESI, m / z): [M+1]+ =[272.3].

[0116] [NMR] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.20-8.41(m,3H),8.08(s,1H),7.83(d,J=8.93Hz,1H),6.95(d,J =10.5Hz,1H), 5.64(brdd,J=4.83,11.31Hz,1H), 2.62-2.89(m,1H),2.52-2.60(m,2H),1.86-2.07(m,1H)

[0117] Example A-3: Compound Preparation

[0118] 3-1) Preparation of methyl 2-fluoro-6-methylbenzoate

[0119]

[0120] 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, yield 103%) MS (ESI, m / z): [M + 1] + =[168.3].

[0121] 3-2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate

[0122]

[0123] At room temperature, 1-bromomerrolidine-2,5-dione (24.7g, 139mmol) and benzoylbenzene carbon peroxyester (1.53g, 6.30mmol) were added sequentially to a solution of methyl 2-fluoro-6-methylbenzoate (21.2g, 126mmol) in ClCH2CH2Cl (250ml). The reactants were heated and refluxed for 16 hours. The time point when the red color disappeared was the time when the reaction was completed. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product can be used for subsequent reactions without further purification. (35g, yield 112%) MS (ESI, m / z): [M+1] + =[245.9].

[0124] 3-3) Preparation of methyl 2-fluoro-6-formylbenzoate

[0125]

[0126] At room temperature, NMO (24.9g, 212mmol) was added to a solution of methyl 2-(bromomethyl)-6-fluorobenzoate (35g, 142mmol) in DCM (280ml). The reactant was stirred at room temperature for 4 hours. The DCM layer was washed with water (200ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography, and the title compound was obtained as a white solid. (11.52g, yield 45%) MS (ESI, m / z): [M+1] + =[183.1].

[0127] 3-4) Preparation of 2-fluoro-6-formylbenzoic acid

[0128]

[0129] At room temperature, lithium hydroxide (7.57g, 180mmol) aqueous solution (41ml) is added to a solution of methyl 2-fluoro-6-formylbenzoate (11.5g, 63.2mmol) in THF (82ml). After stirring for 4 hours, the reactant is concentrated under reduced pressure and the THF is dried. After cooling to 0°C, the reactant is acidified with 1N HCl and the pH is adjusted to 4. The reactant is extracted twice with ethyl acetate (100ml). The combined ethyl acetate layer is dried over magnesium sulfate, concentrated under reduced pressure, and white crystals (10.4g, 97.8%) are obtained. MS (ESI, m / z): [M+1] + =[168.8].

[0130] 3-5) Preparation of 8-fluorophthalazin-1(2H)-one

[0131]

[0132] 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 obtained white crystals were ground with 100 ml of ethyl acetate (EA) and filtered to obtain white crystals (3.05 g, 30%). MS (ESI, m / z): [M+1] + =[164.8].

[0133] 3-6) Preparation of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0134]

[0135] At 0 ° C, NaH (60%, 53.6 mg, 1.34 mmol) is added to a solution of 8-fluorophthalazine-1 (2H) -one (200 mg, 1.22 mmol) in DMF (5 ml) and stirred for 30 minutes. 3-Bromopiperidine-2,6-dione (468 mg, 2.44 mmol) is added to the solution and stirred for 6 hours. The reaction is terminated with water and extracted twice with ethyl acetate (20 ml). The mixed ethyl acetate is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography, and the title compound (70 mg, 20.8%) is obtained as white crystals. MS (ESI, m / z): [M + 1] + =[276.1]. [NMR] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.48(s,1H),7.99(ddd,J=4.6,7.2,8.2Hz,1H),7.80(d,J=7.2Hz,1H),7.6 7 (dd, J=8.2, 11.4Hz, 1H), 5.77 (dd, J=5.3, 12.0HZ, 1H), 2.99-2.77 (m, 1H), 2.68-2.51 (m, 2H), 2.23-2.02 (m, 1H)

[0136] Example A-4: Compound Preparation

[0137] 4-1) Preparation of methyl 5-fluoro-6-methylbenzoate

[0138]

[0139] 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 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].

[0140] 4-2) Preparation of methyl 2-(bromomethyl)-3-fluorobenzoate

[0141]

[0142] At room temperature, 1-bromomerolidin-2,5-dione (15.9 g, 89.2 mmol) and benzoylbenzene carbon peroxy ester (0.72 g, 2.97 mmol) were added sequentially to a solution of methyl 3-fluoro-2-methylbenzoate (10 g, 59.5 mmol) in ClCH2CH2Cl (250 ml). The reactants were heated and refluxed for 16 hours. The time point when the red color disappeared was the time when the reaction was completed. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification. (10.5 g, yield 71%) MS (ESI, m / z): [M+1] + =[245.9].

[0143] 4-3) Preparation of methyl 3-fluoro-2-formylbenzoate

[0144]

[0145] At room temperature, NMO (10.4 g, 89 mmol), 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 obtain the title compound. (5.5 g, 75%) MS (ESI, m / z): [M+1] + =[183.1].

[0146] 4-4) Preparation of 3-fluoro-2-formylbenzoic acid

[0147]

[0148] At room temperature, lithium hydroxide monohydrate (2.88g, 68.6mmol) aqueous solution (41ml) is added to a solution of 3-fluoro-2-formylbenzoic acid methyl ester (2.5g, 13.7mmol) in THF (68ml). After stirring for 4 hours, the reactant is concentrated under reduced pressure, and THF is removed. After cooling to 0°C, the reactant is acidified with 1N HCl, and the pH is adjusted to 4. The reactant is extracted twice with ethyl acetate (100ml). The combined ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (2.5g, 108%). MS (ESI, m / z): [M+1] + =[168.8].

[0149] 4-5) Preparation of 5-fluoro-1,2-dihydrophthalazin-1-one

[0150]

[0151] 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 THF: water = 1: 1 (70 ml) and stirred for 16 hours. The mixture was acidified to pH 4, and the solid was filtered and washed with hexane. The title compound (1.3 g, 53%) was obtained by vacuum drying. MS (ESI, m / z): [M+1] + =[165.3]

[0152] 4-6) Preparation of 3-(5-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione

[0153]

[0154] At 0 ° C, LDA (lithium diisopropylamide, 2.19 mmol) was added to a solution of 5-fluorophthalazin-1-one (300 mg, 1.83 mmol) in DMF (10 ml) and stirred for 30 minutes. 3-Bromopiperidine-2,6-dione (526 mg, 2.74 mmol) was added to the solution and stirred at 80 ° C for 6 hours. After the reaction was completed, the reactant was cooled to room temperature, poured into water (100 ml), the pH was adjusted to 3-4 with 6N HCl, then extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The product was recrystallized into hexane, dried in vacuo, and the title compound was obtained. MS (ESI, m / z): [M + 1] + =[276.1].

[0155] [NMR] 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.53 (s, 1H), 8.05 (d, J = 7.82Hz, 1H), 7.76-7.90 (m, 2 H), 5.78 (dd, J=12.23, 5.26Hz, 1H), 2.80-2.93 (m, 1H), 2.47-2.61 (m, 2H), 2.01-2.16 (m, 1H)

[0156] Example A-5: Compound Preparation

[0157] 5-1) Preparation of methyl 4-fluoro-6-methylbenzoate

[0158]

[0159] According to the preparation method of Example 4-1, methyl 4-fluoro-2-methylbenzoate was prepared from 4-fluoro-2-methylbenzoate.

[0160] 5-2) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate

[0161]

[0162] At room temperature, 1-bromophilolidin-2,5-dione (31.8 g, 178 mmol) and benzoylbenzene carbon peroxy ester (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 4-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CH2Cl (100 ml). The reactants were heated and refluxed for 3 hours. The time point when the red color disappeared was the time when the reaction was complete. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by MPLC (HX / EAEA 0->5%) (22 g, yield 75%). MS (ESI, m / z): [M+1] + =[248.4].

[0163] 5-3) Preparation of methyl 3-fluoro-2-formylbenzoate

[0164]

[0165] At room temperature, NMO (15.6 mg, 134 mmol) and Molecular sieves were sequentially added to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22 g, 89 mmol) in DCM (100 ml). The reactant 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, and the title compound was obtained as a white solid. (12 g, 73.98%) MS (ESI, m / z): [M+1] + =[183.2].

[0166] 5-4) Preparation of 4-fluoro-2-formylbenzoic acid

[0167]

[0168] At room temperature, lithium hydroxide (13.8g, 329mmol) aqueous solution (50ml) is added to a solution of 4-fluoro-6-formylbenzoic acid methyl ester (12g, 65.9mmol) in THF (50ml). After stirring for 2 hours, the reactant is concentrated under reduced pressure to dry THF. After cooling to 0°C, the reactant is acidified with 1N HCl and the pH is adjusted to 4. The reactant is extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer is dried over magnesium sulfate, concentrated under reduced pressure, and white crystals (10g, 90.3%) are obtained. MS (ESI, m / z): [M+1] + =[169.2].

[0169] 5-5) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one

[0170]

[0171] At room temperature, NH2NH2 monohydrate (2.02g, 40.3mmol) was added to a solution of 4-fluoro-2-formylbenzoic acid (6.78g, 40.3mmol) in methanol (50ml). After stirring for 30 minutes, the reactant was heated to 80°C for 2 hours. The reactant was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150ml) and extracted twice with ethyl acetate (150ml). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (5.5g, 83.07%). MS (ESI, m / z): [M+1] + =[165.3].

[0172] 5-6) Preparation of 3-(6-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0173]

[0174] At 0 ° C, 2-methylpropane-2-sodium oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluorophthalazine-1-one (100 mg, 0.609 mmol) in DMF (2 ml). After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (90 mg, 0.471 mmol) was added to the reaction mixture and stirred at room temperature for 6 hours. Water (20 ml) was poured into the reaction mixture and extracted twice with ethyl acetate (20 ml). The mixed ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography, and the title compound (110 mg, 65.5%) was obtained as white crystals. MS (ESI, m / z): [M+1] + =[276.6].

[0175] [NMR] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.50(s,1H),8.38(dd,J=8.86,5.44Hz,1 H),7.72-7.89(m,2H),5.70-5.90(m,11H),2.56-2.70(m,2H),2.11-2.25(m,1H)

[0176] Example A-6: Compound Preparation

[0177] 6-1) Preparation of methyl 4-fluoro-6-methylbenzoate

[0178]

[0179] According to the preparation method of Example 4-1, methyl 5-fluoro-2-methylbenzoate was prepared from 5-fluoro-2-methylbenzoate.

[0180] 6-2) Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate

[0181]

[0182] At room temperature, 1-bromophilidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzene carbon peroxy ester (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 5-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CH2Cl (100 ml). The reactants were heated and refluxed for 3 hours. The time point when the red color disappeared was the time when the reaction was complete. After cooling, the reactants were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by MPLC (HX / EAEA 0->5%) (29 g, yield 98.8%). MS (ESI, m / z): [M+1] + =[248.4].

[0183] 6-3) Preparation of methyl 5-fluoro-2-formylbenzoate

[0184]

[0185] At room temperature, NMO (20.6 mg, 176 mmol) and Molecular sieves were sequentially added to a solution of methyl 2-(bromomethyl)-5-fluorobenzoate (29 g, 117 mmol) in DCM (100 ml). The reactant 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, and the title compound was obtained as a white solid. (15 g, yield 70.16%) MS (ESI, m / z): [M+1] + =[183.2].

[0186] 6-4) Preparation of 5-fluoro-2-formylbenzoic acid

[0187]

[0188] At room temperature, lithium hydroxide (17.3g, 412mmol) aqueous solution (50ml) is added to a solution of 5-fluoro-2-formylbenzoic acid methyl ester (15g, 82.3mmol) in THF (50ml). After stirring for 2 hours, the reactant is concentrated under reduced pressure to dry THF. After cooling to 0°C, the reactant is acidified with 1N HCl and the pH is adjusted to 4. The reactant is extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (12g, 86.67%). MS (ESI, m / z): [M+1] + =[169.2].

[0189] 6-5) Preparation of 7-fluoro-1,2-dihydrophthalazin-1-one

[0190]

[0191] At room temperature, NH2NH2 monohydrate (3.74g, 74.8mmol) was added to a solution of 5-fluoro-2-formylbenzoic acid (8.16g, 48.5mmol) in methanol (50ml). After stirring for 30 minutes, the reactant was heated to 80°C for 2 hours. The reactant was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150ml) and extracted twice with ethyl acetate (150ml). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (6.5g, 81.59%). MS (ESI, m / z): [M+1] + =[165.3].

[0192] 6-6) Preparation of 3-(7-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0193]

[0194] At 0 ° C, 2-methylpropane-2-sodium oleate (586mg, 6.09mmol) was added to a solution of 7-fluoro-1,2-dihydrophthalazine-1-one (500mg, 3.05mmol) in DMF (5ml). After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (1.05mg, 5.48mmol) was added to the reaction mixture and stirred at room temperature for 6 hours. The reaction mixture was poured into water (50ml) and extracted twice with ethyl acetate (50ml). The mixed ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography, and the title compound (300mg, 35.78%) was obtained as white crystals. MS (ESI, m / z): [M+1] + =[276.6].

[0195] [NMR] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.53(s,1H),8.13(dd,J=8.74,5.20Hz,1 H),7.87-8.00(m,2H),5.76-5.88(m,11H),2.54-2.68(m,2H),2.10-2.20(m,1H)

[0196] Example A-7: Compound Preparation (prepared according to formula 2)

[0197] 7-1) Preparation of methyl 2-acetyl-6-fluorobenzoate

[0198]

[0199] Tetrakis (triphenylphosphine) - palladium (0) (557mg, 0.48mmol) is added to a solution of methyl 2-acetyl-6-fluorobenzoate (1.12g, 4.81mmol) and tributyl (1-ethoxyvinyl) tin (1.91g, 5.29mmol) in toluene (20ml) and stirred at 100 ° C for 16 hours. After cooling, 5ml of 1N HCl is added and stirred for 1 hour. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the title compound is obtained as a yellow oil. (820mg, yield 87%) MS (ESI, m / z): [M+1] + =[196.8].

[0200] 7-2) Preparation of 2-acetyl-6-fluorobenzoic acid

[0201]

[0202] 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 about 3. 100 ml of EA was applied, the organic layer was dried over magnesium sulfate, and the title compound was obtained by concentration under reduced pressure. (810 mg yield 108%) MS (ESI, m / z): [M+1] + =[183.1].

[0203] 7-3) Preparation of 8-fluoro-4-methylphthalazin-1(2H)-one

[0204]

[0205] 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 obtain the title compound as a white solid. (612 mg, 79.2% yield) MS (ESI, m / z): [M+1] + =[179.1].

[0206] 7-4) Preparation of 3-(8-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0207]

[0208] At 0 ° C, 1M-diisopropylamide lithium (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) 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 reactant was concentrated and dried under reduced pressure. Water (10 ml) was added and stirred for 1 hour, and acidified with 1N HCl to adjust the pH to 4. The precipitate was filtered, washed with water, and the title compound (760 mg, yield: 86.5%) was obtained as a white solid. MS (ESI, m / z): [M + 1] + =[289.8].

[0209] [NMR] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.04-7.94(m,1H),7.79(d,J=7.9Hz,1H),7.69(dd,J=7.9,11.3Hz, 1H), 5.71 (bedd, J=4.9, 12.1Hz, 1H), 3.0-2.83 (m, 1H), 2.64-2.56 (m, 2H), 2.55 (s, 3H), 2.17-2.05 (m, 1H).

[0210] Example A-8: Compound Preparation

[0211] 8-1) Preparation of 3-(8-((2,4-dimethoxybenzyl)amino)-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0212]

[0213] A solution of 3-(8-fluoro-4-methyl-1-oxophthalazin-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 stirred with microwaves at 120 ° C. for 2 hours. The reaction mixture was purified by reverse phase chromatography (C18, water (0.1% FA) / ACN (0.1% FA), gradient) to obtain 33 mg of a white solid (33 mg, 72% yield). MS (ESI, m / z): [M+1] + =[437.0]

[0214] 8-2) Preparation of 3-(8-amino-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0215]

[0216] 0.3 ml of TFA (trifluoroacetic acid) was added to 3-(8-((2,4-dimethoxybenzyl)amino)4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (14 mg, 0.032 mmol) in toluene (0.7 mL), and the mixture was 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]

[0217] [NMR]1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.54(t,J=8.0Hz,1H),7.37(brs,2H),6.95(d,J=8.2Hz,1H),6.88(d,J=7.6Hz,1H),5.62(br dd,J=5.3,12.0Hz,1H),3.0-2.82(m,1H),2.66-2.52(m,2H),2.39(s,3H),2.11-2.02(m,1H)

[0218] Example A-9: Compound Preparation

[0219] 9-1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0220] 6-Fluoro-1,2-dihydrophthalazin-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 stirred at 120°C overnight. The reaction mixture was quenched with water, extracted with EA, and washed with a saturated aqueous solution of NH4Cl and a brine solution. The organic layer was dried over magnesium sulfate. The reaction mixture was loaded onto silica gel and separated by MPLC (HX / EA 30% -> 50%, continued for 10 minutes) to obtain an oily product (110 mg, 66% yield).

[0221] 9-2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0222]

[0223] Tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazine-1-carboxylate was dissolved in 20% TFA in DCM (1 ml) and allowed to react at room temperature for 2 hours. The reaction was quenched with saturated aqueous 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%). The product was obtained as a white solid (40 mg, 86% yield). MS (ESI, m / f): [M+1] + =[342.2].

[0224] [NMR]1H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H) 8.02 (d, J = 9.05Hz, 1H) 7.47 (dd, J = 8.93, 2.57Hz, 1H) 7.31 (s, 0.5H) 7.23 (d, J = 2.45Hz ,1H)7.13(s,0.5H)5.34(dd,J=8.93,4.52Hz,1H)3.28-3.44(m,6H)2.85-2.95(m,4H)2.30-2.40(m,1H)2.16-2.30(m,2H)

[0225] Example A-10: Compound Preparation

[0226] 10-1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0227]

[0228] 3-(7-Fluoro-1-oxo-1,2-dihydrophthalazin-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), DIPEA (5 equivalents) was added to the reaction mixture and stirred overnight at 120 ° C. The reaction mixture was quenched with water, extracted with EA, and washed with a saturated aqueous solution of NH4Cl and a brine solution. The organic layer was dried over magnesium sulfate, and the reaction mixture was loaded onto silica gel and separated by MPLC (HX / EA 30% -> 50%, for 10 minutes) to obtain the product as an oil (yield: 110 mg, 66%).

[0229] 10-2) Preparation of 3-(1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0230]

[0231] Tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl]piperazine-1-carboxylate (60 mg, 0.14 mmol) was dissolved in DCM (1 ml) containing 20% ​​TFA and allowed to react at room temperature for 2 hours. The reaction was quenched with saturated aqueous 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 obtain the product as a white solid (yield: 40 mg / 86%). MS (ESI, m / f): [M+1] + =[342.2].

[0232] [NMR]1H NMR(400MHz, DMSO-d6)δ8.21-8.29(m,1H)7.76(d,J=8.80Hz,1H)7.58(dd,J=8.93,2.57Hz,1H)7.47(d,J=2.45Hz,1H)7.28(s,0.5H)7.1 3(s,0.5H)5.34-5.44(m,1H)3.26-3.33(m,4H)2.81-2.91(m,3H)2.62-2.69(m,1H)2.55-2.62(m,1H)2.31-2.44(m,1H)2.15-2.31(m,2H)

[0233] Example A-11: Preparation of 3-(8-methoxy-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0234] Compound Preparation

[0235]

[0236] 3-(6-Fluoro-1-oxo-1,2-dihydrophthalazin-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 allowed to react at room temperature for 1 hour. The organic solvent was removed and extracted with EA and water. The mixture was purified by MPLC, and the product was obtained as a white solid (yield: 80 mg / 76%). MS (ESI, m / f): [M+1] + =[288.2].

[0237] [NMR]1H NMR(400MHz,DMSO-d6)δ11.04(br.s.,1H)8.40(s,1H)8.14-8.25(m,1H)7.42-7.49(m,2H)5.8 0(dd,J=12.23,5.38Hz,1H)3.94(s,3H)2.86-2.99(m,1H)2.52-2.67(m,2H)2.07-2.17(m,1H)

[0238] Example A-12: Preparation of 3-(7-methoxy-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0239] Compound Preparation

[0240]

[0241] 3-(7-Fluoro-1-oxophthalazin-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 extracted with EA and water. The mixture was purified by MPLC and the product was obtained as a white solid. (Yield: 78 mg / 75%) MS (ESI, m / f): [M+1] + =[288.2].

[0242] [NMR]1H NMR (400MHz, DMSO-d6) δ11.01-11.11(m,1H)8.38-8.45(m,1H)7.90-7.96(m,1H)7.65(d,J=2.69Hz,1H)7.56(dd ,J=8.68,2.57Hz,1H)5.77-5.85(m,1H)3.93-3.98(m,3H)2.87-3.00(m,1H)2.53-2.70(m,2H)2.06-2.18(m,1H)

[0243] Example A-13: Preparation of 3-(6-methoxy-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0244] Compound Preparation

[0245]

[0246] 3-(6-Fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature for 1 hour. The organic solvent was removed and extracted with EA and water. The mixture was purified by MPLC and the product was obtained as a white solid. (Yield: 80 mg / 76%) MS (ESI, m / f): [M+1] + =[288.2].

[0247] [NMR]1H NMR (400MHz, DMSO-d6) δ11.01(s,1H)8.32(s,1H)7.88(t,J=8.01Hz,1H)7.40(d,J=8.31Hz,1H)7.44(d,J=7 .70Hz,1H)5.64(dd,J=11.49,4.52Hz,1H)3.90(s,3H)2.83-2.96(m,1H)2.52-2.66(m,2H)2.03-2.13(m,1H)

[0248] Example A-14: Preparation of 3-(5-methoxy-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0249] Compound Preparation

[0250] 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate

[0251]

[0252] At room temperature, 1-bromophilidine-2,5-dione (11.5 g, 64.94 mmol) and benzoylbenzene carboperoxate (786 mg, 3.24 mmol) were added sequentially to a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH2CH2Cl (250 ml). The reaction mixture was heated and refluxed for 3 hours. The time point at which the red color disappeared was the time at which the reaction was complete. After cooling, the reactant 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].

[0253] 14-2) Preparation of methyl 2-formyl-3-methoxybenzoate

[0254]

[0255] At room temperature, NMO (12.6 g, 108.1 mmol) and Molecular sieves (50g) were added sequentially to a solution of methyl 2-(bromomethyl)-3-methoxybenzoate (14.1g, 54.1mmol) in DCM (300mL). The reactant was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (100mL). The DCM layer was washed with water (250mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography, and the title compound was obtained as a white solid. (8.3g, 80.01%) MS (ESI, m / f): [M+1] + =[195.0].

[0256] 14-3) Preparation of 2-formyl-3-methoxybenzoic acid

[0257]

[0258] At room temperature, H2O (100 mL) containing lithium hydroxide (2.4 g, 100.5 mmol) was added to a solution of methyl 2-formyl-3-methoxybenzoate (6.5 g, 33.6 mmol) in THF (100 mL). After stirring for 2 hours, the reactant was concentrated under reduced pressure to evaporate THF. After cooling to 0 ° C, the reactant was acidified with 1N HCl and the pH was adjusted to 4. The reactant was extracted twice with ethyl acetate (250 mL). The combined ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and white crystals were obtained. (11.2 g, 82.6%) MS (ESI, m / f): [M+1] + =[199.2].

[0259] 14-4) Preparation of 5-methoxyphthalazin-1(2H)-one

[0260]

[0261] At room temperature, 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). 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 layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals. (9.2 g, 76.35%) MS (ESI, m / f): [M+1] + =[176.9].

[0262] 14-5) Preparation of 3-(5-methoxy-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0263]

[0264] At 0 ° C, 1.0M LDA (37.4mL) was added dropwise to some suspension of 5-methoxyphthalazin-1 (2H) -one (5.1g, 28.9mmol) in THF (250mL). After stirring for 30 minutes, 3-bromopiperidine-2,6-dione was partially added to the reactant. The reactant was heated to 80 ° C and stirred for 2 hours. After the reaction was completed, the reactant was cooled to room temperature, poured into water (100ml), 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 and the title compound was obtained as white crystals. (7.2g, yield 86.5%) MS (ESI, m / f): [M+1] + =[288.3].

[0265] [NMR]1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.51(s,1H),7.87-7.77(m,2H),7.54-7.51(m,1 H),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).

[0266] Example A-15: Preparation of 3-(6-bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0267] Compound Preparation

[0268] 15-1) Preparation of 5-bromo-3-hydroxyisobenzofuran-1(3H)-one

[0269]

[0270] 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 ClCH2CH2Cl and refluxed for 8 hours. After the reaction was complete, TLC was performed. The succinimide was filtered and the filter cake was washed with ClCH2CH2Cl (50 mL). The solvent was removed in vacuo, leaving a 5.2 g residue, to which 50 ml of water was added. The mixture was stirred for 4 hours until refluxed, the mixture was cooled, the product was filtered, neutralized with water, washed and dried, and pale yellowish white crystals were obtained. (4.85 g, 86.7% yield) MS (ESI, m / z): [M+1] + =[229.6] and [230.5]

[0271] 15-2) Preparation of 6-bromophthalazin-1(2H)-one

[0272]

[0273] At room temperature, NH2NH2H2O (315mg, 9.82mmol) was added to a solution of 5-bromo-3-hydroxy-1,3-dihydro-2-benzofuran-1-one (1.5g, 6.55mmol) in MeOH (50mL) and stirred for 30 minutes. The reaction was refluxed for 5 hours. The reactant was cooled to room temperature and concentrated under reduced pressure. The resulting solid was ground with ethyl acetate to obtain white crystals. (1.31g, 5.82mmol) MS (ESI, m / f): [M+1] + =[226.3].

[0274] 15-3) Preparation of 3-(6-bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0275]

[0276] At 0 ° C, 1.0M LDA (7.33mL) was added dropwise to a suspension of 6-bromo-1,2-dihydrophthalazin-1-one (1.31g, 5.82mmol) in THF (150mL). After stirring for 30 minutes, 3-bromopiperidine-2,6-dione was partially added to the reactant. The reactant was heated to 80 ° C and stirred for 2 hours. After the reaction was completed, the reactant was cooled to room temperature, poured into water (100ml), 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, washed with ethyl acetate, and white crystals were obtained. (1.73g, 5.15mmol) MS (ESI, m / f): [M+1] +=[337.2].

[0277] [NMR]1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.45(s,1H),8.28(s,1H),8.18-8.16(m,1H),8.06- 8.04(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).

[0278] Example A-16: Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione dihydrochloride

[0279] Compound Preparation

[0280] 16-1) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione dihydrochloride

[0281]

[0282] Tert-butyl piperazine-1-carboxylate (244 mg, 1.13 mmol) and ethylbis(propane-2-yl)amine (423 mg, 3.24 mmol) were added sequentially to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (0.3 g, 1.09 mmol) in DMA (4 mL). The mixture was stirred at 120 ° C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to obtain a pale yellowish white oil. (415 mg, 86.2%) MS (ESI, m / f): [M+1] + =[442.4]

[0283] 16-2) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione dihydrochloride

[0284]

[0285] 3-Bromopiperidine-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 solution was heated to 85 ° C for 5 hours. After cooling, the reaction mixture was poured into water (5 mL) and extracted twice with ethyl acetate (5 mL). The mixed ethyl acetate was extracted with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography, and the title compound was obtained as white crystals. (68.0 mg, yield 71.7%) MS (ESI, m / f): [M+1] + =[342.6].

[0286] [NMR]1H NMR(400MHz,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).

[0287] Example B: Preparation of ABN derivative-based CMET PROTAC

[0288] 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000922)

[0289] Step 1) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate

[0290]

[0291] At room temperature, 1-bromomerolidine-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 ClCH2CH2Cl (100 ml), followed by the addition of benzoylbenzene carbon peroxy ester (1.92 g, 5.95 mmol). The reactants were heated under reflux for 3 hours. When the reaction was complete, the red color disappeared. After cooling, the reactants were 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.

[0292] Step 2) Preparation of 4-fluoro-2-formylbenzoate

[0293]

[0294] At room temperature, NMO (15.6 mg, 134 mmol) is added to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22.0 g, 89 mmol) in DCM (100 mL), followed by addition of molecular sieves 4A. The reactant is stirred at room temperature for 2 hours. The molecular sieves are filtered and washed with DCM (50 mL). The DCM layer is washed with water (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography, and the title compound (12.0 g) is obtained as a white solid. MS (ESI, m / z): [M+H] + =183.2.

[0295] Step 3) Preparation of 4-fluoro-2-formylbenzoic acid

[0296]

[0297] 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 H2O (50 mL) were added. After stirring for 2 hours, the reactant was concentrated under reduced pressure to dry THF. After cooling to 0 ° C, the reactant was acidified with 1M HCl and the pH was adjusted to 4. The reactant was extracted with ethyl acetate (50 mL x 2). The mixed ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (10.0 g). MS (ESI, m / z): [M + H] + =169.2.

[0298] Step 4) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one

[0299]

[0300] At room temperature, NH2NH2 monohydrate (2.02mg, 40.3mmol) is added to a solution of 4-fluoro-2-formylbenzoic acid (6.78g, 40.3mmol) in MeOH (50mL). After stirring for 30 minutes, the reactant is heated to 80°C for 2 hours. The reactant is cooled to room temperature and concentrated under reduced pressure. The residue is poured into water (150ml) and extracted with ethyl acetate (150mL x 2). The mixed ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (5.5g). MS (ESI, m / z): [M+H] + =165.3.

[0301] Step 5) Preparation of 3-(6-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0302]

[0303] At 0 ° C, 2-methylpropane-2-sodium oleate (175mg, 0.914mmol) is added to a solution of 6-fluoro-1,2-dihydrophthalazine-1-one (100mg, 0.609mmol) in DMF (2mL). After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (90mg, 0.471mmol) is added to the reaction mixture and stirred at room temperature for 6 hours. The reaction mixture is poured into water (20mL) and extracted with ethyl acetate (20mL x 2). The combined ethyl acetate is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography, and the title compound (110.0mg) is obtained as white crystals. MS (ESI, m / z): [M+H] + =276.6.

[0304] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.50(s,1H),8.38(dd,J=8.86,5.44Hz,1 H),7.72-7.89(m,2H),5.70-5.90(m,11H),2.56-2.70(m,2H),2.11-2.25(m,1H)

[0305] Step 6) Preparation of 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butyric acid

[0306]

[0307] Ethylbis(propane-2-yl)amine (4.0 equivalents) 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 4-aminobutyric acid (225 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M+H] + =359.4

[0308] 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-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-4-oxobutyl)amino]-1-oxo-1,2-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000922)

[0309]

[0310] DMF (2.0 ml) was added (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-dihydrophthalazin-6-yl}amino}butanoic acid (13.2 mg, 0.04 mmol) followed by ethylbis(propan-2-yl)amine (5.0 equiv). The reaction was stirred at room temperature for 6 hours. The reaction was poured into a 5% HCl solution. The reaction 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 obtain the title compound (17 mg). MS (ESI, m / z): [M+H] + =894.1.

[0311] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.91(s,1H)9.14(s,1H)8.65-8.70(m,2H)8.58(s,1H)8.21-8.29(m,1 H)8.11(s,1H)7.82-7.87(m,1H)7.54(m,J=8.09Hz,2H)7.27-7.34(m,2H )7.01(dd,J=8.93,2.06Hz,1H)6.86(t,J=5.26Hz,1H)6.69(d,J=1.98Hz,1H)5.65(dd,J=12.05,5.04Hz,1H)4.79-4.91(m,2H)4.66(d,J=12.36 Hz,1H)4.31(d,J=13.28Hz,1H)4.12-4.19(m,1H)3.82-3.90(m,4H)3.3 4-3.47(m,6H)2.99-3.13(m,4H)2.78-2.88(m,1H)2.46-2.59(m,2H)2.3 6(t,J=7.02Hz,1H)2.26(d,J=14.19Hz,4H)1.94-2.03(m,1H)1.83-1.94(m,1H)1.75(t,J=6.87Hz,1H)1.30(t,J=6.71Hz,1H)1.14-1.21(m,1H)

[0312] 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}morpholin-4-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-6-oxohexyl)amino]-1-oxo-1,2-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000923)

[0313] Step 1) Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}hexanoic acid

[0314]

[0315] Ethylbis(propane-2-yl)amine (4.0 equivalents) 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 6-aminohexanoic acid (286 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (270 mg). MS (ESI, m / z): [M + H] + =387.4

[0316] 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-dihydrophthalazin-2-yl}piperidine-2,6-dione

[0317]

[0318] (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-dihydrophthalazin-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. The reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =922.6.

[0319] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98(s,1H)9.21(s,1H)8.74(s,2H)8.65(s,1H)8.31(s,1H)8.18(s,1H)7.91(d,J=8.68Hz,1H)7.61(d,J=8.19Hz,2H)7.37(d,J=8.07Hz,2H) 7.07(dd,J=8.74,2.26Hz,1H)6.84-6.92(m,1H)6.75(d,J=2.20Hz,1H)5.66-5.77(m,1H)4.85-5.00(m,2H)4.73(d,J=12.23Hz,1H)4.38(d,J= 13.45Hz,1H)4.22(d,J=4.28Hz,1H)3.88-3.99(m,4H)3.49(s,2H)3.36-3.47(m,4H)3.05-3.18(m,2H)2.83-2.98(m,1H)2.61(br.s.,1H)2.55 (d,J=8.07Hz,1H)2.25-2.40(m,4H)2.01-2.10(m,2H)1.88-2.01(m,2H )1.74(br.s.,2H)1.47-1.66(m,2H)1.31-1.47(m,2H)1.14-1.31(m,2H)

[0320] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000924)

[0321] Step 1) Preparation of 5-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)pentanoic acid

[0322]

[0323] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl) and 5-aminopentanoic acid (245 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M + H] + =373.4

[0324] 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-oxopentyl)amino)1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000924)

[0325]

[0326] (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-dihydrophthalazine- The mixture was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (23 mg). MS (ESI, m / z): [M+H] + =908.1.

[0327] 1H NMR(400MHz,DMSO-d6)δppm 10.98(s,1H)9.21(s,1H)8.74(s,2H)8.64(s,1H)8.31(s,1H)8.18(s,1H)7.91(d,J=8.93Hz,1H)7.61(m,J=8.19Hz,2H)7.38(m,J=8.19H z,2H)7.04-7.11(m,1H)6.87-6.93(m,1H)6.76(d,J=2.08Hz,1H)5.74(dd,J=11.55,7.15Hz,1H)4.85-5.00(m,2H)4.73(d,J=11.98Hz,1 H)4.38(d,J=12.72Hz,1H)4.22(br.s.,1H)3.87-3.98(m,4H)3.50(s,2H)3.44(br.s.,4H)3.05-3.19(m,2H)2.85-2.97(m,2H)2.59(d,J =19.93Hz,1H)2.35(br.s.,4H)2.30(br.s.,3H)2.07(dd,J=11.92,4.22Hz,1H)1.89-2.01(m,2H)1.61(br.s.,2H)1.37(t,J=5.93Hz,2H)

[0328] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000925)

[0329] Step 1) Preparation of 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)heptanoic acid

[0330]

[0331] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl) and 7-aminoheptanoic acid (260 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M + H]+ =401.4

[0332] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000925)

[0333]

[0334] (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-(dioxopiperidin-3-yl)1-oxo-1,2-dihydrophthalazin-6-yl)amino)heptanoic acid ( The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into a reaction vessel. The reaction 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 obtain the title compound (19 mg). MS (ESI, m / z): [M+H] + =936.8.

[0335] 1H NMR(400MHz,DMSO-d6)δppm10.98(s,1H)9.21(s,1H)8.74(s,2H)8.64(s,1H )8.31(s,1H)8.18(s,1H)7.91(d,J=8.93Hz,1H)7.61(m,J=8.07Hz,2H)7.38 (m,J=8.07Hz,2H)7.07(dd,J=8.86,2.14Hz,1H)6.88(t,J=4.77Hz,1H)6.75 (d,J=1.83Hz,1H)5.72(dd,J=11.92,5.32Hz,1H)4.85-4.99(m,2H)4.73(d, J=12.84Hz,1H)4.38(d,J=13.45Hz,1H)4.22(d,J=4.77Hz,1H)3.88-3.97(m ,4H)3.50(s,2H)3.44(br.s.,4H)3.05-3.17(m,2H)2.84-2.96(m,2H)2.61( br.s.,1H)2.56(br.s.,1H)2.36(br.s.,2H)2.24-2.33(m,4H)2.01-2.10(m ,1H)1.90-2.01(m,2H)1.55-1.65(m,2H)1.45-1.55(m,2H)1.31-1.43(m,4H)

[0336] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000935)

[0337] Step 1) Preparation of 2-(2-(2-((2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetate

[0338]

[0339] Ethylbis(propan-2-yl)amine (4.0 equivalents) 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 reactants were stirred at 130° C. for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. The subjective compound (240 mg) was obtained. MS (ESI, m / z): [M+H] + =419.4

[0340] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000935)

[0341]

[0342] HATU (41.3 mg, 0.11 mmol) was added to (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-(2,6-dioxopiperidin-3-yl)-1-oxo-1 ,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)acetic acid (43.1 mg, 0.06 mmol) was added, and then ethylbis(propane-2-yl)amine (5 equivalents) was added. The reactants were stirred at room temperature for 6 hours. The reactants were 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 obtain the title compound (35 mg). MS (ESI, m / z): [M+H] + =954.1.

[0343] 1H NMR(400MHz, DMSO-d6)δppm10.99(s,1H)9.21(s,1H)8.79(br.s.,2H)8.65(s,1H)8.31(s,1H)8.17(s,1H)7.92(d,J=8.93Hz,1H )7.78(br.s.,2H)7.57(br.s.,2H)7.12(dd,J=8.93,2.20Hz,1H)6.93(br.s.,1H)6.82(s,1H)5.73(d,J=10.88Hz,1H)4.86-5.0 0(m,2H)4.73(d,J=12.23Hz,1H)4.39(d,J=12.59Hz,3H)4.21(br.s.,3H)3.88-3.98(m,4H)3.56-3.66(m,6H)3.13(br.s.,2H)2 .84-2.98(m,2H)2.59(d,J=18.10Hz,2H)2.08(d,J=4.28Hz,2H)1.91-2.02(m,2H)1.75(s,2H)1.46(br.s.,2H)1.34-1.42(m,3H)

[0344] 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-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000938)

[0345] Step 1) Preparation of 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}ethoxy)ethoxy]ethoxy]ethoxy}acetic acid

[0346]

[0347] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-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). The reactants were stirred at 130 ° C for 48 hours. After the reaction was completed, 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

[0348] 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-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000938)

[0349]

[0350] 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-dihydrophthalazin-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 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =998.2.

[0351] 1H NMR(400MHz,DMSO-d6)δppm 10.99(s,1H)9.21(s,1H)8.79(br.s.,2H)8.65(s,1H)8.31(s,1H)8.16(s,1H)7.91(d,J=8.80Hz,1H)7.78(b r.s.,2H)7.57(br.s.,2H)7.08-7.14(m,1H)6.92(br.s.,1H)6.80(s,1H)5.72(dd,J=11.37,4.89Hz,1H)4.85 -5.00(m,2H)4.73(d,J=12.10Hz,1H)4.39(d,J=11.62Hz,3H)4.15-4.21(m,3H)3.88-3.97(m,4H)3.44-3.67( m,15H)3.10(d,J=12.84Hz,3H)2.78-2.98(m,2H)2.59(d,J=17.97Hz,2H)1.88-2.09(m,2H)1.33-1.41(m,3H)

[0352] 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-azapentadecan-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000939)

[0353] Step 1) Preparation of 14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}-3,6,9,12-tetracosanoic acid

[0354]

[0355] Ethylbis(propane-2-yl)amine (4.0 equivalents) 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 14-amino-3,6,9,12-tetracosanoic acid (548 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (270 mg). MS (ESI, m / z): [M + H] +=507.4

[0356] 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-azapentadecan-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000939)

[0357]

[0358] (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-dihydrophthalazin-6-yl]amino}-3,6,9,12-tetraoxatetradecanoic acid (20.5 mg, 0.06 mmol) in DMF (2.0 ml) were mixed with HATU (41.3 mg, 0.11 mmol) 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 reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =1042.8.

[0359] 1H NMR(400MHz,DMSO-d6)δppm 10.99(s,1H)9.21(s,1H)8.79(br.s.,2H)8.65(s,1H)8.31(s,1H)8.17(s,1H)7.91(d,J=8.93Hz,1H)7.78(br.s.,2H )7.58(br.s.,2H)7.11(dd,J=8.93,2.20Hz,1H)6.93(br.s.,1H)6.80(d,J=2.08Hz,1H)5.67-5.77(m,1H)4.85-5.00( m,2H)4.73(d,J=12.84Hz,2H)4.39(d,J=12.59Hz,3H)4.09-4.21(m,3H)3.86-4.00(m,4H)3.44-3.66(m,12H)3.12(dd ,J=17.97,12.59Hz,3H)2.83-3.00(m,2H)2.56-2.62(m,2H)1.88-2.11(m,6H)1.45(br.s.,2H)1.37(t,J=5.87Hz,3H)

[0360] 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-oxophthalazin-2-(1H)-yl]piperidine-2,6-dione (ICT-0000940)

[0361] Step 1) Preparation of methyl 2-fluoro-6-methylbenzoate

[0362]

[0363] 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, 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.

[0364] Step 2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate

[0365]

[0366] To a solution of methyl 2-fluoro-6-methylbenzoate (21.2 g, 126 mmol) in ClCH2CH2Cl (250 ml) was added 1-bromophilolidin-2,5-dione (24.7 g, 139 mmol) at room temperature, followed by benzoylbenzene carbonoperoxyester (1.53 g, 6.30 mmol). The reactants were heated under reflux for 16 hours. At the end of the reaction, the red color disappeared. After cooling, the reactants were 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.

[0367] Step 3) Synthesis of methyl 2-fluoro-6-formylbenzoate

[0368]

[0369] At room temperature, NMO (24.9g, 212mmol) is added to a solution of methyl 2-(bromomethyl)-6-fluorobenzoate (35g, 142mmol) in DCM (280mL). The reactant is stirred at room temperature for 4 hours. The DCM layer is washed with water (200mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography, and the title compound (11.52g) is obtained as a white solid. MS (ESI, m / z): [M+H] + =183.1.

[0370] Step 4) Preparation of 2-fluoro-6-formylbenzoic acid

[0371]

[0372] At room temperature, a solution of 2-fluoro-6-formylbenzoic acid methyl ester (11.5g, 63.2mmol) in THF (82mL) and a solution of lithium hydroxide (1+) in H2O (41mL) (7.57g, 180mmol) were added to the solution THF. After stirring for 4 hours, the reactant was concentrated under reduced pressure and THF was dried. After cooling to 0°C, the reactant was acidified to 1M HCl and the pH was adjusted to 4. The reactant was extracted with ethyl acetate (100mL x 2). The mixed ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain white crystals (10.4g). MS (ESI, m / z): [M+H] + =168.8

[0373] Step 5) Preparation of 8-fluorophthalazin-1(2H)-one

[0374]

[0375] 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 MeOH (120 mL) and stirred at room temperature for 16 hours. The white precipitate was filtered and washed with MeOH. The obtained white solid was ground into 100 ml of EA, filtered, and white crystals (3.05 g, 30%) were obtained. MS (ESI, m / z): [M+H] + =165.1.

[0376] Step 6) Preparation of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0377]

[0378] At 0 ° C, NaH (60%, 53.6 mg, 1.34 mmol) was added to a solution of 8-fluorophthalazine-1 (2H) -one (200 mg, 1.22 mmol) in DMF (5 mL) and stirred for 30 minutes. 3-Bromopiperidine-2,6-dione (468 mg, 2.44 mmol) was added to the solution and stirred at room temperature for 6 hours. The reactant was quenched with water and extracted with ethyl acetate (20 mL x2). 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.

[0379] 1H NMR(400MHz,DMSO-d6)δppm 11.06(s,1H),8.48(s,1H),7.99(ddd,J=4.6,7.2,8.2Hz,1H),7.80(d,J=7.2Hz,1H),7.67(dd,J=8.2 ,11.4Hz,1H),5.77(dd,J=5.3,12.0Hz,1H),2.99-2.77(m,1H),2.68-2.51(m,2H),2.23-2.02(m,1H)

[0380] Step 7) Preparation of 3-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl]amino}ethoxy)ethoxy]propanoic acid

[0381]

[0382] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 3-[2-(2-aminoethoxy)ethoxy]propionic acid (257 mg, 1.45 mmol) in NMP (2.0 ml). The reactants were 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 subjective compound (290 mg) was obtained. MS (ESI, m / z): [M + H] + =433.4

[0383] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000940)

[0384]

[0385] 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-dihydrophthalazin-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 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =968.1.

[0386] 1H NMR(400MHz,DMSO-d6)δppm 10.96(s,1H)9.14(s,1H)8.71-8.79(m,1H)8.67(s,2H)8.57(s,1H)8.24(s,1H)8.15(s,1H)7.51-7.61(m,2H)7 .29(d,J=7.93Hz,2H)6.84(d,J=7.48Hz,2H)5.64(d,J=7.32Hz,1H)4.79-4.93(m,2H)4.66(d,J=12.36Hz,1H)4. 31(d,J=12.97Hz,1H)4.15(br.s.,1H)3.52-3.62(m,4H)3.39-3.52(m,4H)3.36(br.s.,4H)2.98-3.11(m,3H)2. 78-2.88(m,1H)2.39-2.58(m,5H)2.25(d,J=16.63Hz,2H)1.98-2.05(m,1H)1.83-1.93(m,1H)1.12-1.24(m,6H)

[0387] 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-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-12-oxo-4,7,10-trioxa-1-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000942)

[0388] Step 1) Preparation of 2-{2-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl}amino}ethoxy)ethoxy]ethoxy}ethoxy}acetate

[0389]

[0390] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (399 mg, 1.45 mmol) and 2-{2-[2-(2-aminoethoxy)ethoxy}acetic acid (300 mg, 1.45 mmol). The reactants were 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 subjective compound (290 mg) was obtained. MS (ESI, m / z): [M+H] + =463.5

[0391] 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-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000942)

[0392]

[0393] HATU (38.0 mg, 0.10 mmol) was added to (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-dihydrophthalazin-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 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 obtain the title compound (26 mg). MS (ESI, m / z): [M+H] + =998.1.

[0394] 1H NMR(400MHz,DMSO-d6)δppm 10.96(s,1H)9.14(s,1H)8.72-8.78(m,1H)8.64-8.69(m,2H)8.58(s,1H)8.24(s,1H)8.13-8.16(m,1H)7.51-7.60(m,2H)7 .29(d,J=7.93Hz,2H)6.80-6.87(m,2H)4.79-4.91(m,2H)4.65(d,J=12.97Hz,1H)4.31(d,J=13.12Hz,1H)4.04(s,2H)3.97- 4.02(m,1H)3.82-3.90(m,4H)3.52-3.63(m,4H)3.44-3.52(m,4H)3.29-3.36(m,4H)2.99-3.09(m,2H)2.78-2.88(m,1H)2. 56(br.s.,1H)2.52(br.s.,1H)2.29(br.s.,2H)2.24(br.s.,1H)1.82-1.94(m,2H)1.30(t,J=6.56Hz,2H)1.11-1.25(m,6H)

[0395] 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-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-16-oxo-4,7,10,13-tetraoxa-1-azahexadec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000946)

[0396] Step 1) Preparation of 2-{2-[2-(2-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl}amino}ethoxy)ethoxy]ethoxy}ethoxy}acetate

[0397]

[0398] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (399 mg, 1.45 mmol) and 2-{2-[2-(2-aminoethoxy)ethoxy}acetic acid (300 mg, 1.45 mmol). The reactants were 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 subjective compound (290 mg) was obtained. MS (ESI, m / z): [M+H] + =463.5

[0399] 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}morpholin-4-yl]pyrimidin-5-yl}phenyl)methyl]piperazin-1-yl}-16-oxo-4,7,10,13-tetraoxa-1-azahexadec-1-yl)-1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000946)

[0400]

[0401] 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-dihydrophthalazin-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 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 obtain the title compound (26 mg). MS (ESI, m / z): [M+H] + =998.1. 1H NMR (400MHz, DMSO-d6)

[0402] 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000959)

[0403] Step 1) Preparation of 5-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl]amino}pentanoic acid

[0404]

[0405] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl) and 5-aminopentanoic acid (255 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (300 mg). MS (ESI, m / z): [M + H] + =373.4

[0406] 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000959)

[0407]

[0408] (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-dihydrophthalazin-5-yl}amino}pentanoic acid (22.2 mg, 0.06 mmol) in DMF (2.0 ml) were added, followed by ethylbis(propan-2-yl)amine (5 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on MeOH / DCM (0-20%) to obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =908.8.

[0409] 1H NMR(400MHz,DMSO-d6)δppm 11.04(s,1H)9.21(s,1H)8.81(s,2H)8.72(br.s.,1H)8.65(s,1H)8.31(s,1H)8.24(s,1H)7.79(d,J=7.46Hz,2H)7.66 (t,J=7.95Hz,1H)7.56(d,J=8.44Hz,2H)6.92(d,J=7.21Hz,1H)6.89(d,J=8.80Hz,1H)5.69(br.s.,1H)4.82-4.99(m, 2H)4.73(d,J=12.96Hz,1H)4.42(br.s.,2H)4.38(br.s.,2H)4.22(br.s.,1H)4.07(br.s.,1H)3.87-4.00(m,4H)3.23 (m,4H)3.02-3.20(m,4H)2.77-3.01(m,2H)2.52-2.68(m,2H)2.33(br.s.,4H)2.09(s,1H)1.64(br.s.,2H)1.23(s,2H)

[0410] 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)

[0411] Step 1) Preparation of 7-{[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl]amino}heptanoic acid

[0412]

[0413] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl) and 4-aminobutyric acid (317 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (300 mg). MS (ESI, m / z): [M + H] + =401.4

[0414] 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (ICT-0000960)

[0415]

[0416] (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-dihydrophthalazin-5-yl]amino}amino} in DMF (2.0 ml) were added, followed by ethylbis(propan-2-yl)amine (5 equivalents). The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =936.1

[0417] 1H NMR(400MHz,DMSO-d6)δppm 11.03(s,1H)9.21(s,1H)8.71(s,1H)8.75(s,2H)8.65(s,1H)8.31(s,1H)8.23(s,1H)7.79(br.s.,1H)7.54-7.70(m,3H)7 .39(br.s.,1H)6.87(d,J=8.56Hz,1H)6.91(d,J=7.46Hz,1H)5.69(br.s.,1H)4.85-4.99(m,2H)4.73(d,J=12.23Hz,1H)4 .38(d,J=14.06Hz,2H)4.21(br.s.,1H)3.88-3.98(m,4H)3.50(br.s.,2H)3.43(br.s.,4H)3.04-3.23(m,4H)2.80-2.96( m,2H)2.55-2.69(m,2H)2.33(s,2H)1.62(br.s.,2H)1.50(br.s.,2H)1.40(br.s.,2H)1.34(br.s.,2H)1.14-1.28(m,4H)

[0418] 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-oxopropoxy)ethoxy]ethyl}amino)1-oxo-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (ICT-0000967)

[0419] Step 1) Preparation of 17-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12,15-pentaoxaheptadecanoic acid

[0420]

[0421] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 17-amino-3,6,9,12,15-pentaoxaheptadecanoic acid (327 mg, 1.45 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (310 mg). MS (ESI, m / z): [M+H] + =551.1

[0422] 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-pentaheptacel)amino)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000967)

[0423]

[0424] (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-dihydrophthalazin-5-yl]amino}-3,6,9,12,15-pentaoxaheptadecanoic acid (30.0 mg, 0.05 mmol) in DMF (2.0 ml) were mixed with HATU (41.4 mg, 0.10 mmol) 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 reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =1086.1.

[0425] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.97(s,1H)9.14(s,1H)8.69(s,2H)8.64(t,J=4.88Hz,1H)8.58(s,1H )8.24(s,1H)8.16(s,1H)7.52-7.61(m,2H)7.29(d,J=7.93Hz,2H)6.84( d,J=7.32Hz,1H)6.81(d,J=8.54Hz,1H)5.63(d,J=7.48Hz,1H)4.79-4.92(m,2H)4.66(d,J=12.66Hz,1H)4.31(d,J=13.12Hz,1H)4.06-4.19(m,1 H)3.82-3.90(m,4H)3.51-3.61(m,1H)3.38-3.50(m,3H)3.36(br.s.,2 H)2.98-3.18(m,5H)2.76-2.88(m,1H)2.45-2.59(m,4H)2.29(br.s.,1H )2.25(br.s.,3H)1.98-2.07(m,1H)1.82-1.94(m,1H)1.57(quin,J=6.98Hz,2H)1.48(quin,J=7.36Hz,2H)1.29-1.40(m,2H)1.13-1.24(m,11H)

[0426] 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-hexaoxaheneicosane)amino)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000968)

[0427] Step 1) Preparation of 1-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12,15,18-hexaoxaheneicosanoic acid-21-oleic acid

[0428]

[0429] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(8-fluoro-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (8-fluoro-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.45 mmol) and 1-amino-3,6,9,12,15,18-hexaoxaheneicosanoic acid-21-oleic acid (327 mg, 1.45 mmol). The reactants were 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 subjective compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =609.6

[0430] 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-hexaoxaheneicosane)amino)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000968)

[0431]

[0432] (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-hexaoxaheneicosanoic acid-21-oleic acid (35.0 mg, 0.05 mmol), HATU (43.7 mg, 0.10 mmol) were 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. The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =1144.1.

[0433] 1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H)9.14(s,1H)8.64-8.70(m,2H)8.57(s,1H)8.24(s,1H)8.13-8.17(m,1H)7.52-7.60(m,3H)7.31(d,J=8.0 9Hz,2H)6.81-6.88(m,2H)5.62(br.s.,1H)4.79-4.92(m,2H)4.66(d,J=13.43Hz,2H)4.31(d,J=12.36Hz,1H)4.15(br .s.,2H)3.81-3.90(m,4H)3.59(t,J=5.19Hz,2H)3.32-3.55(m,8H)2.99-3.09(m,2H)2.77-2.88(m,2H)2.57(br.s.,1 H)2.46-2.55(m,6H)2.30(br.s.,2H)2.24(br.s.,1H)1.81-1.93(m,5H)1.68(br.s.,2H)1.38(br.s.,3H)1.17(s,7H)

[0434] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000969)

[0435] Step 1) Preparation of 4-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)butyric acid

[0436]

[0437] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione 3-(8-fluoro-1-oxophthalazin-2(1H)-yl) and 4-aminobutyric 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione 3-(8-fluoro-1-oxophthalazin-2(1H)-yl). The subjective compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =359.6

[0438] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000969)

[0439]

[0440] (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-dihydrophthalazin-5-yl)amino)butanoic acid (25.0 mg, 0.10 mmol) in DMF (2.0 ml) were added, followed by ethylbis(propan-2-yl)amine (5 equiv). The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =893.9

[0441] 1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H)9.14(s,1H)8.64-8.70(m,2H)8.57(s,1H)8.24(s,1H)8.13-8.17(m,1H)7.52-7.60(m,3H)7.31(d,J=8.0 9Hz,2H)6.81-6.88(m,2H)5.62(br.s.,1H)4.79-4.92(m,2H)4.66(d,J=13.43Hz,2H)4.31(d,J=12.36Hz,1H)4.15(br .s.,2H)3.81-3.90(m,4H)3.59(t,J=5.19Hz,2H)3.32-3.55(m,8H)2.99-3.09(m,2H)2.77-2.88(m,2H)2.57(br.s.,1 H)2.46-2.55(m,6H)2.30(br.s.,2H)2.24(br.s.,1H)1.81-1.93(m,5H)1.68(br.s.,2H)1.38(br.s.,3H)1.17(s,7H)

[0442] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000970)

[0443] Step 1) Preparation of 6-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)hexanoic acid

[0444]

[0445] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (8-fluoro-1-oxophthalazin-2(1H)-yl) 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione 3-(8-fluoro-1-oxophthalazin-2(1H)-yl). The subjective compound (310 mg) was obtained. MS (ESI, m / z): [M+H] + =387.6

[0446] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000970)

[0447]

[0448] 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-dihydrophthalazin-5-yl)amino)hexanoic acid (29.0 mg, 0.05 mmol) in DMF (2.0 ml) was mixed with HATU (43.7 mg, 0.10 mmol) followed by ethylbis(propan-2-yl)amine (5 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =922.3.

[0449] 1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H)9.14(s,1H)8.64-8.70(m,2H)8.57(s,1H)8.24(s,1H)8.13-8.17(m,1H)7.52-7.60(m,3H)7.31(d,J=8.0 9Hz,2H)6.81-6.88(m,2H)5.62(br.s.,1H)4.79-4.92(m,2H)4.66(d,J=13.43Hz,2H)4.31(d,J=12.36Hz,1H)4.15(br .s.,2H)3.81-3.90(m,4H)3.59(t,J=5.19Hz,2H)3.32-3.55(m,8H)2.99-3.09(m,2H)2.77-2.88(m,2H)2.57(br.s.,1 H)2.46-2.55(m,10H)2.30(br.s.,2H)2.24(br.s.,1H)1.81-1.93(m,5H)1.68(br.s.,2H)1.38(br.s.,3H)1.17(s,7H)

[0450] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000978)

[0451] Step 1) Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0452]

[0453] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxophthalazine-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 reactants were 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 obtain the title compound (400 mg). MS (ESI, m / z): [M+H] + =539.4

[0454] Step 2) Preparation of 3-(1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0455]

[0456] TFA (10 ml) was added to a solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (400 mg, 1.52 mmol) in DCM (30 ml). The reactants were 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 obtain the title compound (400 mg). MS (ESI, m / z): [M+H] + =439.4

[0457] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000978)

[0458]

[0459] Potassium carbonate (6 mg, 0.02 mmol) was added to a mixture containing (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)piperazin-1-yl)phthalazine-2-yl)benzyl methanesulfonate (12 mg, 0.02 mmol). 1H)-1,2-piperidine-2,6-dione (9.5 mg, 0.02 mmol) was dissolved in DMF (2.0 ml). The reaction was stirred at 60 ° C for 2 hours. The reaction was poured into water. The reaction 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 obtain the title compound (5 mg). MS (ESI, m / z): [M + H] + =906.8.

[0460] 1H NMR(400MHz,DMSO-d6)δppm 10.98(s,1H)9.21(s,1H)8.74(s,2H)8.64(s,1H)8.31(s,1H)8.18(s,1H)7.91(d,J=8.93Hz,1H)7.61(m,J=8.19Hz,2H)7.38(m,J= 8.19Hz,2H)7.04-7.11(m,1H)6.87-6.93(m,1H)5.74(dd,J=11.55,7.15Hz,1H)4.85-5.00(m,2H)4.73(d,J=11.98Hz,1H)4.38(d,J =12.72Hz,1H)4.22(br.s.,1H)3.87-3.98(m,4H)3.50(s,2H)3.44(br.s.,4H)3.05-3.19(m,2H)2.85-2.97(m,2H)2.59(d,J=19.9 3Hz,1H)2.35(br.s.,4H)2.30(br.s.,4H)2.07(dd,J=11.92,4.22Hz,1H)1.89-2.01(m,2H)1.61(br.s.,2H)1.37(t,J=5.93Hz,2H)

[0461] Example B-18: Preparation of 3-(4-methyl-8-((2-(4-(4-(2-((S)-2-((5-(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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000983)

[0462] Step 1) Preparation of methyl 2-acetyl-6-fluorobenzoate

[0463]

[0464] Tetrakis (triphenylphosphine) -palladium (0) (557mg, 0.48mmol) is added to a solution of methyl 2-acetyl-6-fluorobenzoate (1.12g, 4.81mmol) and tributyl (1-ethoxyvinyl) tin (1.91g, 5.29mmol) in toluene (20ml), and stirred at 100 ° C for 16 hours. After cooling, 5ml of 1N HCl is added and stirred for 1 hour. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the title compound (820mg) is obtained. MS (ESI, m / z): [M + H] + =196.8

[0465] Step 2) Preparation of 2-acetyl-6-fluorobenzoic acid

[0466]

[0467] 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 about 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

[0468] Step 3) Preparation of 8-fluoro-4-methylphthalazin-1(2H)-one

[0469]

[0470] 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

[0471] Step 4) Preparation of 3-(8-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0472]

[0473] 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 minutes. 3-Bromopiperidine-2,6-dione (32.3 mg, 0.168 mmol) was added to the solution and stirred at room temperature for 1 hour. The title compound (2 mg) was obtained as a solid. MS (ESI, m / z): [M+H] + =289.8

[0474] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.04-7.94(m,1H),7.79(d,J=7.9Hz,1H),7.69(dd,J=7.9,11.3Hz,1H),5.71(br dd,J=4.9,12.1Hz,1H),3.0-2.83(m,1H),2.64-2.56(m,2H),2.55(s,3H),2.17-2.05(m,1H).

[0475] Step 5) Preparation of (3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-5-yl)glycine

[0476]

[0477] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(8-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl) and glycine (125 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M + H] + =345.4

[0478] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0000983)

[0479]

[0480] 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-dihydrophthalazin-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 equiv). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (17 mg). MS (ESI, m / z): [M+H] + =879.8

[0481] 1H NMR(400MHz,DMSO-d6)δppm 10.94(s,1H)9.36(br.s.,1H)1 9.14(s,1H)8.73(br.s.,2H)8.58(s,1H)8.24(s,1H)7.65-7.77(m,2H)7.62(t,J=7.78Hz,1H)7.42-7.56(m ,2H)6.78-6.93(m,1H)4.80-4.92(m,2H)4.67(d,J=12.51Hz,1H)4.33(d,J=12.97Hz,2H)4.15(br.s.,1H)3 .82-3.90(m,4H)3.55(dq,J=10.59,6.54Hz,2H)3.43(t,J=10.45Hz,2H)3.00-3.12(m,4H)2.78-2.89(m,1H )2.47-2.59(m,3H)2.01(d,J=5.04Hz,1H)1.89(d,J=17.09Hz,2H)1.38(d,J=6.87Hz,2H)1.09-1.23(m,6H)

[0482] 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)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0001109)

[0483] Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0484]

[0485] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxophthalazine-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 reactants were 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 obtain the title compound (350 mg). MS (ESI, m / z): [M+H] + =442.4

[0486] Step 2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0487]

[0488] TFA (10 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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 obtain the title compound (200 mg). MS (ESI, m / z): [M+H] + =342.4

[0489] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetate

[0490]

[0491] Ethylbis(propane-2-yl)amine (2.0 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 2-bromoacetate (121 mg, 0.62 mmol) in ACN (10.0 ml). The reactants were 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 obtain the title compound (210 mg). MS (ESI, m / z): [M+H] + =456.4

[0492] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetic acid

[0493]

[0494] TFA (1 ml) was added to tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)acetate (30 mg, 0.06 mmol) in DCM (3 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 obtain the title compound (15 mg). MS (ESI, m / z): [M+H] + =400.4

[0495] 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (ICT-0001109)

[0496]

[0497] HATU (20.6 mg, 0.06 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 (15 mg, 0.03 mmol) and 2-(4-(2-(2,6-dioxopiperidin-3-yl)1-oxo-1,2-dioxopiperidin-3-yl)- ... To the mixture of 1,4-dihydrophthalazin-6-yl)piperazin-1-yl)piperazin-1-yl)acetic acid (12.3 mg, 0.06 mmol) was added ethylbis(propan-2-yl)amine (5 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (8 mg). MS (ESI, m / z): [M+H] + =935.1.

[0498] 1H NMR(400MHz,DMSO-d6)δppm 10.98(s,1H)9.21(s,1H)8.74(s,2H)8.64(s,1H)8.31(s,1H)8.18(s,1H)7.91(d,J=8.93Hz,1H)7.61(m,J=8.19Hz,2H)7.38(m, J=8.19Hz,2H)7.04-7.11(m,1H)6.87-6.93(m,1H)6.76(d,J=2.08Hz,1H)4.85-5.00(m,2H)4.73(d,J=11.98Hz,1H)4.38(d,J=12 .72Hz,1H)4.22(br.s.,1H)3.87-3.98(m,4H)3.50(s,2H)3.44(br.s.,4H)3.05-3.19(m,2H)2.85-2.97(m,2H)2.59(d,J=19.93H z,2H)2.35(br.s.,4H)2.30(br.s.,4H)2.07(dd,J=11.92,4.22Hz,1H)1.89-2.01(m,2H)1.61(br.s.,2H)1.37(t,J=5.93Hz,2H)

[0499] 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)

[0500] 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

[0501]

[0502] Ethylbis(propan-2-yl)amine (35.1 mg, 0.27 mmol) was added to DMF (2 ml) containing (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). 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 obtain the title compound (95 mg). MS (ESI, m / z): [M+H] + =692.6.

[0503] 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

[0504]

[0505] 2 mL of saturated NH4Cl was added to a solution containing (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 hours. After cooling to room temperature, the reaction was filtered and the filtrate was poured into water. Ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (69 mg). MS (ESI, m / z): [M+H] + =662.6.

[0506] 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)

[0507]

[0508] 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-bromomorphidine-2,6-dione (69.6 mg, 0.36 mmol). The reactants were stirred at 60° C. for 12 hours. The reactants were 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 obtain the title compound (121 mg). MS (ESI, m / z): [M+H] + =773.9.

[0509] 1H NMR(400MHz,DMSO-d6)δppm 10.71(s,1H)9.14(s,1H)8.68(s,2H)8.58(s,1H)8.25(s,1H)7.55(m,J=8.09Hz,2H)7.33(m,J=8.09Hz,2H)6.76(t, J=9.31Hz,1H)6.43(dd,J=14.95,2.29Hz,1H)6.35(d,J=8.54Hz,1H)5.74(d,J=7.78Hz,1H)4.79-4.93(m,2H)4.66(d ,J=12.36Hz,1H)4.31(d,J=12.97Hz,1H)4.09-4.25(m,1H)3.79-3.89(m,4H)3.37-3.55(m,3H)3.00-3.10(m,2H)2. 80(br.s.,2H)2.61-2.71(m,1H)2.51(d,J=4.43Hz,1H)2.47(s,2H)1.97-2.05(m,1H)1.77(dd,J=12.13,4.50Hz,1H)

[0510] 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)

[0511] Step 1) Preparation of (S)-tert-butyl 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

[0512]

[0513] Tert-butyl 2-bromoacetate (150 mg, 0.62 mmol), ethylbis(propan-2-yl)amine (2.0 equiv) were added to a flask containing (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 (300 mg, 0.62 mmol). mol) in ACN (10.0 ml). 2-Bromoacetic acid tert-butyl ester (150 mg, 0.62 mmol) and ethylbis(propane-2-yl)amine (2.0 equivalents) were added to a solution of (S)-2-(5-(1-(1-methyl-1-yl)phenyl-pyridazin-2-yl)morpholine (300 mg, 0.62 mmol). The subjective compound (210 mg) was obtained. MS (ESI, m / z): [M+H] + =667.7

[0514] 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

[0515]

[0516] TFA (1 ml) was added to a solution of (S)-tert-butyl 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 reactants were 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 obtain the subjective compound (150 mg). MS (ESI, m / z): [M+H] + =611.4

[0517] 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)

[0518]

[0519] 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 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 MeOH / DCM (0-10%) MPLC to obtain the title compound (79 mg). MS (ESI, m / z): [M+H] + =900.1.

[0520] 1H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H)9.21(s,1H)8.75(s,2H)8.65(s,1H)8.32(s,1H)7.60(m,J=7.93Hz,2H)7.37(m,J=8.09Hz,2H)6.78-6.8 8(m,1H)6.53(dd,J=14.80,2.29Hz,1H)6.44(d,J=8.70Hz,1H)5.88(d,J=7.78Hz,1H)4.86-4.99(m,2H)4.73(d,J=12. 21Hz,1H)4.38(d,J=13.12Hz,1H)3.89-3.97(m,4H)3.66(br.s.,1H)3.56(br.s.,2H)3.45-3.54(m,3H)3.17(br.s., 1H)3.04-3.14(m,2H)2.86(br.s.,2H)2.78(br.s.,2H)2.74(s,1H)2.59(br.s.,1H)2.42(br.s.,4H)2.37(br.s.,2H)

[0521] 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)

[0522]

[0523]

[0266] HATU (74.4 mg, 0.16 mmol) in (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-dimethylbutanoyl)-4-hydroxy-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 MeOH / DCM (0-10%) MPLC to obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =1038.1.

[0524] 1H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H)8.92(s,1H)8.65-8.74(m,2H)8.58(s,1H)8.24(s,1H)7.54(d,J=7.93Hz,2H)7.35 -7.40(m,2H)7.22-7.35(m,4H)5.05(d,J=3.20Hz,1H)4.79-4.94(m,3H)4.66(d,J=12.66Hz,1 H)4.40-4.49(m,1H)4.26-4.40(m,2H)4.21(br.s.,1H)3.82-3.89(m,4H)3.37-3.55(m,4H)2. 95-3.09(m,2H)2.37-2.40(m,4H)1.91-2.05(m,1H)1.31(d,J=7.02Hz,3H)0.80-0.94(m,10H)

[0525] [Table 1] In vitro degradation analysis and cell viability analysis of C-MET PROTAC compounds (see Experimental Examples 1 to 3 below)

[0526]

[0527]

[0528] A:IC 50 or DC 50 <100nM

[0529] B: 100nM <IC 50 or DC 50 <1uM

[0530] C:1uM <IC 50 or DC 50

[0531] Example C: Preparation of Tepotinib-based cMET PROTAC

[0532] Example C-1: Preparation of 3-(1-(3-(5-((1-(1-(1-(1-((1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000907)

[0533] Step 1) Preparation of tert-butyl 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12-tetraoxopentadecane-15-olate

[0534]

[0535] A solution of 3-(8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (200 mg, 0.73 mmol), tert-butyl 1-amino-3,6,9,12-tetraoxopentadecane-15-ate (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.

[0536] Step 2) Preparation of 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oleic acid

[0537]

[0538] 1 ml of TFA solution was added to tert-butyl 1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12-tetraoxopentadecane-15-olate (360 mg, 0.62 mmol) in DCM (5 mL) and stirred at room temperature for 2 hours. MS (ESI, m / z): [M+H]+ =521.2.

[0539] Step 3) Preparation of 3-(1-(3-(5-((1-(1-(1-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl)amino)3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000907)

[0540]

[0541] 3-{6-oxo-1-[(3-{5-[(piperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-1, HATU (13.5 mmol, 0.06 mmol) was added to a solution of 6-dihydropyridazin-3-yl}benzonitrile (25 mg, 0.05 mmol) and 1-((3-(2,6-dioxopiperidin-3-yl)4-oxo-3,4-dihydrophthalazin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-one (27.2 mmol, 0.05 mmol) in DMF (5 ml) at room temperature, followed by the addition of ethylbis(propan-2-yl)amine (33.8 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) MPLC to obtain the title compound (51.3 mg). MS (ESI, m / z): [M+H] + =982.1.

[0542] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53 (m,2H)7.17(d,J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.67-5.77(m ,1H)4.85-5.00(m,2H)4.73(d,J=12.84Hz,2H)4.39(d,J=12.59Hz,3H)4.09-4.21(m,3H)3.86-4.00(m,4H)3.44-3 .66(m,8H)3.12(dd,J=17.97,12.59Hz,3H)2.83-3.00(m,2H)2.56-2.62(m,2H)1.88-2.11(m,6H)1.45(br.s.,2H)

[0543] 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)

[0544] Step 1) Preparation of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0545]

[0546] 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 reactant 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. Benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.95 g) was obtained. MS (ESI, m / z): [M + H] + =418.2.

[0547] Step 2) Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

[0548]

[0549] 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 celite 545 phase. The solvent was removed under reduced pressure, and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.35 g) was obtained. MS (ESI, m / z): [M+H] + =284.0.

[0550] Step 3) Preparation of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0551]

[0552] A solution of 3-(6-fluoro-1-oxophthalazin-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 obtain tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)piperazine-1-carboxylate (910 mg). MS (ESI, m / z): [M + H] + =552.3.

[0553] Step 4) Preparation of 3-(1-oxo-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0554]

[0555] 2 ml of TFA was added to a solution of tert-butyl 4-((1-(2-(2-(2-(2-(2-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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.

[0556] Step 5) Preparation of 3-(1-(1-(3-(5-((1-(2-(4-((1-(2-(2,6-dioxopiperidin-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)

[0557]

[0558] HATU (47.7 mg, 0.13 mmol) was added to 2-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-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)phthalazin-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 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =972.1.

[0559] 1H NMR(500MHz,DMSO-d6)δppm 11.03(s,1H)8.65-8.70(m,3H)8.38(s,3H)8.22-8.30(m,3H)8.19(d,J=9.78Hz,1H)8.12(d,J=9.29Hz,1H)7.94(d ,J=7.58Hz,1H)7.73(t,J=7.83Hz,1H)7.48-7.53(m,2H)7.17(d,J=9.78Hz,1H)5.45(s,2H)4.10(d,J=5.99Hz,1H)

[0560] 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-yl}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-000979)

[0561] Step 1) Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0562]

[0563] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxophthalazine-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 reactants were 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 obtain the title compound (350 mg). MS (ESI, m / z): [M+H] + =442.4

[0564] Step 2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0565]

[0566] 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-dihydrophthalazin-6-yl) in DCM (30.0 ml). TFA (10.0 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-piperazine-1-carboxylate-6-in DCM (30.0 ml). The reactants were 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 obtain the title compound (200 mg). MS (ESI, m / z): [M+H] + =342.4

[0567] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetate

[0568]

[0569] Ethylbis(propane-2-yl)amine (2.0 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 2-bromoacetate (121 mg, 0.62 mmol) in ACN (10.0 ml). The reactants were 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 obtain the title compound (210 mg). MS (ESI, m / z): [M+H] + =456.4

[0570] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetic acid

[0571]

[0572] TFA (1.0 ml) was added to a solution of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)acetate (30 mg, 0.06 mmol) in DCM (3.0 ml). The reactants were 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 obtain the title compound (15 mg). MS (ESI, m / z): [M+H] + =400.4

[0573] Step 5) Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-yl}acetyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-000979)

[0574]

[0575] 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-dihydrophthalazin-5-yl}acetic acid (20.6 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propane-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =860.9.

[0576] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)8.65(s,2H)8.38(s,2H)8.20-8.27(m,3H)8.18(d,J=9.77Hz,1H)8.04(d,J=9.16Hz,1H)7.93(d,J=7.63Hz, 1H)7.72(t,J=7.86Hz,1H)7.44-7.53(m,3H)7.26(s,1H)7.17(d,J=9.77Hz,1H)5.75(dd,J=11.90,4.73Hz,1H)5.44(s,2H )4.42(d,J=12.21Hz,1H)4.06-4.16(m,3H)3.43(br.s.,6H)3.12(d,J=12.97Hz,1H)3.05(t,J=11.98Hz,1H)2.86-2.98( m,1H)2.64(br.s.,1H)2.60(br.s.,6H)2.09(d,J=5.04Hz,1H)1.96(d,J=16.48Hz,1H)1.83(br.s.,2H)1.32-1.40(m,1H)

[0577] 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-dihydrophthalazin-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)

[0578] 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

[0579]

[0580] Ethylbis(2-[(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-[(methylsulfonyloxy)methyl]piperidine-1-carboxylate (184 mg, 0.62 mmol) were added to a solution of tert-butyl 4-[(methylsulfonyloxy)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 MeOH / DCM (0-10%) MPLC to obtain a Boc-protected compound. This compound was treated with 4.0 M HCl in dioxane and stirred for 4 hours. After completion of the reaction, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM, passed through a pad of NH-DM 1020 Chromatorex, and the title compound (205 mg) was obtained. MS (ESI, m / z): [M+H] + = 576.7.

[0581] 1H NMR(500MHz,DMSO-d6)δppm 11.02(s,1H)8.60-8.71(m,2H)8.37(s,2H)8.13-8.28(m,4H)8.04(d,J=9.05Hz,1H)7.93(d, J=7.70Hz,1H)7.71(t,J=7.89Hz,1H)7.42-7.54(m,3H)7.25(d,J=2.08Hz,1H)7.16(d,J=9.78 Hz,1H)5.75(dd,J=12.10,4.89Hz,1H)5.44(s,2H)3.98-4.13(m,2H)3.37-3.47(m,4H)2.99-3 .15(m,2H)2.85-2.98(m,1H)2.59(br.s.,5H)1.99(s,1H)1.29-1.39(m,1H)1.11-1.25(m,2H)

[0582] Step 2) Preparation of 2-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-5-yl]amino}acetic acid

[0583]

[0584] At room temperature, a solution of 3-(8-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione was added, followed by ethylbis(propane-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 x 2). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the intermediate and treated with CH2Cl2 (4 mL) containing 50% TFA. The reaction was stirred for 2 hours, concentrated under reduced pressure, and the title compound (189 mg) was obtained. MS (ESI, m / z): [M+H]+=.345.2

[0585] Step 3) 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)methyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000980)

[0586]

[0587] 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-dihydrophthalazin-5-yl]amino}acetic acid (29.2 mg, 0.09 mmol) were added, followed by ethylbis(propan-2-yl)amine (33.7 mmol). The reaction was stirred for 6 hours. The reaction was poured into water. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) MPLC to obtain the title compound (34.2 mg). MS (ESI, m / z): [M+H] + =903.0.

[0588] 1H NMR(500MHz,DMSO-d6)δppm 11.00(s,1H)9.45(br.s.,1H)8.65(s,2H)8.38(s,2H)8.15-8.29(m,3H)7.94(d,J=7.70Hz,1H)7.61-7.79(m,2H)7.45- 7.53(m,2H)7.17(d,J=9.78Hz,1H)6.94(d,J=7.46Hz,2H)5.63(br.s.,1H)5.45(s,2H)4.40(d,J=12.35Hz,1H)4.08(br .s.,4H)3.92(d,J=13.82Hz,1H)3.02(d,J=12.23Hz,1H)2.79-2.97(m,3H)2.54-2.71(m,4H)2.42(s,4H)2.01-2.18(m, 3H)1.82-2.01(m,3H)1.77(br.s.,6H)1.31(br.s.,1H)1.08-1.27(m,4H)1.04(d,J=6.11Hz,1H)0.94(d,J=5.87Hz,1H)

[0589] 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)

[0590]

[0591] At room temperature, HATU (36.8 mg, 0.1 mmol) was added to a solution containing 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-dihydrophthalazin-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). The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) MPLC to obtain the title compound (35.6 mg). MS (ESI, m / z): [M+H] + =805.9.

[0592] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)9.47(br.s.,1H)8.61-8.71(m,2H)8.33-8.43(m,2H)8.20-8.28(m,2H)8.18(d,J= 9.90Hz,1H)7.85-7.99(m,1H)7.72(t,J=7.89Hz,1H)7.67(t,J=8.13Hz,1H)7.41-7.54(m,2H)7 .17(d,J=9.78Hz,1H)6.95(dd,J=8.13,3.12Hz,2H)5.45(s,2H)3.95-4.15(m,3H)3.10(t,J=12 .23Hz,1H)2.82-2.98(m,1H)2.52-2.81(m,3H)2.42(s,3H)2.02-2.16(m,1H)1.11-1.29(m,1H)

[0593] Example C-6: Preparation of 3-(1-{[3-(5-{[1-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}hexanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000984)

[0594] Step 1) Preparation of 6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}hexanoic acid

[0595]

[0596] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl) and 6-aminohexanoic acid (286 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (270 mg). MS (ESI, m / z): [M + H] + =387.4

[0597] Step 2) Preparation of 3-(1-{[3-(5-{[1-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}hexanoyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000984)

[0598]

[0599] 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-dihydrophthalazin-6-yl]amino}hexanoic acid (24.2 mg, 0.06 mmol), followed by the addition of ethylbis(propane-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =847.9.

[0600] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53(m,2H)7.17(d, J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.72(dd,J=11.83,4.65Hz,1H)5.45(s,2H) 4.44(d,J=14.04Hz,1H)4.06(d,J=6.41Hz,2H)3.91(d,J=13.89Hz,2H)3.62(dq,J=10.49,6.62Hz,2H)3.10-3.19(m,4H)3.02(t, J=12.44Hz,2H)2.86-2.96(m,2H)2.30-2.37(m,2H)2.02-2.11(m,2H)1.80(t,J=15.03Hz,2H)1.51-1.67(m,4H)1.36-1.45(m,2H)

[0601] Example C-7: 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)

[0602] Step 1) Preparation of 7-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)heptanoic acid

[0603]

[0604] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl) and 7-aminoheptanoic acid (260 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M + H] + =401.4

[0605] 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)

[0606]

[0607] 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-dihydrophthalazin-6-yl)amino)heptanoic acid (25.2 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. The reaction was poured into water. The reaction 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 obtain the title compound (30 mg). MS (ESI, m / z): [M+H]+ =861.9.

[0608] 1H NMR(500MHz,DMSO-d6)δppm 10.99(s,1H)8.62-8.69(m,2H)8.39(s,2H)8.14-8.30(m,2H)7.86-7.97(m,2H)7.73(t,J=7.93Hz,1H)7.44-7.54(m,2H)7.17(d,J= 9.61Hz,1H)7.08(dd,J=8.93,2.06Hz,1H)6.89(br.s.,1H)6.73-6.80(m,1H)5.72(dd,J=12.05,5.04Hz,1H)5.45(s,2H))4.43(d,J= 12.66Hz,1H)4.07(d,J=6.26Hz,2H)3.90(d,J=13.12Hz,1H)3.62(dq,J=10.47,6.53Hz,4H)3.09-3.20(m,6H)3.02(t,J=11.60Hz,2H )2.85-2.97(m,1H)2.32(t,J=7.40Hz,2H)2.02-2.12(m,1H)1.88-2.01(m,2H)1.75-1.87(m,2H)1.57-1.64(m,2H)1.31-1.55(m,2H)

[0609] Example C-8: Preparation of 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 (ICT-0000986)

[0610] Step 1) Preparation of 2-(2-(2-((2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetate

[0611]

[0612] Ethylbis(propan-2-yl)amine (4.0 equivalents) 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 reactants were stirred at 130° C. for 48 hours. 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 obtain the subjective compound (240 mg). MS (ESI, m / z): [M+H] + =419.4

[0613] Step 2) Preparation of 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 (ICT-0000986)

[0614]

[0615] 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-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)amino)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. The reaction 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 obtain the title compound (30 mg). MS (ESI, m / z): [M+H] + =879.9.

[0616] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53(m, 2H)7.17(d,J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.73(d,J=10.88Hz, 1H)4.86-5.00(m,2H)4.73(d,J=12.23Hz,1H)4.39(d,J=12.59Hz,2H)4.21(br.s.,2H)3.88-3.98(m,4H)3.56-3.66( m,6H)3.13(br.s.,2H)2.84-2.98(m,2H)2.59(d,J=18.10Hz,2H)2.08(d,J=4.28Hz,2H)1.91-2.02(m,2H)1.75(s,2H)

[0617] 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-dihydrophthalazin-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)

[0618] Step 1) Preparation of 2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}ethoxy)ethoxy]ethoxy}ethoxy}ethoxy}acetate

[0619]

[0620] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(6-fluoro-1-oxo-1,2-dihydrophthalazin-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). The reactants were stirred at 130 ° C for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Subjective compound (250 mg) MS (ESI, m / z): [M+H]+ =463.4

[0621] Step 2) Preparation of 3-(1-{[3-(5-{[1-(2-{2-{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 (ICT-0000987)

[0622]

[0623] 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-dihydrophthalazin-6-yl]amino}ethoxy]ethoxy]ethoxy The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =823.9.

[0624] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53(m, 2H)7.17(d,J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.72(dd,J=11.37, 4.89Hz,1H)4.85-5.00(m,2H)4.73(d,J=12.10Hz,1H)4.39(d,J=11.62Hz,3H)4.15-4.21(m,3H)3.88-3.97(m,4H)3. 44-3.67(m,8H)3.10(d,J=12.84Hz,3H)2.78-2.98(m,2H)2.59(d,J=17.97Hz,2H)1.88-2.09(m,2H)1.33-1.41(m,3H)

[0625] Example C-10: Preparation of 3-(1-{[3-(5-{[1-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0626] Step 1) Synthesis of 14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]amino}-3,6,9,12-tetracosanoic acid

[0627]

[0628] Ethylbis(propane-2-yl)amine (4.0 equivalents) 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 14-amino-3,6,9,12-tetracosanoic acid (548 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (270 mg). MS (ESI, m / z): [M + H] + =507.4

[0629] Step 2) Preparation of 3-(1-{[3-(5-{[1-(14-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0630]

[0631] 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-dihydrophthalazin-6-yl]amino}hexanoic acid (31.8 mg, 0.06 mmol), followed by the addition of ethylbis(propane-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =968.3.

[0632] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53 (m,2H)7.17(d,J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.67-5.77(m ,1H)4.85-5.00(m,2H)4.73(d,J=12.84Hz,2H)4.39(d,J=12.59Hz,3H)4.09-4.21(m,3H)3.86-4.00(m,4H)3.44-3 .66(m,8H)3.12(dd,J=17.97,12.59Hz,3H)2.83-3.00(m,2H)2.56-2.62(m,2H)1.88-2.11(m,6H)1.45(br.s.,2H)

[0633] 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)

[0634] Step 1) Preparation of 4-((2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butyric acid

[0635]

[0636] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.mmol) and 4-aminobutyric acid (225 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (270 mg). MS (ESI, m / z): [M+H] + =373.4.

[0637] Step 2) Preparation of 3-(1-(3-(5-((1-(4-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butyryl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0000989)

[0638]

[0639] 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 4-((2-(2-(2-(2-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)butanoic acid (30.8 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 was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =833.9.

[0640] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53(m,2H)7.17(d, J=9.61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.72(dd,J=11.83,4.65Hz,1H)5.45(s,2H) 4.44(d,J=14.04Hz,1H)4.06(d,J=6.41Hz,2H)3.91(d,J=13.89Hz,2H)3.62(dq,J=10.49,6.62Hz,2H)3.10-3.19(m,4H)3.02(t, J=12.44Hz,2H)2.86-2.96(m,2H)2.30-2.37(m,2H)2.02-2.11(m,3H)1.80(t,J=15.03Hz,2H)1.51-1.67(m,2H)1.36-1.45(m,2H)

[0641] 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)

[0642] Step 1) Preparation of 6-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)hexanoic acid

[0643]

[0644] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazine-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). The reactants were 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 obtain the title compound (280 mg). MS (ESI, m / z): [M+H] + =401.4.

[0645] Step 2) Preparation of 3-(1-(3-(5-((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)benzonitrile (ICT-0000990)

[0646]

[0647] 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 6-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)hexanoic acid (38.8 mg, 0.13 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 was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =861.9.

[0648] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.63-8.68(m,2H)8.39(s,2H)8.15-8.28(m,2H)7.89-7.96(m,2H)7.73(t,J=7.86Hz,1H)7.46-7.53(m,2H)7.17(d,J=9. 61Hz,1H)7.08(dd,J=8.85,1.98Hz,1H)6.89(t,J=5.11Hz,1H)6.72-6.78(m,1H)5.72(dd,J=11.83,4.65Hz,1H)5.45(s,2H)4.44(d,J =14.04Hz,1H)4.06(d,J=6.41Hz,2H)3.91(d,J=13.89Hz,2H)3.62(dq,J=10.49,6.62Hz,2H)3.10-3.19(m,4H)3.02(t,J=12.44Hz,2H )2.86-2.96(m,2H)2.30-2.37(m,2H)2.02-2.11(m,2H)1.95-2.00(s,3H)1.80(t,J=15.03Hz,2H)1.51-1.67(m,4H)1.36-1.45(m,2H)

[0649] Example C-13: Preparation of 3-(1-(3-(5-((1-(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)

[0650] Step 1) Preparation of 2-(2-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)ethoxy)acetic acid

[0651]

[0652] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-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 reactants were 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 subjective compound (270 mg) was obtained. MS (ESI, m / z): [M + H] + =433.4.

[0653] Step 2) Preparation of 3-(1-(3-(5-((1-(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)

[0654]

[0655] 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 2-(2-(2-((2-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)acetic acid (58.8 mg, 0.06 mmol), followed by the addition of ethylbis(propan-2-yl)amine (3 equiv). The reactant 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =893.9.

[0656] 1H NMR(500MHz,DMSO-d6)δppm 10.93(s,1H)8.60-8.66(m,2H)8.37(d,J=5.34Hz,2H)8.20-8.29(m,3H)8.17(d,J=9.77Hz,1H)7.94(t,J=9.46Hz,2H)7.71( t,J=7.86Hz,1H)7.45-7.52(m,2H)7.09-7.18(m,2H)6.88(t,J=5.42Hz,1H)6.72-6.79(m,1H)5.60-5.69(m,1H)5.44(s,2H)4 .37(d,J=12.36Hz,1H)4.10-4.21(m,2H)4.04(d,J=6.26Hz,2H)3.80(d,J=13.43Hz,1H)3.55-3.68(m,8H)3.35-3.44(m,2H) 3.10-3.19(m,2H)2.82-3.02(m,2H)2.52-2.63(m,3H)2.41(s,3H)1.98-2.09(m,2H)1.77(br.s.,2H)1.25(q,J=7.12Hz,17H)

[0657] 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-dihydrophthalazin-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)

[0658] Step 1) Preparation of 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)ethoxy)ethoxy)ethoxy)acetic acid

[0659]

[0660] Ethylbis(propan-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.mmol) and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid (455 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were stirred at 130° C. for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. The subjective compound (290 mg) was obtained. MS (ESI, m / z): [M+H] + =477.4.

[0661] 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-dihydrophthalazin-6-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001088)

[0662]

[0663] 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 2-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)ethoxy )ethoxy)ethoxy)acetic acid (63.8 mg, 0.06 mmol), followed by the addition of ethylbis(propane-2-yl)amine (3 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =837.9.

[0664] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.58-8.65(m,2H)8.35-8.39(m,2H)8.20-8.27(m,2H)8.15-8.19(m,1H)7.90-7.96(m,2H)7.71(t,J=7.86Hz,1H)7.45-7.52( m,2H)7.16(d,J=9.77Hz,1H)7.10(dd,J=8.77,2.06Hz,1H)6.87(t,J=5.42Hz,1H)6.68-6.77(m,1H)5.65(d,J=7.17Hz,1H)5.44(s,2H)4.3 6(d,J=12.66Hz,1H)4.13-4.19(m,1H)4.07-4.13(m,1H)4.04(d,J=6.10Hz,2H)3.82(d,J=12.51Hz,1H)3.62(t,J=5.49Hz,3H)3.51-3.58( m,8H)3.35-3.41(m,2H)3.11-3.18(m,1H)2.83-3.05(m,2H)2.54-2.62(m,2H)2.38-2.44(s,3H)1.93-2.07(m,2H)1.78(d,J=11.60Hz,2H)

[0665] 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-dihydrophthalazin-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)

[0666] Step 1) Preparation of 14-((2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)-3,6,9,12-tetracosanoic acid

[0667]

[0668] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.mmol) and 14-amino-3,6,9,12-tetracosanoic acid (485 mg, 2.18 mmol) in NMP (2.0 ml). The reactants were stirred at 130 ° C for 48 hours. 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 obtain the title compound (290 mg). MS (ESI, m / z): [M + H] + =521.4.

[0669] 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-tetradecanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001089)

[0670]

[0671] 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 14-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)3,6,9,12-tetrahydrobenzonitrile. To the mixture of tetradecanoic acid (68.8 mg, 0.06 mmol), ethylbis(propane-2-yl)amine (3 equivalents) was added. The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =837.9.

[0672] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.58-8.65(m,2H)8.35-8.39(m,2H)8.20-8.27(m,2H)8.15-8.19(m,1H)7.90-7.96(m,2H)7.71(t,J=7.86Hz,1H)7.45-7.52( m,2H)7.16(d,J=9.77Hz,1H)7.10(dd,J=8.77,2.06Hz,1H)6.87(t,J=5.42Hz,1H)6.68-6.77(m,1H)5.65(d,J=7.17Hz,1H)5.44(s,2H)4.3 6(d,J=12.66Hz,1H)4.13-4.19(m,1H)4.07-4.13(m,1H)4.04(d,J=6.10Hz,2H)3.82(d,J=12.51Hz,1H)3.62(t,J=5.49Hz,3H)3.51-3.58( m,8H)3.35-3.41(m,2H)3.11-3.18(m,1H)2.83-3.05(m,2H)2.54-2.62(m,6H)2.38-2.44(s,3H)1.93-2.07(m,2H)1.78(d,J=11.60Hz,2H)

[0673] 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-dihydrophthalazin-6-yl)amino)-3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001091)

[0674] Step 1) Preparation of 1-((2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)-3,6,9,12-tetraoxopentadecane-15-oleic acid

[0675]

[0676] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to NMP (2.0 ml) containing 3-(6-fluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.mmol) and 1-amino-3,6,9,12-tetraoxapentadecane-15-oleic acid (515 mg, 2.18 mmol). The reactants were 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 obtain the title compound (300 mg). MS (ESI, m / z): [M+H] + =535.4.

[0677] Step 2) Preparation of 3-(1-(3-(5-((1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001091)

[0678]

[0679] 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 1-((2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)amino)-3,6,9,12-tetraoxopentadecane -15-ketone (71.8 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, 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + = 996.1.

[0680] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.61-8.68(m,2H)8.38(br.s.,2H)8.23(t,J=8.39Hz,2H)8.17(d,J=9.77Hz,1H)7.89-7.97(m,2H)7.71(t,J=7.86Hz,1H) 7.42-7.53(m,2H)7.16(d,J=9.77Hz,1H)7.07-7.14(m,1H)6.87(t,J=5.42Hz,1H)6.70-6.79(m,1H)5.65(d,J=6.71Hz,1H)5.44(s,2H)4 .36(d,J=12.51Hz,1H)4.13-4.19(m,1H)4.07-4.13(m,1H)3.98-4.07(m,2H)3.77-3.89(m,1H)3.58-3.65(m,2H)3.45-3.58(m,12H)3. 35-3.41(m,2H)2.84-3.04(m,2H)2.52-2.66(m,3H)2.39-2.44(m,3H)2.00-2.07(m,2H)1.96(d,J=17.40Hz,1H)1.78(d,J=11.60Hz,2H)

[0681] 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-dihydrophthalazin-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)

[0682] Step 1) Preparation of benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0683]

[0684] 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 hours. After cooling, the reactant (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 obtain benzyl 4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (1.95 g). MS (ESI, m / z): [M+H] + =418.2.

[0685] Step 2) Preparation of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate

[0686]

[0687] 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 phase. The solvent was removed under reduced pressure to obtain tert-butyl 4-(piperazine-1-monomethyl)piperidine-1-carboxylate (0.35 g). MS (ESI, m / z): [M+H] + =284.0.

[0688] Step 3) Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0689]

[0690] A solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-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 obtain tert-butyl 4-((4-(2-(2-(2,6-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methylpiperidine-1-carboxylate (910 mg). MS (ESI, m / z): [M + H]+ =552.3.

[0691] 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

[0692]

[0693] 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-dihydrophthalazin-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.

[0694] 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-dihydrophthalazin-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)

[0695]

[0696] HATU (47.7 mg, 0.13 mmol) was added to 2-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-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)phthalazin-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 equiv). The reaction was stirred at room temperature for 6 hours. The reaction 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =972.1.

[0697] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H)8.60-8.70(m,2H)8.39(s,1H)8.37(s,1H)8.20-8.26(m,2H)8.17(d,J=9.77Hz,1H)8.06(d,J=9.00Hz,1H)7.92(d,J=7.6 3Hz,1H)7.71(t,J=7.86Hz,1H)7.46-7.53(m,3H)7.16(d,J=9.77Hz,1H)7.07(s,1H)5.68(dd,J=11.75,4.73Hz,1H)5.44(s,2H)4.34( d,J=12.21Hz,1H)4.00-4.08(m,3H)3.43(br.s.,5H)2.80-3.03(m,3H)2.53-2.67(m,4H)2.43-2.49(m,4H)2.19(d,J=6.56Hz,2H)1.9 1-2.13(m,4H)1.77(br.s.,7H)1.36-1.45(m,1H)1.32(d,J=10.68Hz,2H)1.23(s,1H)1.08(d,J=11.44Hz,1H)0.92(d,J=10.83Hz,1H)

[0698] Example C-18: Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-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)

[0699] Step 1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0700]

[0701] A solution of 3-(7-fluoro-4-methyl-1-oxophthalazin-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 obtain tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (910 mg). MS (ESI, m / z): [M + H] + =456.3.

[0702] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0703]

[0704] 2 ml of TFA was added to a solution of 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)- ... + =356.3.

[0705] 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-dihydrophthalazin-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)

[0706]

[0707] HATU (47.7 mg, 0.13 mmol) was added to DMF (2.0 ml) containing 2-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-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 (20 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 was poured into water. The reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =874.9.

[0708] 1H NMR(500MHz,DMSO-d6)δppm 10.93(s,1H)8.53-8.61(m,2H)8.26-8.35(m,2H)8.13-8.20(m,2H)8.08-8.13(m,1H)7.86(d,J=7.70Hz,1H)7.74(d,J=8.93H z,1H)7.64(t,J=7.89Hz,1H)7.55(dd,J=8.99,2.51Hz,1H)7.48(d,J=2.45Hz,1H)7.35-7.45(m,2H)7.05-7.13(m,1H)5.60-5 .72(m,2H)5.37(s,2H)3.97(d,J=5.87Hz,2H)3.70(br.s.,1H)3.57(br.s.,1H)3.40(br.s.,2H)3.07-3.19(m,2H)2.78-2.89 (m,2H)2.46-2.58(m,2H)2.36-2.42(m,3H)1.92-2.05(m,2H)1.71(d,J=9.29Hz,2H)1.19-1.32(m,2H)1.06(d,J=6.60Hz,1H)

[0709] Example C-19: Preparation of 3-(1-(4-(5-((1-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001173)

[0710] Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0711]

[0712] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of (3.0 ml) 3-(6-fluoro-4-methyl-1-oxophthalazine-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. The reactants were 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 obtain the title compound (350 mg). MS (ESI, m / z): [M+H] + =456.4

[0713] Step 2) Preparation of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0714]

[0715] 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-dihydrophthalazin-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 reactants were 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 obtain the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4

[0716] Step 3) Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetate

[0717]

[0718] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-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 reactants were 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 obtain the title compound (210 mg). MS (ESI, m / z): [M+H] + =470.4

[0719] Step 4) Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetic acid

[0720]

[0721] TFA (1.0 ml) was added to tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetate (30 mg, 0.06 mmol) in DCM (3.0 ml). The reactants were 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 obtain the title compound (15 mg). MS (ESI, m / z): [M+H] + =414.4

[0722] 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-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001173)

[0723]

[0724] HATU (47.7 mg, 0.13 mmol) was added to a mixture containing 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-dihydrophthalazin-6-yl)piperazin-1-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 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H]+ = 874.9.

[0725] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.54-8.62(m,2H)8.31(s,2H)8.13-8.20(m,2H)8.10(d,J=9.77Hz,1H)8.00(d,J=8.85Hz,1H)7.86(d,J=7.63Hz ,1H)7.64(t,J=7.86Hz,1H)7.37-7.49(m,3H)7.09(d,J=9.77Hz,1H)7.02(br.s.,1H)5.61(d,J=6.56Hz,1H)5.37(s,2H)4.35 (d,J=12.36Hz,1H)3.60-4.24(m,1H)4.01(d,J=6.10Hz,2H)(3.42-3.52(m,2H)3.39(br.s.,2H)3.33-3.37(m,1H)3.12(s,1H )2.94-3.04(m,1H)2.79-2.90(m,1H)2.45-2.64(m,8H)2.38-2.44(s,3H)1.94-2.04(m,1H)1.81-1.94(m,2H)1.76(br.s.,2H)

[0726] Example C-20: Preparation of 3-(1-(3-(5-((1-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001174)

[0727] Step 1) Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate

[0728]

[0729] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropionate (140 mg, 0.62 mmol) in ACN (10.0 ml). The reactants were 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 obtain the title compound (210 mg). MS (ESI, m / z): [M+H] + =484.4

[0730] Step 2) Preparation of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propanoic acid

[0731]

[0732] TFA (1.0 ml) was added to tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reactants were 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =428.4

[0733] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propionyl-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001174)

[0734]

[0735] HATU (47.7 mg, 0.13 mmol) was added to a mixture containing 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-dihydrophthalazin-6-yl)piperazin-1-yl)propanoic acid (2 To the mixture of 4-[ ...

[0736] 1H NMR (500MHz, DMSO-d6) δ10.98 (s, 1H) 8.61-8.68 (m, 2H) 8.38 (s, 2H) 8.24 (t, J = 8.24Hz, 2H) 8.18 (d, J = 9.77Hz, 1H) 8.07 (d, J = 9.0 0Hz,1H)7.90-7.97(m,1H)7.72(t,J=7.86Hz,1H)7.44-7.54(m,3H)7.17(d,J=9.77Hz,1H)7.09(s,1H)5.68(d,J=6.71Hz,1H)5. 45(s,2H)4.44(d,J=13.73Hz,1H)4.08(d,J=6.10Hz,2H)3.98(d,J=13.28Hz,1H)3.37-3.48(m,4H)3.06(t,J=12.74Hz,1H)2.85 -2.96(m,2H)2.52-2.67(m,12H)2.38-2.44(s,3H)2.03-2.13(m,1H)1.90-2.00(m,1H)1.84(d,J=12.36Hz,1H)1.78(br.s.,1H)

[0737] 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-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001175)

[0738] Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate

[0739]

[0740] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 4-bromobutyrate (145 mg, 0.62 mmol) in ACN (10.0 ml). The reactants were 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 obtain the title compound (210 mg). MS (ESI, m / z): [M+H] + =498.4

[0741] Step 2) Preparation of 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoic acid

[0742]

[0743] TFA (1.0 ml) was added to tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reactants were 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 obtain the title compound (25 mg). MS (ESI, m / z): [M+H] + =442.4

[0744] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butyryl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001175)

[0745]

[0746] 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 4-(4-(2-(2-(2-(2-(2-dioxopiperidin-3-yl)4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoic acid (22. To a solution of 4-[ ...

[0747] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.54-8.60(m,2H)8.31(br.s.,2H)8.13-8.20(m,2H)8.11(d,J=9.77Hz,1H)7.99(d,J=9.00Hz,1H)7.86(d,J =7.48Hz,1H)7.65(t,J=7.86Hz,1H)7.37-7.47(m,3H)7.10(d,J=9.77Hz,1H)7.01(br.s.,1H)5.61(d,J=6.87Hz,1H)5.38 (s,2H)4.38(d,J=12.51Hz,1H)4.00(d,J=6.10Hz,2H)3.87(d,J=12.36Hz,1H)3.37(br.s.,3H)2.97(t,J=11.98Hz,1H)2. 76-2.89(m,1H)2.46-2.59(m,6H)2.41(s,4H)2.30(t,J=6.79Hz,3H)1.94-2.04(m,3H)1.83-1.94(m,3H)1.61-1.79(m,4H)

[0748] 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)

[0749] Step 1) Preparation of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoate

[0750]

[0751] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-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 reactants were 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 obtain the title compound (250 mg). MS (ESI, m / z): [M+H] + =512.4

[0752] Step 2) Preparation of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoic acid

[0753]

[0754] TFA (1.0 ml) was added to tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoate (40 mg, 0.08 mmol) in DCM (3.0 ml). The reactants were 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 obtain the title compound (28 mg). MS (ESI, m / z): [M+H] + =456.4

[0755] 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-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)

[0756]

[0757] 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-dihydrophthalazin-6-yl)piperazine- The mixture was added to a solution of 1-amino-2-yl)pentanoic acid (23 mg, 0.06 mmol), followed by the addition of ethylbis(propane-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 obtain the title compound (35 mg). MS (ESI, m / z): [M+H] + =917.1.

[0758] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.53-8.61(m,2H)8.31(br.s.,2H)8.17(t,J=8.93Hz,2H)8.11(d,J=9.77Hz,1H)8.02(d,J=8.70Hz,1H)7.86(d,J=7.78Hz,1 H)7.65(t,J=7.86Hz,1H)7.37-7.50(m,3H)7.01-7.11(m,2H)5.62(d,J=7.32Hz,1H)5.37(s,2H)4.37(d,J=12.82Hz,1H)4.00(d,J=6.26Hz ,2H)3.86(d,J=12.97Hz,1H)3.49-3.58(m,1H)3.44(br.s.,1H)3.31-3.39(m,2H)3.06(dd,J=7.25,4.20Hz,1H)2.97(t,J=12.21Hz,1H)2. 77-2.90(m,1H)2.46-2.58(m,6H)2.42(br.s.,5H)2.30(br.s.,2H)1.95-2.05(m,2H)1.67-1.80(m,2H)1.48(br.s.,2H)1.11-1.26(m,4H)

[0759] Example C-23: Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[0760] 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

[0761]

[0762] Ethylbis(propan-2-yl)amine (2.0 equiv) was added to ACN (5 ml) containing 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). 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. Subjective compound (210 mg) MS (ESI, m / z): [M+H] + =593.7

[0763] 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

[0764]

[0765] TFA (3 ml) was added to tert-butyl 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-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 completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to obtain the title compound (130 mg). MS (ESI, m / z): [M+H] + =537.6

[0766] Step 3) Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[0767]

[0768] HATU (42.5 mg, 0.12 mmol) was added to DMF (2.0 ml) containing 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-dihydrophthalazin-2-yl]piperidine-2,6-dione (19.9 mg, 0.05 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 was poured into water. The reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =874.9.

[0769] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.57(s,2H)8.31(s,2H)8.13-8.20(m,2H)8.11(d,J=9.77Hz,1H)8.02(d,J=9.00Hz,1H)7.86(d,J= 7.63Hz, 1H) 7.65 (t, J = 7.86Hz, 1H) 7.36-7.48 (m, 3H) 7.09 (d, J = 9.77Hz, 1H) 7.05 (d, J = 1.98Hz, 1H) 5.62 (d, J = 7. 17Hz,1H)5.37(s,2H)3.98(d,J=5.80Hz,2H)3.70(br.s.,2H)3.57(br.s.,2H)3.46(br.s.,2H)3.39(br.s.,2H) 2.77-2.89(m,3H)2.48-2.56(m,2H)1.94-2.04(m,4H)1.71(d,J=9.77Hz,4H)1.26(d,J=10.68Hz,2H)1.16(s,3H)

[0770] 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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001195)

[0771] Step 1) Preparation of 3-(4-methyl-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0772]

[0773] Ethylbis(propan-2-yl)amine (1.34 g, 10.4 mmol) was added to 5 ml of DMA containing 3-(7-fluoro-4-methyl-1-oxophthalazin-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) 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, treated with 50% TFA in DCM (5 mL) and stirred for 5 hours. After the reaction was complete, the reaction was concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and purified by Chromatorex pad and NH-DM 1020 to obtain the title compound (550 mg). MS (ESI, m / z): [M+H] + =453.6.

[0774] 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)

[0775]

[0776] K2CO3 (68.1 mg, 0.5 mmol) was added to DMF (5 ml) containing 5-chloro-N2-[5-methyl-4-(piperidin-4-yl)2-(propane-2-oxy)phenyl]-N4-[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-dihydrophthalazin-2-yl}piperidine-2,6-dione (42.6 mg, 0.1 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was poured into water. Ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (38.2 mg). MS (ESI, m / z): [M+H] + =[972.2],

[0777] 1H NMR(500MHz,DMSO-d6)δppm 11.02(s,1H)8.67(s,1H)8.50(s,2H)8.38(s,1H)8.11-8.29(m,2H)7.83-7.99(m,1H)7.73(t,J=7.95Hz,1H)7.46-7.56(m,1 H)7.38-7.45(m,4H)7.31(d,J=8.07Hz,1H)7.17(d,J=9.66Hz,1H)5.71(br.s.,1H)5.45(s,1H)4.37(d,J=13.20Hz,1H)4.19- 4.29(m,1H)4.05-4.19(m,2H)3.71(d,J=12.96Hz,2H)3.44(br.s.,1H)2.86-3.13(m,3H)2.78(br.s.,2H)2.56-2.72(m,1H) 2.53(s,1H)2.43(d,J=6.85Hz,1H)2.06-2.12(m,1H)1.96(d,J=10.27Hz,2H)1.84(d,J=11.25Hz,1H)1.67(d,J=11.49Hz,1H)

[0778] Example C-25: Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0779] Step 1) Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate

[0780]

[0781] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydrophthalazin-2-yl]piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropionate (153 mg, 0.73 mmol) in ACN (10 ml). The reactants were 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 obtain the title compound (150 mg) MS (ESI, m / z): [M+H] + =484.4

[0782] Step 2) Preparation of 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-yl}propionic acid

[0783]

[0784] TFA (5 ml) was added to a solution of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate (150 mg, 0.32 mmol) in DCM (15 ml). The reactants were 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =414.4

[0785] Step 3) Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-yl}propionyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001199)

[0786]

[0787] 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-dihydrophthalazin-6-yl]piperazin-1-yl}piperazin-1-yl}propanoic acid (26.0 mg, 0.13 mmol), followed by ethylbis(propan-2-yl)amine (3 equiv). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (43 mg). MS (ESI, m / z): [M+H] + =875.1.

[0788] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)8.66(s,2H)8.39(s,2H)8.21-8.29(m,3H)8.18(d,J=9.92Hz,1H)8.05(d,J=8.39Hz,1H)7.94( d,J=7.93Hz,1H)7.73(t,J=7.86Hz,1H)7.44-7.56(m,3H)7.28(br.s.,1H)7.17(d,J=9.77Hz,1H)5.72-5.79 (m,1H)5.45(s,2H)4.44(d,J=12.97Hz,1H)4.08(d,J=6.10Hz,2H)3.97(d,J=12.97Hz,1H)3.62(dq,J=10.49 ,6.52Hz,8H)3.07-3.19(m,8H)2.83-2.97(m,2H)2.04-2.11(m,3H)1.84(d,J=12.82Hz,1H)1.78(br.s.,1H)

[0789] Example C-26: Preparation of 3-(1-{[3-(5-{1-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl}butanoyl)piperidin-4-yl)methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001200)

[0790] Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate

[0791]

[0792] Ethylbis(propane-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-bromobutyrate (188 mg, 0.84 mmol) in NMP (2.0 ml). The reactants were 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 obtain the title compound (200 mg) MS (ESI, m / z): [M+H] + =484.6

[0793] Step 2) Preparation of 4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-yl}butyric acid

[0794]

[0795] TFA (5 ml) was added to a solution of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate (200 mg, 0.41 mmol) in DCM (15 ml). The reactants were 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 obtain the title compound (150 mg). MS (ESI, m / z): [M+H] + =428.4

[0796] Step 3) Preparation of 3-(1-{[3-(5-{[1-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl]piperazin-1-yl}butyryl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-001200)

[0797]

[0798] 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-dihydrophthalazin-6-yl]piperazin-1-yl}piperazin-1-yl}butanoic acid (26.8 mg, 0.06 mmol), followed by ethylbis(propan-2-yl)amine (3 equiv). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (40 mg). MS (ESI, m / z): [M+H] + =889.1.

[0799] 1H NMR(500MHz,DMSO-d6)δppm 10.94(s,1H)8.55-8.61(m,2H)8.31(s,2H)8.13-8.21(m,3H)8.11(d,J=9.92Hz,1H)7.98(d,J=7.93Hz,1H)7.86(d,J=7.63 Hz,1H)7.65(t,J=7.93Hz,1H)7.40-7.46(m,3H)7.21(br.s.,1H)7.10(d,J=9.77Hz,1H)5.63-5.73(m,1H)5.38(s,2H)4.37 (d,J=12.05Hz,1H)4.00(d,J=6.26Hz,2H)3.86(d,J=13.89Hz,1H)3.54(dd,J=10.45,6.33Hz,3H)3.03-3.12(m,3H)2.97(t ,J=12.59Hz,1H)2.79-2.90(m,1H)2.47-2.58(m,4H)2.29(br.s.,3H)1.95-2.04(m,4H)1.68-1.81(m,2H)1.47(br.s.,4H)

[0800] Example C-27: Preparation of 3-(1-{[3-(5-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0801] Step 1) Preparation of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoate

[0802]

[0803] Ethylbis(propane-2-yl)amine (4.0 equivalents) 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 reactants were 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 obtain the title compound (200 mg) MS (ESI, m / z): [M+H] + =512.6

[0804] Step 2) 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0805]

[0806] TFA (5 ml) was added to a solution of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)tert-butyl ester in DCM (15 ml). TFA (5 ml) was added to the solution of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)tert-butyl ester. The reactants were 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 obtain the title compound (150 mg) MS (ESI, m / z): [M+H] + =442.5

[0807] Step 3) Preparation of 3-(1-{[3-(5-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0808]

[0809] 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-dihydrophthalazin-6-yl]piperazin-1-yl}pentanoic acid (27.7 mg, 0.13 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 was poured into water, extracted with acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to obtain the title compound (42 mg). MS (ESI, m / z): [M+H] + =903.0.

[0810] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)8.59-8.73(m,2H)8.38(s,2H)8.21-8.30(m,3H)8.18(d,J=9.77Hz,1H)8.06(d,J=8.24Hz,1H)7.94(d,J=7.63Hz,1H)7.7 2(t,J=7.86Hz,1H)7.45-7.56(m,3H)7.29(br.s.,1H)7.17(d,J=9.77Hz,1H)5.76(dd,J=12.21,4.88Hz,1H)5.45(s,2H)4.45(d,J=12 .82Hz,1H)4.08(d,J=6.26Hz,2H)3.93(d,J=12.21Hz,1H)3.62(dq,J=10.57,6.55Hz,4H)3.09-3.19(m,4H)3.05(t,J=11.75Hz,1H)2. 87-2.97(m,1H)2.54-2.65(m,4H)2.38(d,J=12.05Hz,3H)2.03-2.13(m,3H)1.84(d,J=12.21Hz,2H)1.78(br.s.,2H)1.26-1.32(m,3H)

[0811] 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)

[0812] Step 1) Preparation of 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0813] and 3-(6-fluoro-4-methyl-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0814]

[0815] At ambient temperature, tert-butyl 4-(piperazine-1-yl)piperidine-1-carboxylate (92 mg, 325 μmol) was added to a solution of 3-(6,7-difluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 325 μmol) in DMA (1 mL), followed by addition of ethylbis(propane-2-yl)amine (46.3 mg, 358 μmol). The reactants were heated at 120 ° C for 16 hours. After the reaction was completed, the reactants were poured into water and extracted with ethyl acetate (25 mL x 2). The organic layer was separated. The crude product was obtained by drying with magnesium sulfate, filtering and concentrating, and the crude product was purified by MPLC (1% to 5% MeOH / CH2Cl2). The Boc-protected compound was obtained, treated with DCM (5 mL) containing 50% TFA, and stirred for 5 hours. After the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM, passed through an NH-DM 1020 Chromatorex pad to obtain a mixture of regioisomers, and purified on a C-18 column with 0-80% acetonitrile in H2O to obtain two compounds in a 3:5 ratio. The less polar compound was assigned as 3-(7-fluoro-4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione, and the more polar compound was assigned as 3-(6-fluoro-1-oxo-7-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione. MS (ESI, m / z): [M+H] +=471.3 and 471.2

[0816] 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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001204)

[0817]

[0818] 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)-yl) 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 MeOH / DCM (0-20%) MPLC to obtain the title compound (48.2 mg). MS (ESI, m / z): [M+H] + =990.2.

[0819] 1H NMR(500MHz,DMSO-d6)δppm 10.95-11.03(m,1H)8.63-8.71(m,2H)8.38(d,J=5.65Hz,2H)8.20-8.27(m,2H)8.11-8.20(m,1H)7.93(d,J=7.78Hz,1H)7.86(d,J=12.97Hz ,1H)7.72(t,J=7.93Hz,1H)7.45-7.54(m,2H)7.29(d,J=8.09Hz,1H)7.16(d,J=9.77Hz,1H)5.68-5.77(m,1H)5.45(s,2H)4.36(d,J=11.44Hz ,1H)4.09(d,J=5.34Hz,2H)3.28(br.s.,4H)2.97-3.05(m,1H)2.86-2.97(m,1H)2.60-2.66(m,1H)2.54-2.60(m,5H)2.40-2.48(m,1H)2.23 (br.s.,1H)2.03-2.12(m,1H)1.87(br.s.,3H)1.66-1.84(m,3H)1.53(br.s.,1H)1.39(s,2H)1.11(d,J=11.44Hz,1H)0.96(d,J=8.54Hz,1H)

[0820] 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-dihydrophthalazin-6-yl)pentan-4-phosphoryl-1-yl)acetamide (ICT-0001205)

[0821] Step 1) Preparation of 3-(6-(5-aminopentan-1-phosphin-1-yl)-1-oxopiperazine-2(1H)-yl)piperidine-2,6-dione

[0822]

[0823] CuI (113 mg, 0.6 mmol) and Pd (PPh 3 ) 2 Cl 2 (418 mg, 0.6 mmol) were added to a solution of 3- (6- bromo -1- oxo -1,2- dihydrophthalazine -2- ylphorapazine -2- bases) and tert-butyl pentyl -4- phosphorus -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 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 resulting residue was purified by column chromatography, treated with DCM (5 mL) containing 50% TFA, and stirred for 5 hours. After the deprotection reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM (5 mL) and passed through a Chromatorex pad and NH-DM 1020, Chromatorex pad to afford the title compound (1.59 g) as an off-white oil. MS (ESI, m / z): [M+H] + =339.1.

[0824] 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-dihydrophthalazin-6-yl)pentan-4-phosphin-1-yl)acetamide (ICT-0001205)

[0825]

[0826] 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-aminopentan-1-phosphin-1-yl)-1-oxophthalazin-2(1H)-yl)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 MeOH / DCM (0-20%) MPLC to obtain the title compound (45 mg). MS (ESI, m / z): [M+H] +=857.9.

[0827] 1H NMR(500MHz,DMSO-d6)δppm 11.05(s,1H)8.60-8.74(m,2H)8.44(s,1H)8.35-8.42(m,2H)8.11-8.29(m,4H)8.01(s,1H)7.90-7.98( m,1H)7.84(dd,J=8.32,1.30Hz,1H)7.72(t,J=7.86Hz,1H)7.43-7.54(m,2H)7.16(d,J=9.77Hz,1H)5.8 0(dd,J=12.13,5.26Hz,1H)5.45(s,2H)4.07(d,J=5.49Hz,1H)3.29(br.s.,1H)2.87-2.98(m,2H)2.58- 2.66(m,1H)2.52-2.57(m,2H)2.08-2.17(m,1H)1.85(br.s.,2H)1.77(quin,J=6.98Hz,2H)1.39(s,1H)

[0828] Example C-30: 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-dihydrophthalazin-6-yl)pentyl)acetamide (ICT-0001206)

[0829] Step 1) Preparation of 3-(6-(5-aminopentyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0830]

[0831] 10% Pd / C (10 mg) was added to a solution of 3-(6-(5-aminopentan-1-phosphin-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (0.1 g, 0.3 mmol) in MeOH (5 mL) at ambient temperature. The reaction was carried out by attaching a H2 balloon. After stirring at room temperature for 5 hours, the reaction was filtered and dried under vacuum to obtain the title compound (85 mg). MS (ESI, m / z): [M+H] + =343.4.

[0832] Step 2) Preparation of 2-(4-(((2-(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-dihydrophthalazin-6-yl)pentyl)acetamide (ICT-0001206)

[0833]

[0834] HATU (36.3 mg, 0.09 mmol) was added to a mixture containing 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (2 8.7 mg, 0.09 mmol) in DMF (5 ml), followed by the addition of ethylbis(propane-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (38 mg). MS (ESI, m / z): [M+H] + =861.9.

[0835] 1H NMR(500MHz,DMSO-d6)δppm 11.05(s,1H)8.59-8.72(m,2H)8.33-8.46(m,3H)8.12-8.28(m,4H)7.87-8.00(m,1H)7.68-7.82(m ,3H)7.43-7.57(m,2H)7.17(d,J=9.77Hz,1H)5.81(dd,J=11.98,5.26Hz,1H)5.45(s,2H)4.07(d,J= 4.58Hz,1H)3.12(d,J=6.10Hz,1H)2.85-2.99(m,1H)2.80(t,J=7.48Hz,2H)2.53-2.67(m,2H)2.05- 2.16(m,1H)1.68(quin,J=7.48Hz,2H)1.48(quin,J=7.13Hz,2H)1.39(s,1H)1.31(d,J=6.56Hz,2H)

[0836] 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-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-0001207)

[0837] Step 1) Preparation of 3-(6-(4-(4-aminophenyl)piperazin-1-yl)-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0838]

[0839] Ethylbis(propane-2-yl)amine (670 mg, 5.19 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-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 reactants were stirred at 160 ° C for 16 hours. The reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-10%) MPLC. Subjective compound (621 mg). MS (ESI, m / z): [M+H] + =447.6.

[0840] Step 2) 2-(4-(((2-(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-dihydrophthalazin-6-yl)piperazin-1-yl)phenyl)acetamide (ICT-0001207)

[0841]

[0842] 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-dihydrophthalazin-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (52 mg). MS (ESI, m / z): [M+H] + =966.1.

[0843] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H)8.62-8.67(m,2H)8.33-8.41(m,2H)8.21-8.29(m,2H)8.06-8.21(m,2H)7.93(d ,J=7.78Hz,1H)7.72(t,J=7.86Hz,1H)7.57(d,J=8.39Hz,1H)7.45-7.53(m,4H)7.12-7.20(m ,2H)7.00(d,J=8.54Hz,2H)5.69(d,J=7.48Hz,1H)5.45(s,2H)4.01-4.15(m,1H)3.61(br.s. ,3H)3.28(br.s.,4H)2.82-3.01(m,1H)2.52-2.66(m,2H)1.30-1.43(m,1H)1.14-1.28(m,1H)

[0844] 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)

[0845] 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

[0846]

[0847] 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1 in DCM (3 mL) and chloroacetyl chloride (0.784 mmol) were added to a solution of 6-dihydropyridazin-3-yl)benzonitrile (0.522 mmol) and DIPEA (1.04 mmol) at 0°C and 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, along with 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

[0848] 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)

[0849]

[0850] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-(6-dihydropyridazin-3-yl)benzonitrile (20 mg, 0.02 mmol) and 3-(4-(4-methyl-1-yl)piperidin-1-(4-(piperazin-1-yl)piperidin-2,6-dione(1H)-yl)piperidin-2,6-dione (15 mg, 0.02 mmol) were added to a solution of 0.6 ml DMSO DIPEA (98 μmol) and stirred at 80° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The corresponding fractions were lyophilized. The obtained product was purified by column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) on amino silica gel, 4 mg of 3-(1-(1-(5-((1-(2-(2-(4-(1-(2-(2-(2-(2-(2-(2-(2-(2-(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. MS (ESI, m / z): [M+H] + =971.8.

[0851] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H),8.65(s,2H),8.39(s,1H),8.37(s,1H),8.24(d,J=8.1Hz,1H),8.23(s,1H),8.17(d,J=8.1Hz,1H),8.0 3(m,1H)7.93(d,J=7.8Hz,1H),7.71(t,J=7.9Hz,1H),7.49(s,1H),7.46(m,2H),7.16(d,J=9.8Hz,1H),7.02(s,1H),5 .68(m,1H),5.44(s,2H),4.38(d,J=12.5Hz,1H),4.08(s,2H),4.02(d,J=12.5Hz,2H),3.28(m,4H),2.98(m,2H),2.9 0(m,3H),2.59(m,2H),2.47(s,3H),2.38(brd,6H),2.10(brd,2H),1.77(m,3H),1.3(m,1H),1.23(m,2H),1.10(m,6H)

[0852] Example C-33: Preparation of 3-(1-(3-(5-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001214)

[0853] Step 1) Preparation of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)acetate

[0854]

[0855] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-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 reactants were 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 obtain the title compound (150 mg). MS (ESI, m / z): [M+H] + =470.4

[0856] Step 2) Preparation of 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)acetic acid

[0857]

[0858] TFA (5 ml) was added to tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =414.4

[0859] 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-dihydrophthalazin-6-yl)piperazin-1-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001214)

[0860]

[0861] 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 2-(4-(4-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)acetic acid ( The mixture 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 on MeOH / DCM (0-20%) to obtain the title compound (33 mg). MS (ESI, m / z): [M+H] + = 875.1.

[0862] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.65(s,2H)8.38(br.s.,2H)8.20-8.28(m,2H)8.17(d,J=9.77Hz,1H)7.93(d,J=7.63Hz,1H)7.78(d,J=8.85Hz,1H )7.71(t,J=7.86Hz,1H)7.59(d,J=8.54Hz,1H)7.54(br.s.,1H)7.45-7.50(m,2H)7.16(d,J=9.77Hz,1H)5.70(br.s.,1H)5.44( s,2H)4.41(d,J=12.82Hz,1H)4.08(d,J=6.26Hz,3H)3.62(dd,J=10.38,6.56Hz,1H)3.41(br.s.,4H)3.09-3.19(m,2H)3.05(t, J=12.05Hz,1H)2.86-2.96(m,1H)2.54-2.66(m,6H)2.45(s,3H)2.07(dd,J=8.85,4.88Hz,2H)1.95-2.05(m,2H)1.81(br.s.,2H)

[0863] Example C-34: Preparation of 3-(1-(3-(5-((1-(1-(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)

[0864] Step 1) Preparation of tert-butyl 3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate

[0865]

[0866] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 3-bromopropionate (143 mg, 0.73 mmol) in ACN (10 ml). The reactants were 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 obtain the title compound (160 mg). MS (ESI, m / z): [M+H] + =484.4

[0867] Step 2) Preparation of 3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)propanoic acid

[0868]

[0869] 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-dihydrophthalazin-6-yl)piperazin-1-yl)propanoate (160 mg, 0.32 mmol) in DCM (15 ml). The reactants were 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =428.4

[0870] 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-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)

[0871]

[0872] 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-dihydrophthalazin-6-yl)piperazin-1-yl)propanoic acid (28.0 mg, 0.06 mmol) in DMF (2.0 ml), 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 MeOH / DCM (0-20%) column chromatography to obtain the title compound (33 mg). MS (ESI, m / z): [M+H]+=875.1.

[0873] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.65(s,2H)8.38(br.s.,2H)8.20-8.28(m,2H)8.17(d,J=9.77Hz,1H)7.93(d,J=7.63Hz,1H)7.78(d,J=8.85Hz,1H )7.71(t,J=7.86Hz,1H)7.59(d,J=8.54Hz,1H)7.54(br.s.,1H)7.45-7.50(m,2H)7.16(d,J=9.77Hz,1H)5.70(br.s.,1H)5.44(s ,2H)4.41(d,J=12.82Hz,1H)4.08(d,J=6.26Hz,3H)3.62(dd,J=10.38,6.56Hz,1H)3.41(br.s.,4H)3.09-3.19(m,2H)3.05(t,J =12.05Hz,1H)2.86-2.96(m,1H)2.54-2.66(m,10H)2.45(s,3H)2.07(dd,J=8.85,4.88Hz,2H)1.95-2.05(m,2H)1.81(br.s.,2H)

[0874] Example C-35: Preparation of 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)butanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001216)

[0875] Step 1) Preparation of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate

[0876]

[0877] Ethylbis(propane-2-yl)amine (2.0 equivalents) was added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (200 mg, 0.56 mmol) and tert-butyl 4-bromobutyrate (153 mg, 0.73 mmol) in ACN (10 ml). The reactants were 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 obtain the title compound (165 mg). MS (ESI, m / z): [M+H] +=498.4

[0878] Step 2) Preparation of 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)butanoic acid

[0879]

[0880] TFA (5 ml) was added to tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)butanoate (165 mg, 0.32 mmol) in DCM (15 ml). The reactants were 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =442.4

[0881] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)butyryl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001216)

[0882]

[0883] HATU (47.7 mg, 0.13 mmol) was added to a mixture containing 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-dihydrophthalazin-6-yl)piperazin-1-yl)butanoic acid (30.0 mg, 0.06 mmol). g, 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 obtain the title compound (33 mg). MS (ESI, m / z): [M+H] + = 889.1.

[0884] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.65(s,2H)8.38(br.s.,2H)8.20-8.28(m,2H)8.17(d,J=9.77Hz,1H)7.93(d,J=7.63Hz,1H)7.78(d,J=8.85Hz,1H )7.71(t,J=7.86Hz,1H)7.59(d,J=8.54Hz,1H)7.54(br.s.,1H)7.45-7.50(m,2H)7.16(d,J=9.77Hz,1H)5.70(br.s.,1H)5.44( s,2H)4.41(d,J=12.82Hz,1H)4.08(d,J=6.26Hz,3H)3.62(dd,J=10.38,6.56Hz,1H)3.41(br.s.,4H)3.09-3.19(m,2H)3.05(t, J=12.05Hz,1H)2.86-2.94(m,1H)2.54-2.66(m,8H)2.45(s,3H)2.08(dd,J=8.85,4.88Hz,2H)1.95-2.02(m,2H)1.83(br.s.,2H)

[0885] 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-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001217)

[0886] Step 1) Preparation of tert-butyl 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoate

[0887]

[0888] 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 reactants were 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 obtain the title compound (170 mg). MS (ESI, m / z): [M+H] +=512.4

[0889] Step 2) Preparation of 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoic acid

[0890]

[0891] TFA (5 ml) was added to tert-butyl 5-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoate (165 mg, 0.32 mmol) in DCM (15 ml). The reactants were 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =456.4

[0892] 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-dihydrophthalazin-6-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001217)

[0893]

[0894] 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-dihydrophthalazin-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 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 MeOH / DCM (0-20%) column chromatography to obtain the title compound (33 mg). MS (ESI, m / z): [M+H]+=917.1.

[0895] 1H NMR(500MHz,DMSO-d6)δppm 10.96(s,1H)8.58-8.67(m,2H)8.34-8.41(m,2H)8.23(t,J=8.62Hz,2H)8.17(d,J=9.77Hz,1H)7.93(d,J=7.78Hz,1H)7.74-7.81(m, 1H)7.71(t,J=7.86Hz,1H)7.59(d,J=10.07Hz,1H)7.54(br.s.,1H)7.44-7.51(m,2H)7.16(d,J=9.77Hz,1H)5.69(d,J=5.49Hz,1H)5 .44(s,2H)4.44(d,J=12.36Hz,1H)4.07(d,J=6.26Hz,2H)3.93(d,J=12.66Hz,1H)3.42-3.54(m,2H)3.37(br.s.,2H)3.04(t,J=12.1 3Hz,1H)2.87-2.96(m,2H)2.52-2.66(m,6H)2.41-2.46(m,6H)2.36(br.s.,3H)2.01-2.12(m,2H)1.74-1.88(m,2H)1.54(br.s.,4H)

[0896] Example C-37: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(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)

[0897]

[0898] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (24.7 μmol) and 3-(4-methyl-1-oxo-6-(4-(piperidine-4-carbonyl)piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (24.7 μmol) were added to a solution of 0.6 ml DMSO DIPEA (123 μmol) and stirred at 80° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% The corresponding fractions were lyophilized. The obtained product was treated by amino silica gel column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) to obtain 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-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. MS (ESI, m / z): [M+H] + =985.8

[0899] 1H NMR(500MHz,DMSO-d6)δppm 10.96(s,1H),8.64(s,2H),8.38(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8Hz,1H),8.08(d,J=9Hz,1H),7.93(d,J =7.6Hz,1H),7.71(t,J=7.9Hz,1H),7.48(m,3H),7.16(d,J=7.9Hz,1H),7.09(s,1H),5.68(m,1H),5.44(s,2H),4.38(d,J =12.5Hz,1H),4.14(d,J=12.5Hz,1H),4.08(d,J=6.6Hz,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)

[0900] 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)

[0901]

[0902] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1-DIPEA (123 μmol) in 0.6 ml of DMSO 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)phthalazin-2(1H)-yl)piperidine-2,6-dione (24.7 μmol), and stirred at 80° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% The corresponding fractions were lyophilized. The obtained product was processed by amino silica gel column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) and 15 mg of 3-(1-(3-(5-((1-(2-(4-((1-(2-(2-(2-(2-(2-(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. MS (ESI, m / z): [M+H] + =971.8

[0903] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H),8.65(s,2H),8.39(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8Hz,1H),8.03(d,J=9Hz,1H),7.93(d,J =7.6Hz,1H),7.71(t,J=7.9Hz,1H),7.48(m,3H),7.16(d,J=9.8Hz,1H),7.03(s,1H),5.68(m,1H),5.44(s,2H),4.38(d,J =12.5Hz,1H),4.12(d,J=12.5Hz,1H),4.07(d,J=6.6Hz,2H),3.97(d,J=12.7Hz,2H),3.36(m,2H),3.26(d,J=13Hz,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).

[0904] Example C-39: Preparation of 3-(1-(3-(5-((1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0905] 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

[0906]

[0907] Ethylbis(propane-2-yl)amine (4.0 equiv) 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 (200 mg, 0.42 mmol) and tert-butyl 2-bromoacetate (160 mg, 0.84 mmol) in NMP (2.0 ml). The reactants were stirred at 130 ° C. for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Subjective compound (150 mg) MS (ESI, m / z): [M+H]+ =593.7

[0908] Step 2) Preparation of 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid

[0909]

[0910] TFA (5 ml) was added to tert-butyl 2-(((2-(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 completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =537.6

[0911] Step 3) Preparation of 3-(1-(3-(5-((1-(2-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0912]

[0913] HATU (56.7 mg, 0.15 mmol) was added to 2-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-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 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (30 mg). MS (ESI, m / z): [M+H] + =860.9.

[0914] 1H NMR(500MHz,DMSO-d6)δppm 11.02(s,1H)8.66(s,2H)8.39(s,2H)8.13-8.30(m,4H)8.08(d,J=8.85Hz,1H)7.94(d,J=7.6 3Hz,1H)7.73(t,J=7.86Hz,1H)7.45-7.58(m,3H)7.29(d,J=1.83Hz,1H)7.17(d,J=9.77Hz,1H )5.76(dd,J=11.75,5.04Hz,1H)5.45(s,2H)4.08(br.s.,2H)3.57-3.75(m,6H)3.54(br.s., 2H)3.42-3.51(m,2H)3.10-3.20(m,6H)2.86-2.97(m,2H)2.55-2.65(m,2H)1.26-1.31(m,3H)

[0915] Example C-40: Preparation of 3-(1-(3-(5-((1-(1-(3-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0916] 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

[0917]

[0918] Ethylbis(propan-2-yl)amine (4.0 equiv) was added to NMP (2.0 ml) containing 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 3-bromopropionate (131 mg, 0.63 mmol). The reaction was stirred at 130° C. for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Subjective compound (100 mg) MS (ESI, m / z): [M+H] + =607.7

[0919] Step 2) Preparation of 3-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid

[0920]

[0921] TFA (5 ml) was added to 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 (150 mg, 0.25 mmol) in DCM. 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =551.6

[0922] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0923]

[0924] 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-(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 ethylbis(propan-2-yl)amine (3 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (35 mg). MS (ESI, m / z): [M+H] + =875.0.

[0925] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.58(s,2H)8.32(s,2H)8.14-8.23(m,3H)8.11(d,J=9.77Hz,1H)8.00(d,J=9.00Hz,1H)7.87(d ,J=7.63Hz,1H)7.66(t,J=7.86Hz,1H)7.39-7.48(m,3H)7.21(s,1H)7.10(d,J=9.61Hz,1H)5.69(dd,J=11.6 0,5.04Hz,1H)5.38(s,2H)4.00(br.s.,2H)3.59(br.s.,4H)3.45(br.s.,2H)3.38(br.s.,3H)2.80-2.89(m, 2H)2.47-2.59(m,3H)2.00-2.06(m,2H)1.82-1.93(m,2H)1.80(br.s.,1H)1.40(d,J=6.87Hz,2H)1.17(s,4H)

[0926] Example C-41: Preparation of 3-(1-{[3-(5-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[0927] Step 1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0928]

[0929] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazine-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 reactants were 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 obtain the title compound (350 mg) MS (ESI, m / z): [M+H] + =456.4

[0930] Step 2) Preparation of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0931]

[0932] TFA (10 ml) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl) 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 obtain the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4

[0933] Step 3) Preparation of 3-(1-(3-(5-((1-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[0934]

[0935] 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)phthalazin-2(1H)-yl)piperidine-2,6-dione (25.8 mg, 0.06 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (20 mg). MS (ESI, m / z): [M+H] + =889.1.

[0936] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.66(s,2H)8.39(s,2H)8.21-8.29(m,2H)8.19(d,J=9.77Hz,1H)8.06-8.14(m,1H)7.94(d,J =7.78Hz,1H)7.73(t,J=7.86Hz,1H)7.44-7.58(m,3H)7.17(d,J=9.77Hz,1H)7.11(s,1H)5.67-5.73(m,1H )5.45(s,2H)4.08(br.s.,1H)3.67(br.s.,4H)3.44-3.58(m,4H)3.12(br.s.,1H)3.08(s,1H)2.87-2.98( m,2H)2.75(br.s.,1H)2.70(br.s.,1H)2.54-2.67(m,11H)2.03-2.09(m,1H)1.90-2.00(m,1H)1.24(s,2H)

[0937] 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-dihydrophthalazin-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)

[0938] Step 1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazine-1-carboxylate

[0939]

[0940] Ethylbis(propane-2-yl)amine (4.0 equivalents) was added to a solution of 3-(7-fluoro-4-methyl-1-oxophthalazine-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 reactants were 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 obtain the title compound (350 mg) MS (ESI, m / z): [M+H] + =456.4

[0941] Step 2) Preparation of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione

[0942]

[0943] TFA (10 ml) was added to a solution of 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)tert-butyl ester in DCM (30 ml). TFA (10 ml) was added to 4-(3,6-dioxopiperidin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester-6-yl. The reactants were 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 obtain the title compound (200 mg) MS (ESI, m / z): [M+H] + =356.4

[0944] 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-dihydrophthalazin-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)

[0945]

[0946] 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)phthalazin-2,6(1H)-yl)piperidine-2,6-dione (25.8 mg, 0.07 mmol) in DMF (2.0 ml), followed by the addition of ethylbis(propan-2-yl)amine (3 eq). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (30 mg). MS (ESI, m / z): [M+H] + =889.1.

[0947] 1H NMR(500MHz,DMSO-d6)δppm 11.00(s,1H)8.62-8.67(m,2H)8.39(s,2H)8.21-8.28(m,2H)8.19(d,J=9.77Hz,1H)7.94(d,J=7.63Hz,1H)7.83(d,J=9.16Hz ,1H)7.73(t,J=7.86Hz,1H)7.63(dd,J=9.00,2.29Hz,1H)7.55(d,J=2.29Hz,1H)7.47-7.53(m,2H)7.17(d,J=9.77Hz,1H)5.71 (d,J=5.95Hz,1H)5.45(s,2H)4.09(d,J=6.10Hz,2H)3.67(br.s.,4H)3.49(br.s.,2H)3.43(br.s.,1H)2.87-2.97(m,1H)2.71 -2.81(m,2H)2.54-2.64(m,8H)2.47(s,3H)2.04-2.11(m,1H)1.89(d,J=12.82Hz,1H)1.49(d,J=11.29Hz,1H)1.25(br.s.,4H)

[0948] Example C-43: Preparation of 3-(1-(3-(5-((1-(1-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0949] Step 1) Preparation of tert-butyl 4-(4-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)butanoate

[0950]

[0951] Ethylbis(propan-2-yl)amine (4.0 equiv) was added to NMP (2.0 ml) containing 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (200 mg, 0.42 mmol) and tert-butyl 4-bromobutyrate (280 mg, 1.25 mmol). The reaction was stirred at 130° C. for 48 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography. Subjective compound (100 mg) MS (ESI, m / z): [M+H]+ =621.7

[0952] 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

[0953]

[0954] TFA (5 ml) was added to a solution of tert-butyl 4-(4-(((2-(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 reactants were 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 obtain the title compound (100 mg). MS (ESI, m / z): [M+H] + =565.6

[0955] Step 3) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[0956]

[0957] 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 ethylbis(propan-2-yl)amine (3.0 equiv). The reaction was stirred at room temperature for 6 hours. The reaction 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =889.0.

[0958] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)8.65(s,2H)8.39(s,2H)8.22-8.29(m,3H)8.19(d,J=9.77Hz,1H)8.06(d,J=8.85Hz,1H) 7.94(d,J=7.93Hz,1H)7.73(t,J=7.86Hz,1H)7.45-7.53(m,3H)7.27(d,J=2.29Hz,1H)7.17(d,J=9.77 Hz,1H)5.70-5.81(m,1H)5.45(s,2H)4.05(d,J=5.80Hz,2H)3.59-3.69(m,4H)3.35-3.47(m,6H)2.85 -2.98(m,2H)2.53-2.65(m,2H)2.35-2.43(m,5H)1.90-2.02(m,2H)1.69-1.82(m,2H)1.18(br.s.,4H)

[0959] Example C-44: Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[0960] Step 1) Preparation of 3-(1-(3-(5-((1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (ICT-0001227)

[0961]

[0962] HATU (54.0 mg, 0.14 mmol) was added to 4-(4-((2-(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-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (25.2 mg, 0.07 mmol) in DMF (2.0 ml), followed by ethylbis(propan-2-yl)amine (3.0 equiv). The reaction was stirred at room temperature for 6 hours. The reaction 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =903.0.

[0963] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.57(s,2H)8.31(s,2H)8.27(d,J=8.24Hz,1H)8.14-8.21(m,2H)8.02(d,J=9.00Hz,1H)7.87(d,J =7.78Hz,1H)7.65(t,J=7.93Hz,1H)7.40-7.46(m,3H)7.10(d,J=9.77Hz,1H)7.02(s,1H)5.62(d,J=7.02Hz,1H )5.38(s,2H)4.00(d,J=6.10Hz,2H)3.57(br.s.,4H)3.44(br.s.,2H)3.39(br.s.,2H)2.78-2.89(m,2H)2.46- 2.60(m,7H)2.37(t,J=6.94Hz,2H)1.97-2.04(m,2H)1.71-1.93(m,2H)1.39(d,J=10.99Hz,1H)1.16(br.s.,6H)

[0964] Example C-45: Preparation of 3-(1-(3-(5-((1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-ylpiperazin-1-yl)piperazin-4-oxobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001228)

[0965] 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-dihydrophthalazin-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)

[0966]

[0967] HATU (54.0 mg, 0.14 mmol) was added to a mixture containing 4-(((2-(3-((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-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazine-2,6-dione(1H)-yl)piperidine-2,6-dione. (25.2 mg, 0.07 mmol) in DMF (2.0 ml) was added, followed by the addition of ethylbis(propane-2-yl)amine (3.0 equivalents). The reaction was stirred at room temperature for 6 hours. The reaction was poured into water. The reaction 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 obtain the title compound (50 mg). MS (ESI, m / z): [M+H] + =903.0.

[0968] 1H NMR(500MHz,DMSO-d6)δppm 10.92(s,1H)8.57(s,2H)8.31(s,2H)8.14-8.20(m,2H)8.11(d,J=9.77Hz,1H)7.87(d,J=7.78Hz,1H)7.74(d, J=9.00Hz,1H)7.65(t,J=7.78Hz,1H)7.51-7.56(m,1H)7.45-7.49(m,1H)7.39-7.45(m,2H)7.10(d,J=9.77Hz, 1H)5.63(d,J=6.87Hz,1H)5.38(s,2H)3.99(d,J=5.80Hz,2H)3.58(br.s.,4H)3.39(br.s.,3H)3.34(br.s.,3H )2.78-2.90(m,1H)2.45-2.59(m,4H)2.33-2.41(m,10H)1.95-2.05(m,2H)1.84-1.95(m,1H)1.66-1.80(m,2H)

[0969] 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)

[0970]

[0971] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1-(6-dihydropyridazin-3-yl)benzonitrile (18 μmol) and 3-(4-methyl-1-oxo-6-((R)-2-(piperazin-1-ylmethyl)morpholino)phthalazin-2(1H)-yl)piperidine-2,6-dione (18 μmol) were added to 0.6 ml of DMSO DIPEA (98 μmol) and stirred at 80° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% HCl). The corresponding fractions were lyophilized. The obtained product was processed by amino silica gel column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) to obtain 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-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. MS (ESI, m / z): [M+H] + =973.8

[0972] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H),8.65(s,2H),8.38(s,1H),8.37(s,1H),8.23(m,2H),8.17(d,J=9.8Hz,1H),8.08(d,J=9Hz,1H),7.93(d,J=7.6 Hz,1H),7.71(t,J=7.9Hz,1H),7.48(m,3H),7.16(d,J=9.8Hz,1H),7.07(s,1H),5.68(m,1H),5.44(s,2H),5.32(s,2H),4.38 (d,J=12.5Hz,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,2 H),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)

[0973] Example C-47: Preparation of 3-(1-(3-(5-((1-(2-(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)

[0974]

[0975] HATU (34.0 mg, 0.12 mmol) was added to 2-(4-(((2-(3-(3-(3-cyanophenyl)-6-oxopyridazin-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)piperazine-2,6-diol at room temperature. To a solution of ketone (40.9 mg, 0.09 mmol) in DMF (2 ml) was added ethylbis(propane-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (43 mg). MS (ESI, m / z): [M+H] + =990.0

[0976] 1H NMR(500MHz,DMSO-d6)δppm 11.02(s,1H)9.43(br.s.,1H)8.58-8.80(m,2H)8.34-8.46(m,2H)8.11-8.28(m,3H)7.94(d,J=7.63Hz,1H)7.73(t,J=7.86Hz,2H)7. 46-7.54(m,2H)7.17(d,J=9.77Hz,1H)5.70(br.s.,1H)5.45(s,2H)4.38(d,J=12.66Hz,1H)4.30(br.s.,1H)4.25(br.s.,1H)4.06-4 .14(m,2H)3.76(br.s.,1H)3.65(br.s.,1H)3.54(br.s.,2H)2.99-3.14(m,3H)2.83-2.99(m,2H)2.73(s,1H)2.54-2.66(m,3H)2.48 (br.s.,3H)2.22(br.s.,1H)2.04-2.16(m,2H)1.89-2.04(m,2H)1.84(br.s.,2H)1.70(br.s.,2H)1.07-1.31(m,2H)1.01(br.s.,1H)

[0977] 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-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 (ICT-0001232)

[0978] Step 1) Preparation of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate

[0979]

[0980] 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 benzyl piperazine-1-carboxylate (15 g, 68.1 mmol) in methanol (300 ml) and AcOH (6 ml) and stirred at room temperature for 16 hours. The reactant was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by HX / EA (20-90%) MPLC to obtain the title compound (22 g). MS (ESI, m / z): [M+H] + =376.0.

[0981] Step 2) Preparation of tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate

[0982]

[0983] Pd / C (10 wt %, 50 mg) was added to a solution of benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate (1 g, 2.66 mmol) in MeOH (10 ml) and stirred at room temperature under a hydrogen atmosphere for 5 hours. The solution was filtered through a celite 545 phase. The solvent was removed under reduced pressure, and the title compound (0.7 g) was obtained. MS (ESI, m / z): [M+H] + =242.0.

[0984] Step 3) Preparation of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate

[0985]

[0986] A solution of 3-(6-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (642 mg, 2.4 mmol) and 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.

[0987] Step 4) Preparation of 3-(6-(4-(azetidin-3-yl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0988]

[0989] TFA (0.3 ml) was added to a solution of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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 the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM, NH-DM 1020, and the title compound was obtained by Chromatorex pad and used in the next step without further purification (140 mg). MS (ESI, m / z): [M+H] + =397.3.

[0990] 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-yl)azetidin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001232)

[0991]

[0992] At room temperature, 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (34.4 mg, 0.09 mmol) in DMF (2 ml) were added, 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 MeOH / DCM (0-20%) MPLC to obtain the title compound (30 mg). MS (ESI, m / z): [M+H] + =916.0.

[0993] 1H NMR(500MHz,DMSO-d6)δppm 11.01(s,1H)8.66(s,2H)8.38(s,2H)8.21-8.28(m,3H)8.11-8.21(m,1H)8.06(d,J=9.00Hz,1H)7.88-7.9 6(m,1H)7.72(t,J=7.86Hz,1H)7.46-7.57(m,3H)7.28(s,1H)7.17(d,J=9.77Hz,1H)5.75(dd,J=11.44,5. 19Hz,1H)5.45(s,2H)4.18-4.26(m,1H)4.09(br.s.,2H)4.04(t,J=8.77Hz,1H)3.88(br.s.,1H)3.50(s,1 H)3.45(br.s.,4H)3.27(br.s.,1H)2.86-2.97(m,1H)2.61(d,J=17.85Hz,1H)2.54(br.s.,3H)1.39(s,1H)

[0994] 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-dihydrophthalazin-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)

[0995] Step 1) Preparation of benzyl 4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidin-4-yl)piperazine-1-carboxylate

[0996]

[0997] At room temperature, 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 4- (piperidin-4-yl) piperazine-1-carboxylic acid benzyl ester (0.53 g, 1.73 mmol) in solvent DMF (3 ml). The reactants were stirred at 130 ° C for 16 hours. After cooling, the reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by 100% ethyl acetate MPLC. The title compound (678 mg) was obtained as a white foam. MS (ESI, m / z): [M + H] + =573.2.

[0998] 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

[0999]

[1000] At room temperature, Pd / C 10% (100 mg) was added to a solution of benzyl 4-(1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidin-4-yl)piperazin-4-yl)piperazine-1-carboxylate (1 g, 1.75 mmol). The reaction was carried out by attaching a H2 balloon and stirred at room temperature for 16 hours. After cooling, the reactant was filtered, the filtrate was concentrated, and the title compound (590 mg) was obtained as a white solid. MS (ESI, m / z): [M+H] + =439.5.

[1001] 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-dihydrophthalazin-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)

[1002]

[1003] 2-[4-({[2-(3-{3-(3-cyanophenyl)-6-oxo-1,{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenymidine-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-dihydrophthalazin-2 To a solution of 1-methyl}piperidine-2,6-dione (31.8 mg, 0.086 mmol) in DMF (2 ml) was added ethylbis(propane-2-yl)amine (33.7 mg, 0.26 mmol). The reaction was stirred for 6 hours. The reaction was poured into water. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) MPLC to obtain the title compound (53.2 mg). MS (ESI, m / z): [M+H] + =958.2

[1004] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.66(s,2H)8.38(d,J=1.68Hz,2H)8.21-8.28(m,2H)8.12-8.21(m,1H)7.90-7.9 7(m,1H)7.78(d,J=9.00Hz,1H)7.72(t,J=7.86Hz,1H)7.61(d,J=8.70Hz,1H)7.55(br.s.,1H) 7.46-7.53(m,2H)7.17(d,J=9.77Hz,1H)5.68(d,J=5.95Hz,1H)5.45(s,2H)4.10(br.s.,1H)3 .47-3.56(m,2H)2.85-3.02(m,3H)2.52-2.66(m,4H)2.46(s,4H)2.02-2.12(m,1H)1.39(s,1H)

[1005] 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-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-0001234)

[1006] 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

[1007]

[1008] At room temperature, ethylbis(propane-2-yl)amine (1.34 g, 10.4 mmol) was added to a solution of 3-(7-fluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol) and 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid benzyl ester (1.1 g, 3.46 mmol) in DMA (5 ml). The reactants were heated at 120 ° C for 16 hours. The reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-10%) MPLC. The protected compound was obtained. The CBZ-protected compound was dissolved in MeOH (0.5 mL), 10% Pd / C (100 mg) was added, and stirred under a hydrogen atmosphere for 5 hours. The reactants were filtered, concentrated under reduced pressure, and the compound (1.21 g) was obtained. MS (ESI, m / z): [M+H] + =453.6.

[1009] 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-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-0001234)

[1010]

[1011] HATU (36.3 mg, 0.09 mmol) was added to a mixture containing 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yloxy)methyl)piperidin-1-yl)acetic acid (46 mg, 0.09 mmol) and 3-(4-(4-methyl-1-oxo-7-(4-(piperazin-1-yl)piperidin-1-yl)phthalazin-2(1H)-yl)piperidin-2 ,6-diketone (39 mg, 0.09 mmol) was dissolved in DMF (2 ml), followed by the addition of ethylbis(propane-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (43.2 mg). MS (ESI, m / z): [M+H] + =972.2.

[1012] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H)8.65(s,2H)8.36-8.40(m,2H)8.24(s,1H)8.19(s,1H)8.12-8.14(m,1H)7.96(d,J=6.56Hz ,1H)7.93(d,J=7.93Hz,1H)7.74(s,1H)7.56(d,J=6.10Hz,1H)7.50(s,2H)7.17-7.19(m,1H)7.07(br.s .,1H)6.52(s,2H)5.45(s,2H)5.34(br.s.,1H)4.08(br.s.,1H)3.94-4.01(m,1H)2.88-2.96(m,2H)2.5 3-2.66(m,3H)2.42-2.47(m,6H)2.20(br.s.,1H)1.77-1.88(m,1H)1.34-1.42(m,1H)1.17-1.23(m,10H)

[1013] 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-dihydrophthalazin-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)

[1014] Step 1) Preparation of tert-butyl 3-((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate

[1015]

[1016] At 0 ° C, methanesulfonyl chloride (2.69g, 23.5mmol) was slowly added to a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (4g, 21.4mmol) and DIPEA (5.58ml, 32mmol) in DCM (20ml). After the reaction was completed, the solvent was removed under reduced pressure. The residue was dissolved in EA (150ml) and washed with 150ml water and 150ml saline solution. The organic layer was dried over magnesium sulfate, concentrated, and the title compound (5.8g, red oil) was obtained. MS (ESI, m / z): [M+H] + =266.1.

[1017] Step 2) Preparation of benzyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperazine-1-carboxylate

[1018]

[1019] 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 benzyl piperazine-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 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 obtain the subjective compound (3.87 g). MS (ESI, m / z): [M + H] + =390.1

[1020] Step 3) Preparation of tert-butyl 3-(piperazine-1-monomethyl)azetidine-1-carboxylate

[1021]

[1022] 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 at room temperature for 17 hours under a hydrogen atmosphere. The solution was filtered on Celite 545, the solvent was removed under reduced pressure, and the title compound (1.56 g) was obtained. MS (ESI, m / z): [M+H] + =256.0.

[1023] Step 4) Preparation of tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)azetidine-1-carboxylate

[1024]

[1025] A solution of 3-(6-fluoro-4-methyl-1-oxophthalazin-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

[1026] Step 5) Preparation of 3-(6-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[1027]

[1028] TFA (0.2 ml) was added to tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)azetidine-1-carboxylate (20 mg, 0.038 mmol) in DCM (1 ml) and stirred at room temperature for 2 hours. After the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and passed through a NH-DM 1020, Chromatorex pad to obtain the title compound, which was used in the next step without further purification. MS (ESI, m / z): [M+H] + =425.1.

[1029] 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-dihydrophthalazin-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)

[1030]

[1031] HATU (36.3 mg, 0.1 mmol) was added to a mixture containing 2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-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-oxophthalazin-2(1H)-yl)piperidine at room temperature. -2,6-dione (36.9 mg, 0.08 μmol) in DMF (2 ml) was then added ethylbis(propane-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (37 mg). MS (ESI, m / z): [M+H] + =944.1.

[1032] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H)8.65(s,2H)8.36-8.40(m,2H)8.24(s,1H)8.19(s,1H)8.12-8.14(m,1H)7.96(d,J=6.56Hz ,1H)7.93(d,J=7.93Hz,1H)7.74(s,1H)7.56(d,J=6.10Hz,1H)7.50(s,2H)7.17-7.19(m,1H)7.07(br.s .,1H)6.52(s,2H)5.45(s,2H)5.34(br.s.,1H)4.08(br.s.,1H)3.94-4.01(m,1H)2.88-2.96(m,2H)2.5 3-2.66(m,3H)2.42-2.47(m,2H)2.20(br.s.,1H)1.77-1.88(m,1H)1.34-1.42(m,1H)1.17-1.23(m,10H)

[1033] 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)

[1034] 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

[1035]

[1036] At room temperature, ethyl bis (1.34 g, 10.4 mmol) was added to DMA (5 ml) containing 3-(6-fluoro-4-methyl-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (1.0 g, 3.46 mmol) and 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid benzyl ester (1.1 g, 3.46 mmol). The reactants were heated at 120 ° C for 16 hours. The reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-10%) MPLC. The protected compound was obtained. The CBZ-protected compound was dissolved in MeOH (0.5 mL), 10% Pd / C (100 mg) was added, and stirred under a hydrogen atmosphere for 5 hours. The reactants were filtered, concentrated under reduced pressure, and the subjective compound (1.1 g) was obtained. MS (ESI, m / z): [M+H] + =453.6.

[1037] Step 2) Preparation of 3-(1-(3-(5-((1-(1-(2-(4-((1-(2-(2-(dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperidin-4-yl)methylperazin-1-yl)2-oxoethyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile (ICT-0001236)

[1038]

[1039] HATU (36.3 mg, 0.09 mmol) was added to a mixture containing 2-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-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)phthalazin-2(1H)-yl)piperidin-2, 6-diketone (39 mg, 0.09 mmol) in DMF (2 ml) was then added ethylbis(propane-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (40.2 mg). MS (ESI, m / z): [M+H] + =972.2

[1040] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.64(s,2H)8.38(d,J=4.73Hz,2H)8.20-8.26(m,3H)8.17(d,J=9.77Hz,1H)8.04(d,J=9.00Hz,1H)7.93(d,J= 7.78Hz,1H)7.72(t,J=7.86Hz,1H)7.47-7.51(m,2H)7.16(d,J=9.77Hz,1H)7.04(s,1H)5.44(s,2H)4.05(d,J=5.80Hz,2H)3 .55(br.s.,1H)3.09-3.15(m,2H)2.77-2.97(m,5H)2.76(s,1H)2.52-2.65(m,4H)2.43-2.49(m,5H)2.36(br.s.,2H)2.29( br.s.,1H)2.16(d,J=6.41Hz,1H)1.95-2.06(m,1H)1.73-1.86(m,4H)1.39(s,1H)1.30(d,J=11.14Hz,1H)1.15-1.26(m,1H)

[1041] Example C-53: Preparation of 3-(1-(3-(5-((1-(2-(4-(4-(2-(2-(2-(2-(2-(2-(2-methyl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[1042] Step 1) Preparation of tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)piperidine-1-carboxylate

[1043]

[1044] At room temperature, ethylbis(propane-2-yl)amine (1.34 g, 10.4 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxophthalazine-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). The reactants were heated at 120 ° C for 16 hours. The reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-10%) MPLC. The subjective compound (1.3 g) was obtained. MS (ESI, m / z): [M+H] + =539.6

[1045] 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

[1046]

[1047] 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-dihydrophthalazin-6-yl)piperazin-1-yl)piperidine-1-carboxylate (200 mg, 0.5 mmol) in DCM (3 ml) and stirred at room temperature for 2 hours. After the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and the title compound was obtained by NH-DM 1020 and Chromatorex pad and used in the next step without further purification. MS (ESI, m / z): [M+H] + =439.1.

[1048] 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-dihydrophthalazin-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)

[1049]

[1050] HATU (36.3 mg, 0.09 mmol) was added to a solution of 2-(4-(((2-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetic acid (46 mg, 0.09 mmol), 3-(4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)phthalazin-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 MeOH / DCM (0-20%) MPLC to obtain the title compound (40.2 mg). MS (ESI, m / z): [M+H] + =958.2

[1051] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.66(s,2H)8.38(s,2H)8.11-8.28(m,3H)8.08(d,J=8.70Hz,1H) 7.94(d,J=7.78Hz,1H)7.72(t,J=7.86Hz,1H)7.45-7.55(m,3H)7.17(d,J=9.77 Hz,1H)7.09(br.s.,1H)6.54(s,1H)5.68(d,J=7.17Hz,1H)5.45(s,2H)4.10(b r.s.,1H)2.69(br.s.,1H)2.53-2.66(m,1H)2.36(s,1H)1.20(d,J=6.41Hz,1H)

[1052] 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-dihydrophthalazin-6-yl)piperidine-4-carboxamide (ICT-0001238)

[1053] Step 1) Preparation of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidine-4-carboxylic acid

[1054]

[1055] A solution of 3-(7-fluoro-4-methyl-1-oxophthalazine-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 hours. The reaction mixture was purified by reverse phase column chromatography to obtain the protected compound (284 mg), dissolved in DCM (4 ml), TFA (1 ml) was added, and stirred at room temperature for 2 hours. The reactant was concentrated in vacuo. The residue was purified by MeOH / DCM (0-20%) MPLC. Subjective compound (250 mg). MS (ESI, m / z): [M+H] + =399.0.

[1056] Step 2) Preparation of N-(3-aminopropyl)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidine-4-carboxamide

[1057]

[1058] At room temperature, 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-dihydrophthalazin-6-yl) and tert-butyl (3-aminopropyl)carbamate (43.7 mg, 0.25 mmol) in DMF (1 mL), followed by the addition of ethylbis(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. The reaction was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-10%) MPLC to obtain the title compound (102 mg). MS (ESI, m / z): [M+H] + =455.7

[1059] Step 3) Preparation of N-(3-(2-(4-(((2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)acetamide)propyl)-1-(3-(2,6-dioxopiperidin-3-yl)1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidine-4-carboxamide (ICT-0001238)

[1060]

[1061] At room temperature, 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-dihydrophthalazin-6-yl]piperidine-4-carboxamide (39.5 mg, 0.09 mmol) were added to DMF (2 ml), followed by 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 MeOH / DCM (0-20%) MPLC to obtain the title compound (51 mg). MS (ESI, m / z): [M+H] + =974.1

[1062] 1H NMR(500MHz,DMSO-d6)δppm 10.97(s,1H)8.63-8.67(m,2H)8.38(br.s.,2H)8.13-8.27(m,3H)8.05(d,J=9.00Hz,1H)7.84-7 .96(m,2H)7.72(t,J=7.86Hz,1H)7.46-7.52(m,2H)7.17(d,J=9.77Hz,1H)7.03-7.09(m,1H)5.68 (d,J=7.32Hz,1H)5.45(s,2H)4.00-4.14(m,3H)3.45-3.63(m,2H)3.03-3.19(m,4H)2.83-3.03(m ,4H)2.53-2.69(m,2H)2.34-2.49(m,4H)1.99-2.11(m,1H)1.95(br.s.,1H)1.89(br.s.,1H)1.74

[1063] -1.85(m,2H)1.50-1.71(m,5H)1.33-1.43(m,1H)

[1064] 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-dihydrophthalazin-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)

[1065] 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

[1066]

[1067] At room temperature, ethylbis (2.68g, 20.7mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (2.0g, 6.91mmol) and 4-(piperazin-1-yl)aniline (2.63g, 8.3mmol) in DMA (5ml). The reactants were stirred at 130°C for 16 hours. The reactants were 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 (10ml) and 10% Pd / C (100mg) was added. The reactants were stirred under a H2 balloon for 5 hours. The reactants were filtered, concentrated under reduced pressure, and the title compound (2.15g) was obtained. MS (ESI, m / z): [M+H] + =453.2.

[1068] 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-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-0001239)

[1069]

[1070] 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. Ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (45.2 mg). MS (ESI, m / z): [M+H] + =972.1

[1071] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H)8.65(s,2H)8.39(s,1H)8.37(s,1H)8.21-8.26(m,2H)8.13-8.20(m,2H)7.93(d,J=7.63Hz,1H)7.68-7.77(m,2H)7 .54(d,J=9.00Hz,1H)7.45-7.51(m,2H)7.16(d,J=9.77Hz,1H)5.69(d,J=6.10Hz,1H)5.44(s,1H)4.38(d,J=12.21Hz,1H)4.08(t ,J=5.49Hz,2H)3.96(d,J=12.05Hz,1H)3.27(d,J=13.12Hz,1H)2.98(d,J=12.97Hz,1H)2.83-2.94(m,2H)2.53-2.65(m,3H)2.3 9-2.47(m,4H)2.37(br.s.,1H)2.02-2.12(m,3H)1.71-1.84(m,4H)1.31(d,J=16.17Hz,1H)1.06-1.23(m,2H)-0.03-0.03(m,2H)

[1072] Example C-56: Preparation of 3-(1-(3-(5-((1-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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)

[1073]

[1074] 3-(1-(3-(5-(((1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dione (1,18 μmol) in 0.6 ml of DMSO 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (18 μmol), and the mixture was stirred at 90° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% FA) / ACN (0.1% The corresponding fractions were lyophilized. The obtained product was purified by amino silica gel column chromatography (DCM / MeOH, 100 / 0 to 97 / 3, gradient) and 1.8 mg of 3-(1-(3-(5-((1-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)phenyl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was obtained. MS (ESI, m / z): [M+H] + =965.8

[1075] 1H NMR(500MHz,DMSO-d6)δppm 10.98(s,1H),8.65(s,2H),8.38(s,2H),8.24(m,2H),8.18(d,J=9.8Hz,1H),8.08(d,J=9Hz,1H),7.93(d,J=7.6Hz,1H),7.71(t,J=7 .9Hz,1H),7.58(m,1H),7.49(brd,2H),7.26(d,J=9.8Hz,1H),7.1(d,J=9.6Hz,2H),6.84(d,J=9.6Hz,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=12.5Hz,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,2H),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)

[1076] 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-dihydrophthalazin-6-yl)piperazin-1-yl)piperazin-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001250)

[1077] Step 1) Preparation of tert-butyl 5-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoate

[1078]

[1079] Triethylamine (3 equivalents) was added to a solution of 3-(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)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 obtain the title compound (133 mg). MS (ESI, m / z): [M+H] + =635.7

[1080] Step 2) Preparation of 5-(4-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)piperidin-1-yl)pentanoic acid

[1081]

[1082] TFA (2 ml) was added to a solution of tert-butyl 5-(4-(((2-(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 reactants were 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 obtain the title compound (121 mg). MS (ESI, m / z): [M+H] + =579.6

[1083] Step 3) Preparation of 3-(1-(3-(5-((1-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (ICT-0001250)

[1084]

[1085] Ethylbis(propan-2-yl)amine (3 equiv) was added to 5-(4-(((2-(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)phthalazin-2(1H)-yl)piperidine-2,6-dione ( To a solution of 4-[ ... + =917.1

[1086] 1H NMR(500MHz,DMSO-d6)δppm 10.91(s,1H)8.56(s,2H)8.31(s,2H)8.19(d,J=8.39Hz,2H)8.11(d,J=9.77Hz,1H)8.00-8.07(m,1H)7.86(d,J=7.48Hz,1H )7.65(t,J=7.93Hz,1H)7.39-7.44(m,3H)7.09(d,J=9.77Hz,1H)7.01(s,1H)5.56-5.68(m,1H)5.38(s,2H)3.97(d,J=5.95 Hz,2H)3.43(br.s.,4H)3.38(br.s.,2H)3.14-3.26(m,2H)3.00(br.s.,2H)2.83(d,J=13.43Hz,2H)2.70(br.s.,2H)2.47- 2.59(m,4H)2.40-2.44(m,2H)2.30(t,J=7.02Hz,2H)1.96-2.04(m,4H)1.78-1.93(m,2H)1.68(br.s.,2H)1.54(br.s.,2H)

[1087] 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-dihydrophthalazin-6-yl)piperazin-1-yl)piperazin-5-oxopentyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001251)

[1088]

[1089] Ethylbis(propan-2-yl)amine (3 equiv) was added to 5-(4-(((2-(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)phthalazin-2(1H)-yl)piperidine-2,6-dione ( To a solution of 4-[ ... + =917.1

[1090] 1H NMR(500MHz,DMSO-d6)δppm 10.93(s,1H)8.54-8.58(m,2H)8.29-8.33(m,2H)8.14-8.19(m,2H)8.11(d,J=9.77Hz,1H)7.86(d,J=7.78Hz,1H)7.73(d,J=9. 00Hz,1H)7.65(t,J=7.86Hz,1H)7.53(dd,J=9.00,2.59Hz,1H)7.46(d,J=2.44Hz,1H)7.39-7.44(m,2H)7.09(d,J=9.77Hz,1H) 5.64(d,J=6.41Hz,1H)5.38(s,2H)3.95-4.05(m,2H)3.46-3.59(m,4H)3.37(br.s.,2H)3.03(q,J=7.22Hz,2H)2.80-2.90(m,3 H)2.46-2.58(m,2H)2.39(s,3H)2.29(t,J=7.10Hz,1H)1.82-1.94(m,5H)1.67(br.s.,2H)1.56-1.64(m,2H)1.33-1.52(m,6H)

[1091] Example C-59: Preparation of 3-(1-(3-(5-((1-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[1092]

[1093] Ethylbis(propan-2-yl)amine (3 equivalents) was added to a solution of 5-(4-((2-(3-(3-(3-cyanophenyl)-6-oxopyridazin-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)phthalazin-2(1H)-yl)piperidine-2,6-dione (72 mg, 0.21 mmol) and HATU (160 mg, 0.32 mmol) in DCM (10 ml). The reactant was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by MeOH / DCM (0-20%) column chromatography to obtain the title compound (60 mg). MS (ESI, m / z): [M+H] + =903.1

[1094] 1H NMR(500MHz,DMSO-d6)δppm 10.96(s,1H)8.56(s,2H)8.31(d,J=7.48Hz,2H)8.13-8.23(m,3H)8.10(d,J=9.77Hz,1H)7.99(d,J=9.00Hz,1H)7.86(d,J=7.7 8Hz,1H)7.64(t,J=7.86Hz,1H)7.37-7.46(m,3H)7.14-7.19(m,1H)7.09(d,J=9.77Hz,1H)5.69(dd,J=11.90,5.04Hz,1H)5.38 (s,2H)3.98(d,J=5.95Hz,2H)3.41(br.s.,2H)3.35(br.s.,2H)3.26(d,J=9.16Hz,2H)2.96-3.08(m,2H)2.80-2.91(m,2H)2.7 8(br.s.,2H)2.46-2.61(m,3H)2.31(t,J=7.10Hz,2H)1.99-2.06(m,2H)1.80-1.98(m,4H)1.52-1.61(m,2H)1.35-1.51(m,4H)

[1095] 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-dihydrophthalazin-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)

[1096] 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

[1097]

[1098] At 0 ° C, 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 CH2Cl2 (50 mL), warmed to room temperature, and stirred for 1 hour. After the reaction was completed, the reactant 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 obtain the title compound (37 mg). MS (ESI, m / z): [M+H] + =556.1

[1099] 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)

[1100]

[1101] Ethylbis(2-hydroxyethyl)-1-[4-[ ... + =944.1

[1102] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.65(s,1H)8.67(s,1H)8.33-8.40(m,2H)8.31(s,1H)8.23(br.s.,2H)8.11-8.20(m,1H)7.97-8.09(m,1H)7.88-7.94( m,1H)7.66-7.75(m,1H)7.45-7.50(m,2H)7.13-7.18(m,1H)5.66(br.s.,1H)5.39-5.46(m,2H)4.38(br.s.,1H)4.07(br.s.,3H)3.7 6(br.s.,1H)3.63(br.s.,1H)3.44-3.53(m,4H)3.41(br.s.,6H)3.02(d,J=13.58Hz,2H)2.89(br.s.,1H)2.73-2.83(m,1H)2.62(d, J=14.19Hz,2H)2.55(d,J=8.85Hz,4H)2.15(d,J=12.82Hz,1H)2.07(br.s.,2H)1.95-2.04(m,2H)1.86-1.95(m,2H)1.82(br.s.,2H)

[1103] 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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)1,3-oxazin-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001254)

[1104] Step 1: Preparation of tert-butyl (2S)-2-{[(4-methylbenzenesulfonyl)oxy]methyl}morpholine-4-carboxylate

[1105]

[1106] 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 equiv) were added to a solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (10 g, 46 mmol) in DCM (500 ml). The subjective compound (17 g) was obtained. MS (ESI, m / z): [M+H] + =372.4.

[1107] Step 2: Synthesis of tert-butyl (2R)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate

[1108]

[1109] Potassium carbonate (6.04 g, 43.7 mmol) was slowly added to a solution of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (5.8 g, 21.9 mmol) and (S)-tert-butyl 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 obtain the title compound (3.87 g). MS (ESI, m / z): [M + H] + =555.6.

[1110] Step 3) Preparation of 3-(4-methyl-6-(4-(((S)-morpholin-2-yl)methyl)piperazin-1-yl)-1-oxopiperazin-2(1H)-yl)piperidine-2,6-dione

[1111]

[1112] 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-dihydrophthalazin-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 the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and the title compound was obtained by NH-DM 1020 and Chromatorex pad and used in the next step without further purification. MS (ESI, m / z): [M+H] + =455.6.

[1113] 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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)1,3-oxazin-3-yl)acetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001254)

[1114]

[1115] Ethylbis(2-(1-(3-(5-((1-(1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.09 mmol) and 3-(4-methyl-6-(4-((S)-morpholin-2-yl)methyl)piperazin-1-yl)1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (40 mg, 0.09 mmol) in DMF (1 ml) were added at room temperature. The reaction was stirred for 6 hours. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-10%) MPLC to obtain the title compound. MS (ESI, m / z): [M+H] + =974.1

[1116] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.65(s,1H)8.67(s,1H)8.33-8.40(m,2H)8.31(s,1H)8.23(br.s.,2H)8.11-8.20(m,1H)7.97-8.09(m,1H)7.88-7.94( m,1H)7.66-7.75(m,1H)7.45-7.50(m,2H)7.13-7.18(m,1H)5.66(br.s.,1H)5.39-5.46(m,2H)4.38(br.s.,1H)4.07(br.s.,3H)3.7 6(br.s.,1H)3.63(br.s.,1H)3.44-3.53(m,4H)3.41(br.s.,6H)3.02(d,J=13.58Hz,2H)2.89(br.s.,1H)2.73-2.83(m,1H)2.62(d, J=14.19Hz,4H)2.55(d,J=8.85Hz,4H)2.15(d,J=12.82Hz,1H)2.07(br.s.,2H)1.95-2.04(m,2H)1.86-1.95(m,2H)1.82(br.s.,2H)

[1117] 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)

[1118] 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-dihydrophthalazin-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)

[1119]

[1120] Ethylbis(II) (45 μl, 0.26 mmol) was added to a mixture containing 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 (50 mg, 0.09 mmol) and 3-(4-(4-methyl-1-oxo-6-(4-(piperidin-4-yl)piperazin-1-yl)methyl)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.09 mmol) at room temperature. )phthalazine-2(1H)-yl)piperidine-2,6-dione (38 mg, 0.09 mmol) was added to DMF (1 ml). 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 DCM / MeOH (0-10%) MPLC to obtain the title compound. MS (ESI, m / z): [M+H]+ = 958.2

[1121] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.62-8.68(m,2H)8.35(s,1H)8.39(s,1H)8.22(d,J=7.17Hz,2H)8.11-8.19(m,1H)8.03(d,J=9.00Hz,1H)7 .92(d,J=7.93Hz,1H)7.65-7.75(m,1H)7.39-7.52(m,3H)7.10-7.19(m,1H)7.00-7.09(m,1H)5.67(d,J=7.02Hz,1H)5.3 9-5.47(m,2H)4.38(d,J=13.58Hz,1H)4.09(d,J=6.41Hz,3H)2.92-3.05(m,2H)2.82-2.92(m,6H)2.55-2.66(m,8H)2.20 (br.s.,2H)2.07(br.s.,2H)1.93-2.04(m,2H)1.80(br.s.,4H)1.42(br.s.,2H)1.34(d,J=9.31Hz,2H)1.24(br.s.,2H)

[1122] Example C-63: Preparation of 3-(1-(3-(5-((1-(1-(2-(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)

[1123] Step 1) Preparation of 3-(1-(3-(5-((1-(2-(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)benzonitrile (ICT-0001256)

[1124]

[1125] Ethylbis(2-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.09 mmol) and 3-(4-(4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-(1H)-yl)piperidine-2,6-dione (40 mg, 0.09 mmol) in DMF (1 ml) was added 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 DCM / MeOH (0-10%) MPLC to obtain the title compound. MS (ESI, m / z): [M+H]+=972.2

[1126] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.62-8.68(m,2H)8.35(s,1H)8.39(s,1H)8.22(d,J=7.17Hz,2H)8.11-8.19(m,1H)8.03(d,J=9.00Hz,1H)7 .92(d,J=7.93Hz,1H)7.65-7.75(m,1H)7.39-7.52(m,3H)7.10-7.19(m,1H)7.00-7.09(m,1H)5.67(d,J=7.02Hz,1H)5.3 9-5.47(m,2H)4.38(d,J=13.58Hz,1H)4.09(d,J=6.41Hz,3H)2.92-3.05(m,2H)2.82-2.92(m,6H)2.55-2.66(m,8H)2.20 (br.s.,2H)2.07(br.s.,4H)1.93-2.04(m,2H)1.80(br.s.,4H)1.42(br.s.,2H)1.34(d,J=9.31Hz,2H)1.24(br.s.,2H)

[1127] 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-dihydrophthalazin-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)

[1128] 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)

[1129]

[1130] Ethylbis(2-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.09 mmol) and 3-(6-(4-(azetidine-3-carbonyl)piperazin-1-yl)4-methyl-1-oxopiperazin-2(1H)-yl)piperidine-2,6-dione (40 mg, 0.09 mmol) in DMF (1 ml) was added at room temperature. The reaction was stirred for 6 hours. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-10%) MPLC to obtain the title compound. MS (ESI, m / z): [M+H]+=958.2.

[1131] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.62-8.68(m,2H)8.35(s,1H)8.39(s,1H)8.22(d,J=7.17Hz,2H)8.11-8.19(m,1H)8.03(d,J=9.00Hz,1H)7 .92(d,J=7.93Hz,1H)7.65-7.75(m,1H)7.39-7.52(m,3H)7.10-7.19(m,1H)7.00-7.09(m,1H)5.67(d,J=7.02Hz,1H)5.3 9-5.47(m,2H)4.38(d,J=13.58Hz,1H)4.09(d,J=6.41Hz,3H)2.92-3.05(m,2H)2.82-2.92(m,6H)2.55-2.66(m,8H)2.20 (br.s.,2H)2.07(br.s.,2H)1.93-2.04(m,2H)1.80(br.s.,4H)1.42(br.s.,2H)1.34(d,J=9.31Hz,2H)1.24(br.s.,2H)

[1132] 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)

[1133]

[1134] Ethylbis(propan-2-yl)amine (3 equiv) was added to 2-(4-(((2-(3-(3-(3-(3-(3-oxopyridazin-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-oxophthalazin-2(1H)-yl)piperidine -2,6-dione (70 mg, 0.21 mmol) and HATU (160 mg, 0.32 mmol) in DCM (10 ml). The reaction was stirred at room temperature overnight. The reaction was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by MeOH / DCM (0-20%) column chromatography to obtain the title compound (60 mg). MS (ESI, m / z): [M+H]+ =974.1

[1135] 1H NMR(500MHz,DMSO-d6)δppm 10.95(d,J=6.26Hz,1H)8.63(d,J=5.65Hz,2H)8.32-8.42(m,2H)8.12-8.30(m,2H)8.05(dd,J=14.57,8.62Hz,1H)7.86-7.9 8(m,1H)7.67-7.76(m,1H)7.60-7.67(m,1H)7.55(br.s.,1H)7.39-7.52(m,2H)7.15(dd,J=9.92,5.49Hz,1H)7.06(d,J=19.6 8Hz,1H)5.67(br.s.,1H)5.44(br.s.,2H)4.13(br.s.,1H)4.05(d,J=4.73Hz,2H)3.98(d,J=10.99Hz,1H)3.84(br.s.,2H)2. 86(d,J=10.53Hz,4H)2.53-2.68(m,6H)2.01(br.s.,7H)1.93-2.04(m,2H)1.80(br.s.,4H)1.77(br.s.,3H)1.42(br.s.,2H)

[1136] Example C-66: Preparation of 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)phenyl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (ICT-0001262)

[1137]

[1138] 3-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dione (36 μmol) in 0.6 ml of DMSO 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-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (36 μmol), and stirred at 90° C. for 16 hours. The reaction mixture was purified by reverse phase column chromatography (water (0.1% The corresponding fractions were lyophilized. The obtained product was purified by amino silica gel 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-dihydrophthalazin-6-yl)piperazin-1-yl)phenyl)glycyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl 6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile. MS (ESI, m / z): [M+H] + =965.8

[1139] 1H NMR(500MHz,DMSO-d6)δppm 10.99(s,1H),8.65(s,2H),8.38(m,2H),8.24(m,2H),8.17(d,J=9.8Hz,1H),7.94(d,J=9Hz,1H),7.80(d,J=7.6Hz,1H),7.72(t,J=7.9H z,1H),7.58(m,1H),7.49(brd,2H),7.26(d,J=9.8Hz,1H),7.17(d,J=9.6Hz,2H),6.84(d,J=9.6Hz,2H),6.64(m,1H),6.54(s,1H),5.71 (m,1H),5.44(s,2H),5.32(s,2H),4.58(m,1H),4.45(m,1H),4.10-4.03(m,2H),3.86(m,1H),3.72(m,1H),3.58-3.47(m,2H),3.40-3.3 5(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)

[1140] 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)

[1141] Step 1) Preparation of benzyl 4-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperidin-4-yl)piperazine-1-carboxylate

[1142]

[1143] At room temperature, ethylbis(propane-2-yl)amine (670 mg, 5.19 mmol) was added to a solution of 3-(7-fluoro-4-methyl-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (0.5 g, 1.73 mmol) and 4-(piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (524 mg, 1.73 mmol) in DMA (3 mL). The reactants were stirred at 130 ° C for 16 hours. After cooling, the reactants were poured into water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by 100% ethyl acetate MPLC. The subjective compound (678 mg) was obtained. MS (ESI, m / z): [M + H] + =573.3.

[1144] 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

[1145]

[1146] At room temperature, Pd / C 10% (500 mg) was added to a solution of 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl]piperidin-4-yl}piperazine-1-carboxylic acid benzyl ester (1 g, 1.75 mmol) in ethanol (10 mL). The reaction was carried out by attaching a H2 balloon and stirred at room temperature for 16 hours. After cooling, the reactant was filtered and the filtrate was concentrated to obtain the title compound (780 mg), which was used in the next step without further purification. MS (ESI, m / z): [M + H] + =389.5.

[1147] 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-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)

[1148]

[1149] Triethylamine was added to DMF (5 ml) containing 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-dihydrophthalazin-2-yl}piperidine-2,6-dione (39.5 mg, 90.1 μmol). The reactants were stirred at 45° C. for 4 hours. The reactants were poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. Concentrated under reduced pressure, purified by column chromatography, and the subject compound (49 mg) was obtained. MS (ESI, m / z): [M+H] + =957.1

[1150] 1H NMR(500MHz,DMSO-d6)δppm 10.99(s,1H)8.61-8.71(m,2H)8.35-8.41(m,2H)8.21-8.27(m,2H)8.12-8.21(m,2H)7.91-7.96(m,1H)7.68-7 .75(m,2H)7.46-7.53(m,3H)7.12-7.19(m,1H)5.40-5.46(m,2H)4.38(d,J=12.36Hz,1H)4.09(d,J=11.29Hz,3 H)3.89-3.99(m,1H)3.47-3.70(m,3H)3.26(d,J=13.43Hz,2H)2.81-3.04(m,6H)2.54-2.65(m,4H)2.42-2.47( m,5H)2.03-2.12(m,2H)1.75-1.88(m,4H)1.44(br.s.,1H)1.39(s,2H)1.17-1.35(m,3H)1.14(d,J=7.78Hz,1H)

[1151] 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)

[1152] Step 1 Preparation of tert-butyl (2R)-2-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)morpholine-4-carboxylate

[1153]

[1154] Potassium carbonate (6.04 g, 43.7 mmol) was slowly added to a solution of 3-(4-methyl-1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione (5.8 g, 21.9 mmol) and (S)-tert-butyl 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 obtain the title compound (3.87 g). MS (ESI, m / z): [M + H] + =555.6.

[1155] Step 2) Preparation of 3-(4-methyl-7-(4-(((S)-morpholin-2-yl)methyl)piperazin-1-yl)-1-oxopiperazin-2(1H)-yl)piperidine-2,6-dione

[1156]

[1157] 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-dihydrophthalazin-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 the reaction was completed, the reactants were concentrated under reduced pressure and dried in vacuo. The residue was dissolved in DCM and the title compound was obtained by NH-DM 1020 and Chromatorex pad and used in the next step without further purification. MS (ESI, m / z): [M+H] +=455.6.

[1158] 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)

[1159]

[1160] Ethylbis(2-(1-(3-(5-((1-(1-(2-chloroacetyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.26 mmol) and 3-(4-methyl-7-(4-((S)-morpholin-2-yl)methyl)piperazin-1-yl)1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (40 mg, 0.09 mmol) in DMF (1 ml) were added at room temperature. The reaction was stirred for 6 hours. The reaction was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-10%) MPLC to obtain the title compound. MS (ESI, m / z): [M+H] + =974.1

[1161] 1H NMR(500MHz,DMSO-d6)δppm 10.95(s,1H)8.65(s,1H)8.67(s,1H)8.33-8.40(m,2H)8.31(s,1H)8.23(br.s.,2H)8.11-8.20(m,1H)7.97-8.09(m,1H)7.88-7.94( m,1H)7.66-7.75(m,1H)7.45-7.50(m,2H)7.13-7.18(m,1H)5.66(br.s.,1H)5.39-5.46(m,2H)4.38(br.s.,1H)4.07(br.s.,3H)3.7 6(br.s.,1H)3.63(br.s.,1H)3.44-3.53(m,4H)3.41(br.s.,6H)3.02(d,J=13.58Hz,2H)2.89(br.s.,1H)2.73-2.83(m,1H)2.62(d, J=14.19Hz,4H)2.55(d,J=8.85Hz,4H)2.15(d,J=12.82Hz,1H)2.07(br.s.,2H)1.95-2.04(m,2H)1.86-1.95(m,2H)1.82(br.s.,2H)

[1162] 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-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-0001272)

[1163]

[1164] Triethylamine (18.2 mg, 180 μmol) was added to a mixture containing 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-(piperidin-4-yl)piperazine-1-(4 -(piperidin-4-yl)piperazine-2(1H)-yl)piperidine-2,6-dione (42.4 mg, 90.1 μmol) was dissolved in DMF (2 ml). The reaction was stirred at 45° C. for 4 hours. The reaction was poured into water. Ethyl acetate was added. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound (71 mg). MS (ESI, m / z): [M+H] + =990.1

[1165] 1H NMR(500MHz,DMSO-d6)δppm 12.04(s,1H)9.69(s,2H)9.44(s,1H)9.40(s,1H)9.27(d,J=7.17Hz,2H)9.20-9.23(m,1H)8.96(d,J=7.63Hz,1H)8.87(d,J=12 .97Hz,1H)8.75(t,J=7.86Hz,1H)8.50-8.56(m,2H)8.29(d,J=8.09Hz,1H)8.19(d,J=9.61Hz,1H)6.75(d,J=7.32Hz,1H)6.43-6 .54(m,2H)5.43(d,J=12.66Hz,1H)5.09-5.19(m,3H)4.24-4.38(m,4H)4.01-4.11(m,2H)3.90-4.01(m,1H)3.86(br.s.,2H)3.5 7-3.70(m,3H)3.21(d,J=7.02Hz,2H)2.98-3.17(m,3H)2.68-2.89(m,3H)2.38(d,J=10.68Hz,1H)2.08-2.25(m,2H)1.04(s,2H)

[1166] Example C-70: Preparation of 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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)

[1167] 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

[1168]

[1169] Cesium carbonate (4.0 equiv) 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-bromoethane-1-ol (7.18 g, 57.5 mmol) in ACN (300 ml). Cesium carbonate (4.0 equiv) 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-bromoethane-1-ol (7.18 g, 57.5 mmol). The reaction was stirred at 70° C. for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-5%) column chromatography. Subjective compound (2.5 g) MS (ESI, m / z): [M+H] + =523.6

[1170] 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]ethyl methanesulfonate

[1171]

[1172] Triethylamine (4.0 equiv) was added to 3-(1-{[3-(5-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (2.5 g, 4.78 mmol) and methanesulfonyl chloride (1.64 g, 14.4 mmol) in DCM (300 ml). Triethylamine (4.0 equiv) was added to the methanesulfonyl chloride (1.64 g, 14.4 mmol) solution. The reaction was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue w...

Claims

1. A compound represented by the following chemical formula 1: [Chemical Formula 1] cMET targeting protein binding portion (P)-{linker (L)}p-E3 ligase binding portion (E) in, The E3 ligase binding moiety (E) is a compound represented by the following Chemical Formula 2; and The cMET targeting protein binding moiety (P) is a compound represented by any one of the following Formulas 3 to 7; and p is an integer 0 or 1: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] in, X is hydrogen, halogen, amino, nitro, hydroxy, C1 to C6 straight or branched chain alkyl, or a 4 to 8 atom heterocycle containing oxygen or nitrogen; Q1 to Q4 are each independently CF, C—Cl, CH, CX or N, and at least any one of Q1 to Q4 is CX; Y is hydrogen, halogen, or an unsubstituted or halogen-substituted C1 to C6 linear, branched, or cyclic alkoxy group; provided that when one of Q5 and Q6 is a carbon atom and the other is a nitrogen atom, f Z is a carbon atom or a nitrogen atom; and R1 is hydrogen, nitro, amino, carbonyl, C1 to C6 linear, branched or cyclic alkyl, or C1 to C6 linear, branched or cyclic alkyl substituted by halogen.

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

3. In the second paragraph, the other end of the linker (L) is connected to a compound connected to piperidine or piperazine located at the end of any structure of Chemical Formulas 7 to 10.

4. In paragraph 1, the compound according to claim 1, wherein The connector (L) is A structure selected from the group consisting of: wherein 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, phenyl-piperidine, phenyl-piperazine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-piperazine, benzene, triazole or pyrrolidine; and m, n, q, r, s, t, u, v and w are each independently an integer selected from 0 to 7.

5. A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: 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-dihydrophthalazin-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-dihydrophthalazin-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-oxopentyl)amino)1-oxophthalazin-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-oxophthalazin-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-oxophthalazin-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-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-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-yl}phenyl)methyl]piperazin-1-yl}-15-oxo-4,7,10,13-tetraoxa-1-azapentadecan-1-yl)-1-oxo-1,2-dihydrophthalazin-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-oxophthalazin-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-azadodec-1-yl)-1-oxo-1,2-dihydrophthalazin-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-azahexadec-1-yl)-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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}morpholin-4-yl]pyrimidin-5-yl}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-hexaoxaheneicosane)amino)-1-oxophthalazin-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-oxophthalazin-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-oxophthalazin-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-oxophthalazin-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-oxophthalazin-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-oxophthalazin-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)piperazin-1-yl)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-tetraoxopentadec-15-yl)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-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; 3-(1-{[3-(5-{[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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; 3-(1-(3-(5-((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; 3-(1-(3-(5-((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)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile; 3-(1-(3-(5-((1-(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; 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)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-dihydrophthalazin-6-yl)amino)3,6,9,12-tetradecanoyl)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-dihydrophthalazin-6-yl)amino)3,6,9,12-tetraoxopentadec-15-yl)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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-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-dihydrophthalazin-6-yl)pentan-4-phosphin-1-yl)acetamide; 2-(4-(((2-(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-dihydrophthalazin-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-dihydrophthalazin-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-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; 3-(1-(3-(5-((1-(1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-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-(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; 3-(1-(3-(5-((1-(1-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazin-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-dihydrophthalazin-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-(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; 3-(1-(3-(5-((1-(2-(4-((1-(1-(2-(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; 3-(1-(3-(5-((1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-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-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-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-(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-dihydrophthalazin-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-(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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-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-dihydrophthalazin-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-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; 3-(1-(3-(5-((1-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)1,3-oxazin-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-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; 3-(1-(3-(5-((1-(2-(1-(1-(4-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-(2-(4-(1-(3-(2-(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; 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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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)pentan-4-phosphoryl-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-dihydrophthalazin-5-yl)propan-2-phosphin-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-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)morpholino)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-dihydrophthalazin-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-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-(1-(2-(3-(4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-dihydrophthalazin-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-yl)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-dihydrophthalazin-6-yl)piperazin-1-yl)-2-hydroxypropyl)piperazin-1-yl)pyrimidin-2-yl)benzo)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile.

6. An anticancer composition comprising the compound according to any one of claims 1 to 5.

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