Degrading agent containing a novel C-MET protein ligand and pharmaceutical composition containing the same

Abstract

TPD compounds are disclosed. The present invention relates to novel PROTAC compounds that bind to cMET protein and pharmaceutical compositions containing the same. The present invention relates to PROTAC compounds that bind to cMET protein, and since PROTAC compounds can bind to and degrade cMET protein, they can be useful for treating or preventing diseases associated with cMET protein. The compounds of the present invention have excellent anti-cancer effects and can also induce degradation of cMET protein, which can exhibit therapeutic effects against cMET and related diseases.

Description

[Technical Field]

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

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

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

[0004] The present invention aims to provide a PROTAC coupled with a novel E3 ligase binding moiety and a novel cMET protein target binding moiety via a linker, as well as pharmaceutical compositions comprising the same. [Means for solving the problem]

[0005] To achieve the technical task, the present invention provides a TPD compound represented by the following chemical formula 1: A compound represented by the following chemical formula 1: [Chemical formula 1] cMET target protein binding domain (P)-{linker (L)}p-E3 ligase binding domain (E) During the ceremony, The E3 ligase binding moiety (E) is a compound represented by the following chemical formula 2: The cMET target protein binding moiety (P) is a compound represented by any one of the following formulas 3 to 7: p is an integer of 0 or 1, [Chemical formula 2] [ka] [Chemical formula 3] [ka] [Chemical formula 4] [ka] [Chemical formula 5] [ka] [Chemical formula 6] [ka] [Chemical formula 7] [ka] [Chemical formula 8] [ka] During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 straight or branched chain alkyl, or an oxygen- or nitrogen-containing heterocycle of 4-8 atoms; Q1 to Q4 are each independently CF, C—Cl, CH, CX, or N, and at least one of Q1 to Q4 is CX; Y is hydrogen, halogen, or C1-C6 linear, branched, or cyclic alkyloxy unsubstituted or substituted with halogen; R 1 is hydrogen, nitro, amino, carbonyl, C1-C6 straight-chain, branched-chain or cyclic alkyl, or C1-C6 straight-chain, branched-chain or cyclic alkyl substituted with halogen; R 2 and R 3 are each independently hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, tosyl, or an unsubstituted or substituted C1-C6 linear, branched, or cyclic alkyl group; R 4 is hydrogen, a t-butoxycarbonyl group, or a benzyloxycarbonyl group.

[0006] In the present invention, one end of the linker (L) can be connected to the compound of formula 1 by (i) replacing X in the compound of formula 2; or (ii) It can be attached to the nitrogen atom or oxygen atom of X in the compound of formula 2.

[0007] In the present invention, the other end of the linker (L) is (i) any R 2 , R 3 Or R 4 and may be connected to any one of the structures of Chemical Formulae 3 to 7, or may be connected to the benzene ring of the structure of Chemical Formula 8.

[0008] In one embodiment of the present invention, R 2 and R 3 are each independently a halogen or R 5is a C1-C6 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) piperazine unsubstituted or substituted with t-butoxycarbonyl, benzyloxycarbonyl, or tosyl; (ii) R 6 C1-C6 alkoxy groups (R 6 is an amino substituted with a C1-C6 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

[0009] In another embodiment of the present invention, R 2 and R 3 are each independently a halogen or R 5 is a C1-C6 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) a piperazine that is unsubstituted or substituted with a t-butoxycarbonyl or benzyloxycarbonyl group; (ii) R 6 C1-C6 alkoxy group (R 6 is an amino substituted with a C1-C4 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

[0010] In another embodiment of the present invention, R 2 is hydrogen or a C1-C6 linear, branched or cyclic alkyl group, R 3 is R 5 is a C1-C4 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) piperazine, (ii) R 6C1-C4 alkoxy groups (R 6 is a C1-C4 alkoxy group or an amino group), or (iii) a hydroxy group.

[0011] In the present invention, the linker (L) is -(CH2) m -R 7 -(CH2) n -or A formula selected from the following: [ka] In the formula, R 7 is piperazine, piperidine, azetidine, benzene, triazole or pyrrolidine, m and n are each independently an integer selected from 0 to 5.

[0012] In another embodiment of the invention, the linker L is selected from: [ka] or TIFF2025538555000011.tif831 In the formula, m and n are each independently an integer selected from 0 to 5.

[0013] Additionally, the present invention relates to compounds having the following chemical formula 3 or 4, or pharmaceutically acceptable salts thereof: [Chemical formula 3] [ka] [Chemical formula 4] [ka] During the ceremony, R 2 and R 3 are each independently hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, tosyl, or an unsubstituted or substituted C1-C6 straight, branched, or cyclic alkyl group.

[0014] In one embodiment of the present invention, R 2 and R 3 are each independently a halogen or R 5 is a C1-C6 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) piperazine unsubstituted or substituted with t-butoxycarbonyl, benzyloxycarbonyl, or tosyl; (ii) R 6 a C1-C6 alkoxy group (R 6 is a C1-C6 alkoxy group, an amino group, or an amino group substituted with a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a tosyl group), or (iii) a hydroxy group.

[0015] Additionally, in one embodiment of the present invention, R 2 and R 3 are each independently a halogen or R 5 is a C1-C6 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) a piperazine that is unsubstituted or substituted with a t-butoxycarbonyl or benzyloxycarbonyl group; (ii) R 6 C1-C6 alkoxy group (R 6is an amino substituted with a C1-C4 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

[0016] Additionally, in one embodiment of the present invention, R 2 is hydrogen or a C1-C6 linear, branched or cyclic alkyl group, R 3 is R 5 is a C1-C4 linear, branched or cyclic alkyl group unsubstituted or substituted with R 5 is (i) piperazine, (ii) R 6 C1-C4 alkoxy groups (R 6 is a C1-C4 alkoxy or amino), or (iii) a hydroxy group.

[0017] Additionally, the present invention relates to any one of the following chemical formulas 5 to 7, or a pharmaceutically acceptable salt thereof: [Chemical formula 5] [ka] [Chemical formula 6] [ka] [Chemical formula 7] [ka] During the ceremony, R 4 is hydrogen, a t-butoxycarbonyl group, or a benzyloxycarbonyl group.

[0018] In addition to the TPD compound of Formula 1 of the present invention, the compounds of Formulas 3 to 7 can bind to cMET protein and provide anti-cancer effects. Thus, the present invention provides a pharmaceutical composition for treating cancer, comprising any one of Formulas 1 to 7. [Effects of the Invention]

[0019] The present invention relates to a PROTAC compound that binds to cMET protein and can degrade it, making it useful for treating or preventing diseases associated with cMET protein. The compound of the present invention has excellent anti-cancer effects and can also induce degradation of cMET protein, which can exhibit therapeutic effects against cMET-related diseases. [Brief explanation of the drawings]

[0020] [Figure 1] Schematic of a PROTAC compound consisting of an E3 ligase binding moiety, a linker, and a target protein binding moiety.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0023] The terms used in this specification are used only to describe specific embodiments and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. The "including" of an element in the present specification means that it may include more of the other elements rather than excluding other elements, unless otherwise specified.

[0024] The PROTAC according to the present invention may be a compound represented by formula 1: [Chemical formula 1] E3 ligase binding domain (E)-linker (L)-cMET target protein binding domain (P)

[0025] The basic structure of the E3 ligase binding moiety according to the present invention can be prepared according to the following reaction scheme 1 or reaction scheme 2. [Reaction Scheme 1] [ka] [Reaction Scheme 2] [ka]

[0026] In the above reaction formula 1 or 2, X is hydrogen, halogen, amino, nitro, hydroxy, piperazine group, or C1-C4 alkoxy. However, for the sake of convenience, the above formula does not show the substituents that can be bonded to carbons at Q1-Q4 of the compound of formula 1, and R 1 Among the substituents, only simple substituents such as hydrogen or methyl are shown as examples.

[0027] Below, embodiments are used to prepare specific examples of E3 ligase binding moiety compounds.

[0028] Example A: Preparation of E3 Ligase Ligating Moiety Compounds Example A-1: ​​Compound [ka] or JPEG2025538555000020.jpg2999 Preparation of (prepared according to Equation 1) 1-1) Preparation of methyl 2-methyl-6-nitrobenzoate [ka] At room temperature, K2CO3 (19.1 g, 138 mmol) was added to a solution of 2-methyl-6-nitrobenzoic acid (5 g, 27.6 mmol) in acetone (100 ml). After stirring for 30 minutes, iodomethane (19.6 g, 138 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product was used in the next reaction without further purification. (5.45 g, 98%) MS (ESI, m / z): [M+1] + =[195.2].

[0029] 1-2) Preparation of methyl 2-(bromomethyl)-6-nitrobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carboroxoate (0.67 g, 7.26 mmol) were added sequentially to a solution of methyl 2-methyl-6-nitrobenzoate (5.39 g, 27.6 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0030] 1-3) Preparation of methyl 2-formyl-6-nitrobenzoate [ka] At room temperature, NMO (N-methylmorpholine N-oxide) (561 mg, 4.87 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (10 ml). The DCM layer was washed with water (50 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0031] 1-4) Preparation of 2-formyl-6-nitrobenzoic acid [ka] At room temperature, an aqueous solution of lithium (+1) hydroxylate (1.15 g, 47.8 mmol) was added to a solution of methyl 2-formyl-6-nitrobenzoate (2 g, 9.56 mmol) in THF (10 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0032] 1-5) Preparation of 8-nitrobutalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (417 mg, 8.33 mmol) was added to a solution of 2-formyl-6-nitrobenzoic acid (1.2 g, 6.15 mmol) in methanol (10 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0033] 1-6) Preparation of 3-(8-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 8-nitro-1,2-dihydrodroprazine-1-one (60 mg, 0.314 mmol) in DMF (1 ml). The reaction was heated to 85 °C for 5 h. After cooling, the reaction was poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (68 mg, 71.7%). MS (ESI, m / z): [M+1] + =[302.6].

[0034] 1-7) Preparation of 3-(8-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(8-nitro-1-oxo-1,2-dihydrohoptalazin-2-yl) in methanol (5 ml) and stirred under hydrogen in a balloon for 1 hour. The solid was filtered and the filtrate was concentrated under reduced pressure to give the title compound in 99% yield. MS (ESI, m / z): [M+1] + =[272.3].

number

[0035] Example A-2: Compound [ka] or JPEG2025538555000030.jpg39102 Preparation of 2-1) Preparation of methyl 2-methyl-3-nitrobenzoate [ka] At room temperature, K2CO3 (19.1 g, 138 mmol) was added to a solution of 2-methyl-3-nitrobenzoic acid (5 g, 27.6 mmol) in acetone (100 ml). After stirring for 30 minutes, iodomethane (19.6 g, 138 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product was used in the next reaction without further purification. (5.45 g, 98%) MS (ESI, m / z): [M+1] + =[195.3].

[0036] 2-2) Preparation of methyl 2-(bromomethyl)-3-nitrobenzoate [ka] At room temperature, 1-bromophilidine-2,5-dione (7.39 g, 41.4 mmol) and benzoylbenzene carbophoroxoate (0.67 g, 7.26 mmol) were added sequentially to a solution of methyl 2-methyl-3-nitrobenzoate (5.39 g, 27.6 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (7.34 g, 98%) MS (ESI, m / z): [M+1] + =[274.4].

[0037] 2-3) Preparation of methyl 2-formyl-3-nitrobenzoate [ka] At room temperature, NMO (561 mg, 4.87 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-3-nitrobenzoate (580 mg, 2.12 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (10 ml). The DCM layer was washed with water (50 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (350 mg, 79.07%) MS (ESI, m / z): [M+1] + =[210.0].

[0038] 2-4) Preparation of 2-formyl-3-nitrobenzoic acid [ka] At room temperature, an aqueous solution of lithium (+1) hydroxylate (1.15 g, 47.8 mmol) was added to a solution of methyl 2-formyl-3-nitrobenzoate (2 g, 9.56 mmol) in THF (10 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to remove the THF. After cooling to 0°C, the residue was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1.50 g, 80.3%). MS (ESI, m / z): [M+1] + =[195.2].

[0039] 2-5) Preparation of 5-nitrobutalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (417 mg, 8.33 mmol) was added to a solution of 2-formyl-3-nitrobenzoic acid (1.2 g, 6.15 mmol) in methanol (10 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (1 g, 85.07%). MS (ESI, m / z): [M+1] + =[191.8].

[0040] 2-6) Preparation of 3-(5-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 5-nitrophthalazin-1(2H)-one (60 mg, 0.314 mmol) in DMF (1 ml). The reaction was heated to 85 °C for 5 h. After cooling, the reaction was poured into water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (68 mg, 71.7%). MS (ESI, m / z): [M+1] + =[302.4].

[0041] 2-7) Preparation of 3-(5-amino-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 20 mg of 10% Pd / C (wet) (5 mg) was added to a solution of 3-(5-nitro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (25 mg, 0.82 mmol) in methanol (5 ml) and stirred under hydrogen in a balloon for 1 hour. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound in 99% yield. MS (ESI, m / z): [M+1] + =[272.3].

number

[0042] Example A-3: Compound [ka] Preparation of 3-1) Preparation of methyl 2-fluoro-6-methylbenzoate [ka] At room temperature, K2CO3 (44.8 g, 324 mmol) was added to a solution of 2-fluoro-6-methylbenzoic acid (10 g, 64.9 mmol) in acetone (200 ml). After stirring for 30 minutes, iodomethane (46 g, 324 mmol) was added to the reaction and heated to 60 °C for 6 hours. After cooling, the reaction was filtered and concentrated under reduced pressure. The product was used in the next reaction without further purification. (11.2 g, 103% yield) MS (ESI, m / z): [M+1] + =[168.3].

[0043] 3-2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (24.7 g, 139 mmol) and benzoylbenzene carbophoroxoate (1.53 g, 6.30 mmol) were added sequentially to a solution of methyl 2-fluoro-6-methylbenzoate (21.2 g, 126 mmol) in ClCH2CHCl (250 ml). The reaction was heated to reflux for 16 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the following reaction without further purification. (35 g, 112% yield) MS (ESI, m / z): [M+1] + =[245.9].

[0044] 3-3) Preparation of methyl 2-fluoro-6-formylbenzoate [ka] At room temperature, NMO (24.9 g, 212 mmol) was added to a solution of methyl 2-(bromomethyl)-6-fluorobenzoate (35 g, 142 mmol) in DCM (280 ml). The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (11.52 g, 45% yield) MS (ESI, m / z): [M+1] + =[183.1].

[0045] 3-4) Preparation of 2-fluoro-6-formylbenzoic acid [ka] At room temperature, an aqueous solution (41 ml) of lithium hydroxide (+1) (7.57 g, 180 mmol) was added to a solution of methyl 2-fluoro-6-formylbenzoate (11.5 g, 63.2 mmol) in THF (82 ml). After stirring for 4 hours, the reaction was concentrated under reduced pressure and the THF was dried. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (100 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (10.4 g, 97.8%). MS (ESI, m / z): [M+1] + =[168.8].

[0046] 3-5) Preparation of 8-fluorothalazin-1(2H)-one [ka] At room temperature, NH2NH2 monohydrate (3.72 mg, 61.9 mmol) was added to a solution of 2-fluoro-6-formylbenzoic acid (10.4 g, 61.9 mmol) in methanol (120 ml) and stirred at room temperature for 16 hours. The white precipitate was filtered and washed with methanol. The resulting white crystals were slurried with 100 ml of ethyl acetate (EA) and filtered to give white crystals (3.05 g, 30%). MS (ESI, m / z): [M+1] + =[164.8].

[0047] 3-6) Preparation of 3-(8-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] NaH (60%, 53.6 mg, 1.34 mmol) was added to a solution of 8-fluorobutalazine-1(2H)-one (200 mg, 1.22 mmol) in DMF (5 ml) at 0° C. and stirred for 30 minutes. 3-Bromoperidine-2,6-dione (468 mg, 2.44 mmol) was added to the solution and stirred for 6 hours. The reaction was quenched with water and extracted twice with ethyl acetate (20 ml). The combined ethyl acetate was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (70 mg, 20.8%). MS (ESI, m / z): [M+1] + =[276.1].

number

[0048] Example A-4: Compound [ka] Preparation of 4-1) Preparation of methyl 5-fluoro-6-methylbenzoate [ka] At room temperature, sulfuric acid (2 ml) was added to a solution of 3-fluoro-2-methylbenzoic acid (10 g, 64.9 mmol) in methanol (60 ml). The mixture was heated to 80° C. and stirred overnight. After cooling to room temperature, the reaction mixture was evaporated and extracted with NaHCO3 and ethyl acetate (EA). It was dried over MgSO4. 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].

[0049] 4-2) Preparation of methyl 2-(bromomethyl)-3-fluorobenzoate [ka] At room temperature, 1-bromomeloridine-2,5-dione (15.9 g, 89.2 mmol) and benzoylbenzene carbophoroxoate (0.72 g, 2.97 mmol) were added sequentially to a solution of methyl 3-fluoro-2-methylbenzoate (10 g, 59.5 mmol) in ClCH2CHCl (250 ml). The reaction was heated to reflux for 16 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (10.5 g, 71% yield) MS (ESI, m / z): [M+1] + =[245.9].

[0050] 4-3) Preparation of methyl 3-fluoro-2-formylbenzoate [ka] At room temperature, NMO (10.4 g, 89 mmol), 4 Å molecular sieves were added to a solution of methyl 2-(bromomethyl)-3-fluorobenzoate (10 g, 40.5 mmol) in DCM (200 ml). The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound. (5.5 g, 75%) MS (ESI, m / z): [M+1] + =[183.1].

[0051] 4-4) Preparation of 3-fluoro-2-formylbenzoic acid [ka] At room temperature, an aqueous solution (41 ml) of lithium(+1) hydroxyside monohydrate (2.88 g, 68.6 mmol) was added to a solution of methyl 3-fluoro-2-formylbenzoate (2.5 g, 13.7 mmol) in THF (68 ml). After stirring for 4 hours, the reaction was concentrated under reduced pressure to remove the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (100 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (2.5 g, 108%). MS (ESI, m / z): [M+1] + =[168.8].

[0052] 4-5) Preparation of 5-fluoro-1,2-dihydrophthalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (1.22 mg, 16.4 mmol) was added to a solution of 3-fluoro-2-formylbenzoic acid (2.5 g, 14.9 mmol) in 1:1 THF:water (70 ml) and stirred for 16 hours. The mixture was acidified to pH 4, and the solid was filtered and washed with hexane. Vacuum drying afforded the title compound (1.3 g, 53%). MS (ESI, m / z): [M+1]+ =[165.3]

[0053] 4-6) Preparation of 3-(5-fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione [ka] LDA (lithium diisopropylamide, 2.19 mmol) was added to a solution of 5-fluoropreptalazin-1-one (300 mg, 1.83 mmol) in DMF (10 ml) at 0°C and stirred for 30 minutes. 3-Bromoperidine-2,6-dione (526 mg, 2.74 mmol) was added to the solution and stirred at 80°C for 6 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (100 ml), and the pH was adjusted to 3-4 with 6N HCl. The mixture was then extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The product was recrystallized in hexane and dried under vacuum to give the title compound. MS (ESI, m / z): [M+1] + =[276.1].

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[0054] Example A-5: Compound [ka] Preparation of 5-1) Preparation of methyl 4-fluoro-6-methylbenzoate [ka] Methyl 4-fluoro-2-methylbenzoate was prepared from 4-fluoro-2-methylbenzoate according to the preparation method of Example 4-1.

[0055] 5-2) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate [ka] At room temperature, 1-bromophillolidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzebolocarbon (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 4-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The product was purified by MPLC (HX / EA EA 0->5%) (22 g, 75% yield). MS (ESI, m / z): [M+1] + =[248.4].

[0056] 5-3) Preparation of methyl 3-fluoro-2-formylbenzoate [ka] At room temperature, NMO (15.6 mg, 134 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22 g, 89 mmol) in DCM (100 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (50 ml). The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (12 g, 73.98%) MS (ESI, m / z): [M+1] + =[183.2].

[0057] 5-4) Preparation of 4-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution (50 ml) of lithium (+1) hydroxyl (13.8 g, 329 mmol) in water was added to a solution of methyl 4-fluoro-6-formylbenzoate (12 g, 65.9 mmol) in THF (50 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (10 g, 90.3%). MS (ESI, m / z): [M+1] + =[169.2].

[0058] 5-5) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (2.02 g, 40.3 mmol) was added to a solution of 4-fluoro-2-formylbenzoic acid (6.78 g, 40.3 mmol) in methanol (50 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150 ml) and extracted twice with ethyl acetate (150 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (5.5 g, 83.07%). MS (ESI, m / z): [M+1] + =[165.3].

[0059] 5-6) Preparation of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluorophthalazin-1-one (100 mg, 0.609 mmol) in DMF (2 ml) at 0° C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione (90 mg, 0.471 mmol) was added to the reaction mixture, which was then stirred at room temperature for 6 hours. Water (20 ml) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 ml). The combined ethyl acetate solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound as white crystals (110 mg, 65.5%). MS (ESI, m / z): [M+1] + =[276.6].

number

[0060] Example A-6: Compound [ka] Preparation of 6-1) Preparation of methyl 4-fluoro-6-methylbenzoate [ka] Methyl 5-fluoro-2-methylbenzoate was prepared from 5-fluoro-2-methylbenzoate according to the preparation method of Example 4-1.

[0061] 6-2) Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate [ka] At room temperature, 1-bromophilidine-2,5-dione (31.8 g, 178 mmol) and benzoylbenzene carboroxoate (1.92 g, 5.95 mmol) were added sequentially to a solution of methyl 5-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH2CHCl (100 ml). The reaction was heated to reflux for 3 hours. The reaction was complete when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The product was purified by MPLC (HX / EA EA 0->5%) (29 g, 98.8% yield). MS (ESI, m / z): [M+1] + =[248.4].

[0062] 6-3) Preparation of methyl 5-fluoro-2-formylbenzoate [ka] At room temperature, NMO (20.6 mg, 176 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-5-fluorobenzoate (29 g, 117 mmol) in DCM (100 ml). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (50 ml). The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (15 g, 70.16% yield) MS (ESI, m / z): [M+1] + =[183.2].

[0063] 6-4) Preparation of 5-fluoro-2-formylbenzoic acid [ka] At room temperature, a solution (50 ml) of lithium (+1) hydroxyl (17.3 g, 412 mmol) in water was added to a solution of methyl 5-fluoro-2-formylbenzoate (15 g, 82.3 mmol) in THF (50 ml). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (12 g, 86.67%). MS (ESI, m / z): [M+1] + =[169.2].

[0064] 6-5) Preparation of 7-fluoro-1,2-dihydrobutalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (3.74 g, 74.8 mmol) was added to a solution of 5-fluoro-2-formylbenzoic acid (8.16 g, 48.5 mmol) in methanol (50 ml). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150 ml) and extracted twice with ethyl acetate (150 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (6.5 g, 81.59%). MS (ESI, m / z): [M+1] + =[165.3].

[0065] 6-6) Preparation of 3-(7-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (586 mg, 6.09 mmol) was added to a solution of 7-fluorine-1,2-dihydrohoptalazin-1-one (500 mg, 3.05 mmol) in DMF (5 ml) at 0° C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione (1.05 mg, 5.48 mmol) was added to the reaction mixture, which was then stirred at room temperature for 6 hours. The reaction mixture was poured into water (50 ml) and extracted twice with ethyl acetate (50 ml). The combined ethyl acetate solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (300 mg, 35.78%). MS (ESI, m / z): [M+1] + =[276.6].

number

[0066] Example A-7: Compound [ka] Preparation of (prepared according to Equation 2) 7-1) Preparation of methyl 2-acetyl-6-fluorobenzoate [ka] Tetrakis(triphenylphosphine)-palladium(0) (557 mg, 0.48 mmol) was added to a solution of methyl 2-acetyl-6-fluorobenzoate (1.12 g, 4.81 mmol) and tributyl(1-ethoxyvinyl)tin (1.91 g, 5.29 mmol) in toluene (20 ml), and the mixture was stirred at 100° C. for 16 hours. After cooling, 5 ml of 1N HCl was added and the mixture was stirred for 1 hour. The organic layer was dried over MgSO and concentrated under reduced pressure. The residue was purified by silica column chromatography to give the title compound as a yellow oil. (820 mg, 87% yield) MS (ESI, m / z): [M+1] + =[196.8].

[0067] 7-2) Preparation of 2-acetyl-6-fluorobenzoic acid [ka] LiOH (494 mg, 20.6 mmol) was added to a solution of methyl 2-acetyl-6-fluorobenzoate (810 mg, 4.13 mmol) in THF (20 ml) and water (10 ml) and stirred at room temperature for 20 hours. The solution was acidified with 1N HCl to a pH of approximately 3. 100 ml of EA was added, and the organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound. (810 mg, 108% yield) MS (ESI, m / z): [M+1] + =[183.1].

[0068] 7-3) Preparation of 8-fluoro-4-methylphthalazin-1(2H)-one [ka] Hydrazine monohydrate (261 mg, 5.20 mmol) was added to a solution of 2-acetyl-6-fluorobenzoic acid (790 mg, 4.34 mmol) in methanol (23 ml) and stirred at room temperature for 16 hours. The precipitate was filtered and washed with ACN (acetonitrile) to give the title compound as a white solid (612 mg, 79.2% yield). MS (ESI, m / z): [M+1] + =[179.1].

[0069] 7-4) Preparation of 3-(8-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1M-Lithium diisopropylamide (3.6 ml, 3.6 mmol) was added to a solution of 8-fluoro-4-methylphthalazin-1(2H)-one (534 mg, 3 mmol) in THF (30 ml) at 0° C. and stirred for 20 minutes. 3-Bromopiperidine-2,6-dione (863 mg, 4.5 mmol) was added to the solution and stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and dried. Water (10 ml) was added, stirred for 1 hour, and acidified with 1N HCl to adjust the pH to 4. The precipitate was filtered and washed with water to give the title compound as a white solid (760 mg, yield: 86.5%). MS (ESI, m / z): [M+1] + =[289.8].

number

[0070] Example A-8: Compound [ka] Preparation of 8-1) Preparation of 3-(8-((2,4-dimethoxybenzyl)amino)-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of 3-(8-fluoro-4-methyl-1-oxothalamin-2(1H)-yl)piperidine-2,6-dione (0.104 mmol), 2,4-dimethoxybenzylamine (0.207 mmol), and DIPEA (N,N-diisopropylethylamine) (0.312 mmol) in NMP (N-methyl-pyrrolidone) (1 mL) was heated in a microwave oven for 2 hours at 120 °C. The reaction mixture was purified by reverse-phase chromatography (C18, water (0.1% FA) / ACN (0.1% FA), gradient) to give 33 mg of a white solid (33 mg, 72% yield). MS (ESI, m / z): [M+1] + =[437.0]

[0071] 8-2) Preparation of 3-(8-amino-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 0.3 ml of TFA (trifluoroacetic acid) was added to 3-(8-((2,4-dimethoxybenzyl)amino)4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (14 mg, 0.032 mmol) in toluene (0.7 mL) and stirred at 80° C. for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (C18, water (0.1% FA) / ACN (0.1% FA), gradient) to give 7.5 mg of a white solid (7.5 mg, 82% yield). MS (ESI, m / z): [M+1] + =[287.0] [NMR] 1 H NMR(400 MHz,DMSO-d6)δ10.98(s,1H),7.54(t,J=8.0 Hz,1H),7.37(brs,2H),6.95(d,J=8.2 Hz,1H),6.88(d,J=7.6 Hz,1H),5.62(br dd,J=5.3,12.0 Hz,1H),3.0-2.82(m,1H),2.66-2.52(m,2H),2.39(s,3H),2.11-2.02(m,1H)

[0072] Example A-9: Compound [ka] Preparation of 9-1) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] 6-Fluoro-1,2-dihydrobutalazin-1-one (100 mg, 0.36 mmol) and tert-butyl piperazine-1-carboxylate (81.2 mg, 0.36 mmol) were dissolved in NMP (1 mL), and DIPEA (5 equivalents) was added to the reaction mixture, which was then stirred at 120 °C overnight. The reaction mixture was quenched with water, extracted with EA, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4. The reaction mixture was loaded onto silica and separated by MPLC (HX / EA 30% -> 50%, 10 min) to give an oil product (110 mg, 66% yield).

[0073] 9-2) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl]piperazine-1-carboxylate was dissolved in a 20% TFA solution in DCM (1 ml) and reacted at room temperature for 2 hours. The reaction was quenched with an aqueous solution saturated with NaHCO3 and extracted with EA. The organic layer was dried over MgSO4 and evaporated. The reaction mixture was purified by MPLC (MC / ME Me0->10%). White solid product (40 mg, 86% yield). MS (ESI, m / f): [M+1] + =[342.2]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ 8.24(s,1 H)8.02(d,J=9.05 Hz,1 H)7.47(dd,J=8.93,2.57 Hz,1 H)7.31(s,0.5 H)7.23(d,J=2.45 Hz,1 H)7.13(s,0.5 H)5.34(dd,J=8.93,4.52 Hz,1 H)3.28-3.44(m,6 H)2.85-2.95(m,4 H)2.30-2.40(m,1 H)2.16-2.30(m,2 H)

[0074] Example A-10: Compound [ka] Preparation of 10-1) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] 3-(7-Fluoro-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) and tert-butyl piperazine-1-carboxylate (81.2 mg, 0.44 mmol) were dissolved in NMP (1 mL), and DIPEA (5 equivalents) was added to the reaction mixture, which was then stirred at 120 °C overnight. The reaction mixture was quenched with water, extracted with EA, and washed with saturated aqueous NH Cl and brine. The organic layer was dried over MgSO, and the reaction mixture was loaded onto silica and separated by MPLC (HX / EA 30% -> 50%, 10 min) to give the product as an oil (yield: 110 mg, 66%).

[0075] 10-2) Preparation of 3-(1-oxo-7-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] tert-Butyl-4-[3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobutalazin-6-yl]piperazine-1-carboxylate (60 mg, 0.14 mmol) was dissolved in 20% TFA in DCM (1 ml) and reacted at room temperature for 2 hours. The reaction was quenched with an aqueous solution saturated with NaHCO3 and extracted with EA. The organic layer was dried over MgSO4 and evaporated. The reaction mixture was purified by MPLC (MC / ME Me 0->10%) to give a white solid as the product (yield: 40 mg / 86%). MS (ESI, m / f): [M+1] + =[342.2]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ 8.21-8.29(m,1 H)7.76(d,J=8.80 Hz,1 H)7.58(dd,J=8.93,2.57 Hz,1 H)7.47(d,J=2.45 Hz,1 H)7.28(s,0.5 H)7.13(s,0.5 H)5.34-5.44(m,1 H)3.26-3.33(m,4 H)2.81-2.91(m,3 H)2.62-2.69(m,1 H)2.55-2.62(m,1 H)2.31-2.44(m,1 H)2.15-2.31(m,2 H)

[0076] Example A-11: Preparation of 3-(8-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] Preparation of compounds [ka] 3-(6-Fluoro-1-oxo-1,2-dihydroptarazin-2-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The reaction mixture was reacted at room temperature for 1 hour. The organic solvent was removed, and the mixture was extracted with EA and water. The mixture was purified by MPLC to obtain the product as a white solid (yield: 80 mg / 76%). MS (ESI, m / f): [M+1] + =[288.2]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ 11.04(br.s.,1 H)8.40(s,1 H)8.14-8.25(m,1 H)7.42-7.49(m,2 H)5.80(dd,J=12.23,5.38 Hz,1 H)3.94(s,3 H)2.86-2.99(m,1 H)2.52-2.67(m,2 H)2.07-2.17(m,1 H)

[0077] Example A-12: Preparation of 3-(7-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of [ka] 3-(7-Fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The resulting mixture was allowed to react at room temperature for 1 hour. The organic solvent was removed, and the mixture was extracted with EA and water. The mixture was purified by MPLC to obtain the product as a white solid. (Yield: 78 mg / 75%) MS (ESI, m / f): [M+1] + =[288.2]. [NMR] 1H NMR(400 MHz,DMSO-d6)δ 11.01-11.11(m,1 H)8.38-8.45(m,1 H)7.90-7.96(m,1 H)7.65(d,J=2.69 Hz,1 H)7.56(dd,J=8.68,2.57 Hz,1 H)5.77-5.85(m,1 H)3.93-3.98(m,3 H)2.87-3.00(m,1 H)2.53-2.70(m,2 H)2.06-2.18(m,1 H)

[0078] Example A-13: Preparation of 3-(6-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of [ka] 3-(6-Fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (100 mg, 0.36 mmol) was dissolved in DMSO (1 ml), and NaOMe (19.6 mg, 0.36 mmol) was added to the reaction mixture. The resulting mixture was allowed to react at room temperature for 1 hour. The organic solvent was removed, and the mixture was extracted with EA and water. The mixture was purified by MPLC to obtain the product as a white solid. (Yield: 80 mg / 76%) MS (ESI, m / f): [M+1] + =[288.2]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ 11.01(s,1 H)8.32(s,1 H)7.88(t,J=8.01 Hz,1 H)7.40(d,J=8.31 ​​Hz,1 H)7.44(d,J=7.70 Hz,1 H)5.64(dd,J=11.49,4.52 Hz,1 H)3.90(s,3 H)2.83-2.96(m,1 H)2.52-2.66(m,2 H)2.03-2.13(m,1 H)

[0079] Example A-14: Preparation of 3-(5-methoxy-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate [ka] 1-Bromopyridine-2,5-dione (11.5 g, 64.94 mmol) and benzoylbenzenecarboperoxate (786 mg, 3.24 mmol) were added sequentially to a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH2CHCl (250 ml) at room temperature. The reaction mixture was heated to reflux for 3 hours. The reaction was completed when the red color disappeared. After cooling, the reaction mixture was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (16.5 g, 98.2%) MS (ESI, m / z): [M+1] + =[259.4].

[0080] 14-2) Preparation of methyl 2-formyl-3-methoxybenzoate [ka] NMO (12.6 g, 108.1 mmol) and 4 Å molecular sieves (50 g) were added sequentially to a solution of methyl 2-(bromomethyl)-3-methoxybenzoate (14.1 g, 54.1 mmol) in DCM (300 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (100 mL). The DCM layer was washed with water (250 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (8.3 g, 80.01%) MS (ESI, m / f): [M+1] + =[195.0].

[0081] 14-3) Preparation of 2-formyl-3-methoxybenzoic acid [ka] Lithium(1+) hydroxylate (2.4 g, 100.5 mmol) in HO (100 mL) was added to a solution of methyl 2-formyl-3-methoxybenzoate (6.5 g, 33.6 mmol) in THF (100 mL) at room temperature. After stirring for 2 hours, the reaction was concentrated under reduced pressure to evaporate the THF. After cooling to 0 °C, the reaction was acidified with 1 N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (250 mL). The combined ethyl acetate layers were dried over MgSO and concentrated under reduced pressure to give white crystals. (11.2 g, 82.6%) MS (ESI, m / f): [M+1] + =[199.2].

[0082] 14-4) Preparation of 5-methoxyphthalazin-1(2H)-one [ka] NH2NH2 monohydrate (10.3 g, 342 mmol) was added to a solution of 2-formyl-3-methoxybenzoic acid (8.2 g, 45.5 mmol) in MeOH (20 mL) at room temperature. After stirring for 2 hours, the reaction was concentrated under reduced pressure, poured into water (50 mL), and extracted twice with ethyl acetate (150 mL). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals. (9.2 g, 76.35%) MS (ESI, m / f): [M+1] + =[176.9].

[0083] 14-5) Preparation of 3-(5-methoxy-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1.0 M LDA (37.4 mL) was added dropwise to a suspension of 5-methoxyphthalazin-1(2H)-one (5.1 g, 28.9 mmol) in THF (250 mL) at 0 °C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione was added portionwise to the reaction. The reaction was heated to 80 °C and stirred for 2 hours. Upon completion of the reaction, the reaction was cooled to room temperature, poured into water (100 mL), the pH was adjusted to 3-4 with 6N HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound as white crystals. (7.2 g, 86.5% yield) MS (ESI, m / f): [M+1] + =[288.3]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ11.06(s,1H),8.51(s,1H),7.87-7.77(m,2H),7.54-7.51(m,1H), 5.85(m,1H),4.0(s,3H),2.98-2.90(m,1H),2.65-2.55(m,2H),2.14-2.09(m,1H).

[0084] Example A-15: Preparation of 3-(6-bromo-1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione compound [ka] Preparation of 15-1) Preparation of 5-bromo-3-hydroxyisobenzofuran-1(3H)-one [ka] AIBN (401 mg, 2.44 mmol) was added to a mixture of 5-bromophthalide (5.2 g, 24.4 mmol) and N-bromosuccinimide (5.6 g, 31.7 mmol) in 200 ml of ClCH2CHCl and refluxed for 8 hours. After the reaction, TLC was performed. The succinimide was filtered and the cake was washed with ClCH2CHCl (50 mL). The solvent was removed in vacuo, leaving a 5.2 g residue, to which 50 ml of water was added. The mixture was stirred and refluxed for 4 hours, cooled, and the product was filtered, neutralized, washed with water, and dried to give pale yellow-white crystals. (4.85 g, 86.7% yield) MS (ESI, m / z): [M+1] + = [229.6] and [230.5]

[0085] 15-2) Preparation of 6-bromophthalazin-1(2H)-one [ka] NH2NH2H2O (315 mg, 9.82 mmol) was added to a solution of 5-bromo-3-hydroxy-1,3-dihydro-2-benzofuran-1-one (1.5 g, 6.55 mmol) in MeOH (50 mL) at room temperature and stirred for 30 minutes. The reaction was refluxed for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting solid was titrated with ethyl acetate to give white crystals. (1.31 g, 5.82 mmol) MS (ESI, m / f): [M+1] + =[226.3].

[0086] 15-3) Preparation of 3-(6-bromo-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 1.0 M LDA (7.33 mL) was added dropwise to a suspension of 6-bromo-1,2-dihydrobutalazin-1-one (1.31 g, 5.82 mmol) in THF (150 mL) at 0 °C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione was added portionwise to the reaction. The reaction was heated to 80 °C and stirred for 2 hours. Upon completion of the reaction, the reaction was cooled to room temperature, poured into water (100 mL), the pH was adjusted to 3-4 with 6N HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The resulting solid was filtered and washed with ethyl acetate to give white crystals. (1.73 g, 5.15 mmol) MS (ESI, m / f): [M+1] + =[337.2]. [NMR] 1 H NMR(400 MHz,DMSO-d6)δ11.08(s,1H),8.45(s,1H),8.28(s,1H),8.18-8.16(m,1H),8.06-8.0 4(m,1H),5.84-5.80(m,1H),2.93-2.90(m,1H),2.65-2.54(m,2H),2.15-2.12(m,1H).

[0087] Example A-16: Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione dihydrochloride compound [ka] Preparation of 16-1) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione dihydrochloride [ka] tert-Butyl piperazine-1-carboxylate (244 mg, 1.13 mmol) and ethyl bis(propan-2-yl)amine (423 mg, 3.24 mmol) were added sequentially to a solution of 3-(8-fluoro-1-oxo-1,2-dihydrohoptalazin-2-yl)piperidine-2,6-dione (0.3 g, 1.09 mmol) in DMA (4 mL). The mixture was stirred at 120° C. for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give a pale yellow-white oil. (415 mg, 86.2%) MS (ESI, m / f): [M+1] + =[442.4]

[0088] 16-2) Preparation of 3-(1-oxo-8-(piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione dihydrochloride [ka] 3-Bromoperidine-2,6-dione (90 mg, 0.471 mmol) and K2CO3 (129 mg, 0.942 mmol) were added sequentially to a solution of 8-nitro-1,2-dihydrophthalazin-1-one (60 mg, 0.314 mmol) in DMF (1 mL). The reaction was heated to 85 °C for 5 h. After cooling, the reaction mixture was poured into water (5 mL) and extracted twice with ethyl acetate (5 mL). The combined ethyl acetate was extracted with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals. (68.0 mg, 71.7% yield) MS (ESI, m / f): [M+1] + =[342.6]. [NMR] 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),8.35(s,1H),7.87-7.83(m,1H),7.53-7.51(m,1H),7.39-7.41(m,1H),5. 55(m,1H),3.31-3.27(br,8H),2.88-2.80(m,1H),2.64-2.57(m,2H),2.50(br,1H),2.13-2.08(m,1H).

[0089] Example B: Preparation of cMET targeting ligand compounds based on ABN derivatives For the preparation of ABN-based cMET targeting ligand compounds, an intermediate having the formula See U.S. Pat. No. 9,403,831 B2, which is incorporated herein by reference, for (S)-4-(5-bromophimidin-2-yl)-2((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (the chemical formula is set forth in accordance with the U.S. Pat. No. 5,403,831 B2), (2S)-4-(5-bromopyrimidin-2-yl)-2((5-(1-methyl-1H-pyrazol-4-yl)-3a,4a-dihydro-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine was synthesized, and this intermediate was used to prepare the compounds of Examples B-1 to B-13 in the following embodiment.

[0090] [Intermediate chemical formula] [ka] Example B-1: Preparation of tert-butyl (S)-3-((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)piperazin-1-yl)methyl)azetidine-1-carboxylate [ka] Pd2(dba)3 (60.1 mg, 0.07 mmol) was dissolved in (2S)-4-(5-bromopyrimidin-2-yl)-2((5-(1-(1-methyl-1H-pyrazol-4-yl)-3a,4a-dihydro-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (100 mg, 0.22 mmol) and t-butyl 3-[(piperazine To the reaction mixture was added [(1-(4-methyl-1-yl)methyl]azetidine-1-carboxylate (134 mg, 0.53 mmol). The reaction mixture was stirred at 90°C for 3 hours. After completion of the reaction, the mixture was poured into water, extracted with DCM (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (70 mg). MS (ESI, m / z): [M+H] + =632.6.

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[0091] Example B-2: Preparation of (S)-4-(5-(4-(azetidin-3-yl)piperazin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine [ka] 30% TFA was added to a solution of t-butyl 3-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}piperazin-1-yl)methyl]azetidine-1-carboxylate (70 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =532.7.

[0092] Example B-3: Preparation of (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4-((1-methylazetidin-3-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)morpholine [ka] A solution of (2S)-4-(5-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}pyrimidin-2-yl)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (14 mg, 0.026 mmol) was dissolved in methanol (1% acetic acid) (1 mL), and formaldehyde (3.95 mg, 0.13 mmol) and NaBH4 (2.5 mg, 0.07 mmol equivalents) in 35% water were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (50 mg). MS (ESI, m / z): [M+H] + =546.7.

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[0093] Example B-4: Preparation of (S)-4-((1-(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)azetidin-3-yl)methyl)piperazine-1-carboxylate benzyl [ka] Pd2(dba)3 (60.1 mg, 0.07 mmol), Xantphos (38.1 mg, 0.07 mmol), and NaOt-Bu (214 mg, 66 mmol) were dissolved in (2S)-4-(5-(5-methyl-1H-pyrazol-4-yl)-1H-{[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (100 mg, 0.22 mmol) and 4-[(azetidine-3- To a solution of benzyl [(methyl)piperazine-1-carboxylate] (190 mg, 0.66 mmol) was added. The reaction was stirred at 90°C for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (65 mg). MS (ESI, m / z): [M+H] + =666.6.

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[0094] Example B-5: Preparation of (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(3-(piperazin-1-ylmethyl)azetidin-1-yl)pyrimidin-2-yl)morpholine [ka] Pd / C (10% by weight) was added to a solution of benzyl 4-[(1-{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}azetidin-3-yl)methyl]piperazine-1-carboxylate (50 mg, 0.07 mmol). The reaction was stirred under H2 gas at room temperature for 12 hours. After completion of the reaction, the reaction was filtered and concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-10%) to give the title compound (15 mg). MS (ESI, m / z): [M+H] + =532.6.

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[0095] Example B-6: Preparation of (S)-4-(5-(3-((benzyloxy)methyl)azetidin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine [ka] Pd2(dba)3 (0.84 g, 0.92 mmol), Xantphos (0.53 g, 0.92 mmol), and NaOt-Bu (0.89 g, 9.18 mmol) were dissolved in toluene (40 ml) and (2S)-4-(5-(5-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (1.4 g, 3.1 mmol) and A solution of 3-[(benzyloxy)methyl]azetidine (0.98 g, 5.51 mmol) was added. The reaction was stirred at 90 °C for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography with DCM / MeOH (0-5%) to give the title compound (0.8 g). MS (ESI, m / z): [M+H] + =554.6.

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[0096] Example B-7: Preparation of (S)-(1-(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)azetidin-3-yl)methanol [ka] MsOH (0.5 g, 0.91 mmol) was added to (2S)-4-(5-{3-[(benzyloxy)methyl]azetidin-1-yl}pyrimidin-2-yl)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (0.5 g, 0.91 mmol) in DCM (100 ml). The reaction was stirred at 0°C to room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MC / Me (0-10%) column chromatography to give the title compound (0.3 g). MS (ESI, m / z): [M+H]+ =464.5.

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[0097] Example B-8: Preparation of (S)-(1-(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)azetidin-3-yl)methyl 4-methylbenzenesulfonate [ka] TEA (96.2 μL, 0.69 mmol) was added to a solution of (1-{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}azetidin-3-yl)methanol (160 mg, 0.36 mmol) in DCM (5 ml). 4-Methylbenzene-1-sulfonyl chloride (132 mg, 0.69 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with DCM (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by HX / EA (80->95%) column chromatography to give the title compound (155 mg). LC-MS(ESI,m / z):[M+H] + =618.4.

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[0098] Example B-9: Preparation of tert-butyl (S)-4-((1-(2-(2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazine-1-carboxylate [ka] Potassium carbonate (13.4 mg, 0.09 mmol) and sodium iodide (4.8 mg, 0.03 mmol) were added to a solution of (1-{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}azetidin-3-yl)methyl 4-methylbenzene-1-sulfonate (20 mg, 0.03 mmol). The reaction was stirred at 80°C overnight. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by DCM / Me (0-3%) column chromatography to give the title compound (10 mg). MS (ESI, m / z): [M+H] + =632.4.

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[0099] Example B-10: Preparation of (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(3-((4-methylpiperazin-1-yl)methyl)azetidin-1-yl)pyrimidin-2-yl)morpholine [ka] Methanol (1% acetic acid) (1 mL) 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-{3-[(piperazin-1-yl)methyl]azetidin-1-dei}pyrimidin-2-yl)morpholine (20 mg, 0.04 mmol) in a solution of morpholine (20 mg, 0.04 mmol) with formaldehyde in HO (3.95 mg, 0.13 mmol) and NaBH (2.5 mg, 0.07 mmol). The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (15 mg). MS (ESI, m / z): [M+H] + =546.7.

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[0100] Example B-11: Preparation of (S)-4-(5-(3-(((4-methoxybenzyl)oxy)methyl)azetidin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine [ka] Pd2(dba)3 (0.4 g, 5.44 mmol), Xantphos (0.26 g, 0.44 mmol), and NaOt-Bu (0.54 g, 5.47 mmol) were dissolved in (2S)-4-(5-(5-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (1.0 g, 2.2 mmol), 3-{[(4-methoxyphenyl)methoxy]methyl}azetidine (0.7 g, 3 To a solution of NaOH (0.28 mmol), Xantphos (0.26 g, 0.44 mmol), and NaOt-Bu (0.54 g, 5.47 mmol) was added. The reaction was stirred at 90°C for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography in DCM / MeOH (0-5%) to give the title compound (0.85 g). MS (ESI, m / z): [M+H] + =584.6.

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[0101] Example B-12: Preparation of tert-butyl (S)-(4-(((1-(2-(2-((5-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methoxy)methyl)phenyl)carbamate [ka] Sodium hydride (40.0 mg, 0.24 mmol) and t-butyl N-[4-(bromomethyl)phenyl]carbamate (123 mg, 0.43 mmol) were added to a solution of (1-{2-[(2S)-2-{[5-(1S)-2-{5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl}methyl-4-yl}methyl-4-yl-methyl-1-yl-methyl (1,2,3 mmol) in THF (5 ml). The reaction was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with EA (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =670.5.

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[0102] Example B-13: Preparation of tert-butyl (S)-(5-(((1-(2-((5-(1-(2-((5-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methoxy)methyl)pyridin-2-yl)carbamate [ka] Sodium hydride (40.0 mg, 1.66 mmol) and t-butyl N-[5-(bromomethyl)pyridin-2-yl]carbamate (123 mg, 0.43 mmol) in THF (5 ml) and t-butyl N-[5-(5-(bromomethyl)pyridin-2-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}azetidin-3-yl)methanol (110 mg, 0.24 mmol) were added. The reaction was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with EA (twice), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound (100 mg). MS (ESI, m / z): [M+H] + =669.5.

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[0103] Example C: Preparation of cMET targeting ligand compounds based on tepotinib derivatives Example C Example C-1: Preparation of tert-butyl (2R)-2-(((2-(3-((3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)methyl-4-carboxylate 1-1) Preparation of t-butyl (2R)-2-[({2-[3-(hydroxymethyl)phenyl]pyrimidin-5-yl}oxy)methyl]morpholine-4-carboxylate [ka] Under nitrogen atmosphere, a mixture of 1,4-dioxane and t-butyl 2-{[(2-chloropyrimidin-5-yl)oxy]methyl}morpholine-4-carboxylate (6.51 g, 19.7 mmol), [3-(hydroxymethyl)phenyl]boronic acid (6.51 g, 19.7 mmol), Pd(PPh) (1.13 g, 1 mmol), and potassium carbonate (6.80 g, 49.2 mmol) in water was stirred at 80 °C for 2 h. The reaction mixture was then cooled to room temperature, filtered, and extracted with dichloromethane (100 mL × 3). The organic layers were then combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by EA / Hex (50-100%) MPLC to give the title compound (4.5 g). MS (ESI, m / z): [M+H] + =402.5.

[0104] 1-2) Preparation of t-butyl (2R)-2-({[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}methyl)morpholine-4-carboxylate [ka] t-Butyl (2R)-2-[({2-[3-(hydroxymethyl)phenyl]pyrimidin-5-yl}oxy)methyl]morpholine-4-carboxylate (3 g, 7.47 mmol) and 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1.47 g, 7.47 mmol) were dissolved in THF (50 ml). Triphenylphosphine (2.35 g, 8.97 mmol) was slowly added to the mixture at 0 °C. Subsequently, (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (1.81 g, 8.97 mmol) was added. Upon addition of formamide, the reaction mixture immediately turned green. The reaction mixture was stirred at room temperature for 3 hours (color change to orange). The reaction mixture was then concentrated and dissolved in a solution (HX / EA EA 30%). Triethylphosphine seeds were added to the reaction mixture to aid in the crystallization of triethylphosphine. The solidified triethylphosphine was then filtered off, and the liquid product was concentrated. The residue was purified by MPLC with EA / Hex (30-50%) to give the title compound (3.5 g). MS (ESI, m / z): [M+H] + =581.6.

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[0105] Example C-2: Preparation of (S)-3-(1-(3-(5-(morpholin-2-ylmethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 30% TFA was added to a solution of t-butyl (R)-2-(((2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyridin-5-yl)oxomethyl)morpholine-4-carboxylate (4.5 g, 7.74 mmol) in DCM. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (3.11 g). MS (ESI, m / z): [M+H] + =481.5.

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[0106] Example C-3: Preparation of t-butyl 4-(2-{[2-(3-{[3-{3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}ethyl)piperazine-1-carboxylate 3-1) Preparation of t-butyl (2R)-2-[({2-[3-(hydroxymethyl)phenyl]pyrimidin-5-yl}oxy)methyl]morpholine-4-carboxylate [ka] Under nitrogen atmosphere, a mixture of 1,4-dioxane and t-butyl 4-{2-[(2-chloropyrimidin-5-yl)oxy]ethyl}piperazine-1-carboxylate (2.0 g, 5.8 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.87 g, 5.83 mmol), Pd(PPh3)4 (0.34 g, 0.29 mmol), and potassium carbonate (2.0 g, 14.6 mmol) in water was stirred at 80 °C for 2 h. The reaction mixture was then cooled to room temperature, filtered, and extracted with dichloromethane (100 mL × 3). The organic layers were then combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by EA / Hex (50-100%) MPLC to give the title compound (1.8 g). MS (ESI, m / z): [M+H] + =415.5.

[0107] 3-2) Preparation of tert-butyl 4-(2-(2-(3-((3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate [ka] t-Butyl 4-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-5-yl}oxy)ethyl]piperazine-1-carboxylate (2.2 g, 5.31 mmol) and 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1.05 g, 5.31 mmol) were dissolved in THF (50 ml). Triphenylphosphine (1.67 g, 6.37 mmol) was slowly added to the mixture. Subsequently, (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (1.05 g, 6.37 mmol) was added dropwise. The addition of formamide immediately turned green. The reaction mixture was stirred at room temperature for 3 hours (color change to orange). The reaction mixture was then concentrated and dissolved in a solution (HX / EA EA 30%). Triethylphosphine seeds were added to the reaction mixture to aid in the crystallization of triethylphosphine. The solidified triethylphosphine was then filtered, and the liquid product was concentrated. The residual product was purified by MPLC with EA / Hex (30-50%) to give the title compound (3.1 g). MS (ESI, m / z): [M+H] + =594.7.

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[0108] Example C-4: Preparation of 3-(6-oxo-1-(3-(5-(2-(piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 30% TFA was applied to a solution of t-butyl 4-(2-{[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}ethyl)piperazine-1-carboxylate (1.5 g, 2.53 mmol) in DCM. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (1.22 g). MS (ESI, m / z): [M+H] + =494.6.

[0109] Example C-5: Preparation of t-butyl 4-(2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)piperazine-1-carboxylate [ka] A mixture of 3-(1-{[3-(5-bromorimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-ylbenzonitrile (0.3 g, 0.67 mmol), t-butyl piperazine-1-carboxylate (0.17 g, 0.67 mmol), Pd(dba) (19.4 mg, 33.8 μmol), Xantphos (39.1 mg, 67.5 μmol), and Na-t-butoxide (162 mg, 1.69 mmol) in toluene (3 mL) was stirred in a microwave at 100 °C for 2 h. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by EA / Hex (50-100%) MPLC to give the title compound (310 mg). MS (ESI, m / z): [M+H] + =[560.7].

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[0110] Example C-6: Preparation of 3-(6-oxo-1-(3-(5-(piperazin-1-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 30% TFA was applied to a solution of t-butyl 4-(2-(3-(3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)piperazine-1-carboxylate (310 mg, 0.50 mmol) in DCM. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the residue was concentrated under reduced pressure and purified by amine column chromatography in DCM / MeOH (0-5%) to give the title compound (250 mg). MS (ESI, m / z): [M+H] + =[460.6].

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[0111] Example D: Preparation of ABN derivative-based cMET protein-targeting PROTAC Example D-1: Preparation of 3-(6-(4-((1-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)piperazin-1-yl)1-oxoptalazine-2(1H)-dei)piperidine-2,6-dione [ka] 1-1) Preparation of 4-fluoro-2-formyl benzoate [ka] At room temperature, NMO (15.6 mg, 134 mmol) and 4 Å molecular sieves were added sequentially to a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22.0 g, 89 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 2 hours. The molecular sieves were filtered and washed with DCM (50 ml). The DCM layer was washed with water (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid (12.0 g). MS (ESI, m / z): [M+H] + =183.2

[0112] 1-2) Preparation of 4-fluoro-2-formylbenzoic acid [ka] At room temperature, an aqueous solution (50 mL) of lithium hydroxide (+1) (13.8 g, 329 mmol) was added to a solution of methyl 4-fluoro-2-formylbenzoate (12.0 g, 65.9 mmol) in THF (50 mL). After stirring for 2 hours, the reaction was concentrated under reduced pressure to dry the THF. After cooling to 0°C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (10.0 g). MS (ESI, m / z): [M+H] + =169.2.

[0113] 1-3) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one [ka] At room temperature, NH2NH2 monohydrate (2.02 mg, 40.3 mmol) was added to a solution of 4-fluoro-2-formylbenzoic acid (6.78 g, 40.3 mmol) in methanol (50 mL). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150 ml) and extracted twice with ethyl acetate (150 ml). The combined ethyl acetate layers were dried over MgSO4 and concentrated under reduced pressure to give white crystals (5.5 g). MS (ESI, m / z): [M+H] + =165.3.

[0114] 1-4) Preparation of 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] Sodium 2-methylpropane-2-oleate (175 mg, 0.91 mmol) was added to a solution of 6-fluoro-1,2-dihydroptaladin-1-one (100 mg, 0.61 mmol) in DMF (2 mL) at 0° C. After stirring for 30 minutes, 3-bromoperidine-2,6-dione (90 mg, 0.47 mmol) was added to the reaction mixture, which was then stirred at room temperature for 6 hours. Water (20 ml) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 ml). The combined ethyl acetate solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (110.0 mg, 65.6%). MS (ESI, m / z): [M+H] + =276.6.

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[0115] 1-5) Preparation of t-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (4.0 equiv.) was added to a solution of 3-(6-fluoro-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and t-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =442.4

[0116] 1-6) Preparation of 3-(1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of t-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =342.4

[0117] Preparation of 1-7) 3-(6-(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)azetidin-3-yl)methyl)piperazin-1-yl)1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] Potassium carbonate (10.1 mg, 0.07 mmol) and sodium iodide (4.73 mg, 0.032 mmol) were added to a solution of (1-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazon-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl}pyrimidin-4-yl}pyrimidin-5-yl}azetidin-3-yl)methyl 4-methylbenzene-1-sulfonate (15 mg, 0.02 mmol) and 3-[1-oxo-6-(piperazin-1-yl)-1,2-dihydrobutalazin-2-yl]piperidine-2,6-dione (12.4 mg, 0.03 mmol). The reaction was stirred at 80° C. overnight. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by DCM / Me (0-3%) column chromatography to give the title compound (10 mg). MS (ESI, m / z): [M+H] + =787.9.

number

[0118] Example D-2: Preparation of 3-(4-methyl-6-(4-((1-(2-((S)-2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 2-1) Preparation of methyl 2-acetyl-4-fluorobenzoate [ka] Triphenyl[tri(triphenyl-λ-phospanicyl)paradio]-λ-phosphorphane (4.98 g, 4.3 mmol) was added to a solution of methyl 2-bromo-4-fluorobenzoate (10 g, 43.0 mmol) and tributyl(1-ethoxyethetetenyl)stannane (17 g, 47.2 mmol) in toluene (150 ml). The reaction was stirred at 100°C for 20 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residual acid was dissolved in 100 ml of THF and 40 ml of 2N HCl was added. The reaction was stirred at room temperature for 30 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by HX / EA (0-80%) column chromatography to give the title compound (7.5 g). MS (ESI, m / z): [M+H] + =457.4.

[0119] 2-2) Preparation of 6-fluoro-4-methyl-1,2-dihydrophthalazin-1-one [ka] NH2NH2 hydrate was added to a solution of methyl 2-acetyl-4-fluorobenzoate (19 g, 97.1 mmol) in methanol (500 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was stirred at 85 °C for an additional 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (100 mL) was added and stirred for 3 hours, and the solid was filtered and dried in vacuo to give the title compound (15 g). MS (ESI, m / z): [M+H] + =179.2.

[0120] 2-3) Preparation of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione [ka] Butyllithium in 2.5 M hexane (20.6 ml) was added to a solution of bis(propan-2-yl)amine (7.27 ml) in THF (75 mL) at -20°C. The reaction was stirred at 0°C for 30 minutes. 6-Fluoro-4-methyl-1,2-dihydrobutalazin-1-one (7.65 g) was added to the LDA solution and stirred at room temperature for 30 minutes. Subsequently, 3-bromoperidine-2,6-dione was added at the same temperature. The mixture was returned to dryness for 2 hours to remove the solvent and washed with water. The solid was filtered and dried under vacuum to give the title compound (7.9 g). MS (ESI, m / z): [M+H] + =290.2.

[0121] 2-4) Preparation of t-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (1.5 ml, 4.1 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxo-1,2-dihydrobutalazin-2-yl)piperidine-2,6-dione (300 mg, 1.04 mmol) and t-butyl piperazine-1-carboxylate (386 mg, 2.07 mmol) in NMP (3.0 ml). The reaction was stirred at 130°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography using MeOH / DCM (0-20%) to give the title compound (350 mg). MS (ESI, m / z): [M+H] + =456.4.

[0122] 2-5) Preparation of 3-(4-methyl-1-oxo-6-(piperazin-1-yl)phthalazin-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to a solution of t-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptarazin-6-yl) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography in MeOH / DCM (0-20%) to give the title compound (200 mg). MS (ESI, m / z): [M+H] + =356.4.

[0123] 2-6) Preparation of 33-(4-methyl-6-(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)azetidin-3-yl)methyl)piperazin-1-yl)1-oxoptalazin-2(1H)-yl)piperidine-2,6-dione [ka] Potassium carbonate (10.1 mg, 0.03 mmol) and sodium iodide (4.73 mg, 0.03 mmol) were added to 1-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazon-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}azetidin-3-yl)methyl 4-methylbenzene-1-sulfonate (15 mg, 0.02 mmol) and 3-[4-methyl-1-oxo-6-(piperazin-1-yl)-1,2-dihydropetalazin-2-yl]piperidine-2,6-dione (11.2 mg, 0.03 mmol). The reaction was stirred at 80° C. overnight. After the reaction was complete, the reaction was stirred under reduced pressure. The residue was purified by DCM / Me (0-3%) column chromatography to give the title compound (10 mg). MS (ESI, m / z): [M+H] + =801.9.

number

[0124] Example D-3: Preparation of 3-((3-fluoro-4-(4-((1-(2-((S)-2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morphopolino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione [ka] 3-1) Synthesis of t-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate [ka] t-Butyl piperazine-1-carboxylate (5.9 g, 31.4 mmol) and potassium carbonate (21.7 g, 157 mmol) were added to a solution of 1,2-difluoro-4-nitrobenzene (5 g, 31.4 mmol) in DMF (100 mL). The reaction was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction mixture was poured into water and extracted twice with ethyl acetate. The mixture was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography using hexane / ethyl acetate (0-30%) to give the title compound (10.2 g). MS (ESI, m / z): [M+H] + =326.3.

[0125] 3-2) Synthesis of t-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate [ka] Iron powder (16.5 g, 295 mmol) was added to t-butyl 4-(2-fluoro-4-nitrophenyl)piperidine-1-carboxylate (4.8 g, 14.8 mmol) in saturated NH4Cl / THF (1:1) (100 mL). The reaction was stirred at 80 °C for 2 h and used in the next step without further purification. ESI, m / z): [M+H] + =296.4.

[0126] 3-3) Preparation of t-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate [ka] 3-Bromoperidine-2,6-dione (1.95 g, 10.2 mmol) was added to a solution of t-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (1.5 g, 5.1 mmol) in DMF (30 mL). The reaction was stirred at 85 °C overnight. After completion of the reaction, the reaction mixture was poured into water and extracted twice with ethyl acetate. The residue was purified by column chromatography using hexane / ethyl acetate (0-100%) to give the title compound (2.1 g). MS (ESI, m / z): [M+H] + =407.5.

[0127] 3-4) Preparation of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione [ka] 30% TFA was added to a solution of t-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1-carboxylate (20 mg, 49.2 μmol) in DCM. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was stirred under reduced pressure and used in the next step without further purification. MS (ESI, m / z): [M+H] + =307.3.

[0128] 3-5) Preparation of 3-((3-fluoro-4-(4-((1-(2-((S)-2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione [ka] Potassium carbonate (10.1 mg, 0.03 mmol) and sodium iodide (4.73 mg, 0.03 mmol) were added to a solution of (1-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazon-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl}pyrimidin-5-yl}azetidin-3-yl)methyl 4-methylbenzene-1-sulfonate (15 mg, 0.02 mmol) and 3-{[3-fluoro-4-(piperazin-1-yl)phenyl}piperidine-2,6-dione (11.2 mg, 0.04 mmol). The reaction was stirred at 80° C. overnight. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by DCM / Me (0-3%) column chromatography to give the title compound (10 mg). MS (ESI, m / z): [M+H] + =752.9.

number

[0129] Example D-4: Preparation of 3-(4-methyl-6-(4-((1-((1-((1-(1-(2-((S)-2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-dei)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] 4-1) Preparation of t-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)azetidine-1-carboxylate [ka] Ethylbis(propan-2-yl)amine (1 ml, 4.35 mmol) was added to a solution of 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (300 mg, 1.09 mmol) and t-butyl 4-(piperazin-1-yl-methyl)piperidine-1-carboxylate (600 mg, 2.18 mmol) in NMP (2.0 ml). The reaction was stirred at 130° C. for 48 hours. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (400 mg). MS (ESI, m / z): [M+H] + =553.4.

[0130] 4-2) Preparation of 3-(4-methyl-1-oxo-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione [ka] TFA (10 ml) was added to t-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrobutalazin-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (400 mg, 1.52 mmol) in DCM (30 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by MeOH / DCM (0-20%) column chromatography to give the title compound (400 mg). MS (ESI, m / z): [M+H] + =453.4.

[0131] 4-3) Preparation of 33-(4-methyl-6-(4-((1-((1-(2-(((S)-2-((5-(1-(1H)-1H-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-dei)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione [ka] A solution of (1-{2-[(2S)-2-{[5-(1S)-2-{5-(1-methyl-1H)pyrazin-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl}azetidin-3-yl)methyl 4-methylbenzene-1-sulfonate (15 mg, 0.02 mmol) and 3-(4-(4-methyl-4-yl)piperazin-1-yl)phthalazine-2(1H)-yl)piperidine-2,6-dione (16.5 mg, 0.03 mmol, 0.03 mmol) in ACN (1 ml) was prepared using potassium carbonate (10.1 mg, 0.073 mmol) and sodium iodide (4.73 mmol). The reaction mixture was stirred at 80° C. overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography in DCM / Me (0-3%) to give the title compound (11 mg). MS (ESI, m / z): [M+H]+ =899.1.

number

[0132] Example D-5: Preparation of 3-((3-fluoro-4-(4-((4-((4-((1-((S)-2-((5-(1-(1-(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)azetidin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione [ka] 5-1) Preparation of t-butyl 4-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl} piperazine-1-carboxylate [ka] 1,2-Difluoro-4-nitrobenzene (5.61 g, 35.3 mmol) and potassium carbonate (24.4 g, 176 mmol) were added to a solution of t-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (10 g, 35.3 mmol) in DMF (200 mL). The reaction was stirred at 80° C. for 2 hours. After the reaction was complete, the reaction was poured into water and extracted twice with ethyl acetate. It was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (11 g). MS (ESI, m / z): [M+H] + =423.5.

[0133] 5-2) Preparation of t-butyl 4-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl} piperazine-1-carboxylate [ka] Iron powder (29.5 g, 521 mmol) was added to a solution of t-butyl 4-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (11 g, 26 mmol) in saturated NH4Cl / THF (1:1) (200 mL). The reaction was stirred at 80 °C for 2 hours. After completion of the reaction, the reaction mixture was purified, concentrated under reduced pressure, and used in the next step without further purification. MS (ESI, m / z): [M+H] + =393.5.

[0134] 5-3) Preparation of t-butyl 4-[(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate [ka] 3-Bromoperidine-2,6-dione (1.2 g, 6.1 mmol) was added to a solution of t-butyl 4-{[1-(4-amino-2-fluorophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (1.2 g, 3.1 mmol) in DMF (25 mL). The reaction was stirred at 85° C. overnight. After the reaction was complete, the reaction was poured into water and extracted twice with ethyl acetate. The mixture was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.3 g). MS (ESI, m / z): [M+H] + =504.6.

[0135] 5-4) Preparation of 3-[(3-fluoro-4-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}phenyl)amino]piperidine-2,6-dione [ka] 30% TFA was applied to a solution of t-butyl 4-[(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (650 mg, 1.29 mmol) in DCM. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated under reduced pressure. The residue was purified by DCM / MeOH (5-10%) column chromatography to give the title compound (485 mg). MS (ESI, m / z): [M+H] + =404.5.

[0136] 5-5) Preparation of 3-((3-fluoro-4-(4-((4-((4-((1-(2-((S)-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)azetidin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione [ka] A solution of (1-{2-[(2S)-2-{[5-(1S)-2-{5-{5-(1-methyl-1H-pyrazon-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl}pyrimidin-4-yl}pyridine-2,6-dione (14.6 mg, 0.03 mmol) in ACN (1 ml) was added to potassium carbonate (10.1 mg, 0.073 mmol) and sodium iodide (4.73 mg, 0.03 mmol) in ACN (1 ml). The reaction was stirred at 80 °C overnight. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography in DCM / Me (0-3%) to give the target compound (12 mg). MS (ESI, m / z): [M+H] + =850.1.

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[0137] Example E: Preparation of a Tepotinib Derivative-Based PROTAC Targeting cMET Protein Example E-1: Preparation of 3-(1-(3-(5-(((2R)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(2,50 μl, 0.5 mmol) was added to (R)-3-(1-(3-(5-(5-(morpholin-2-ylmethoxy)pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.1 mmol) and 3-(6-fluoro-4-methyl-1-oxotalazine-2(1H)-yl)piperidine-2,6-dione (29 mg, 0.1 mmol) in NMP (2 ml). The reaction was stirred at 140° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Subsequent purification by MeOH / DCM (0-20%) column chromatography afforded the title compound (48 mg). MS (ESI, m / z): [M+H] + =750.8.

number

[0138] Example E-2: Preparation of 3-(1-(3-(5-(((2R)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(2,50 μl, 0.5 mmol) was added to (R)-3-(1-(3-(5-(5-(morpholin-2-ylmethoxy-2-yl)benzyl)benzonitrile (50 mg, 0.1 mmol) and 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (27 mg, 0.1 mmol) in NMP (2 ml). The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. Purification was then performed by column chromatography using MeOH / DCM (0-20%) to give the title compound (35 mg). MS (ESI, m / z): [M+H] + =736.7.

number

[0139] Example E-3: Preparation of 3-(1-(3-(5-(((2R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 3-1) Preparation of (R)-3-(1-(3-(5-((4-(2-fluoro-4-nitrophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(224 mg, 1.73 mmol) was added to a solution of (R)-3-(1-(3-(5-(5-(morpholin-2-ylmethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (180 mg, 0.38 mmol) and 1,2-difluoro-4-nitrobenzene (55.2 mg, 0.38 mmol) in acetonitrile (2 ml). The reaction was stirred at 100° C. for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and then purified by column chromatography and the compound of interest (110 mg) was obtained. MS (ESI, m / z): [M+H] + =620.7.

[0140] 3-2) Preparation of (R)-3-(1-(3-(5-((4-(4-amino-2-fluorophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] THF (2 ml) was added to a solution of (R)-3-(1-(3-(5-((4-(2-(2-fluoro-4-nitrophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzonitrile (110 mg, 0.18 mmol) and 2 ml of NH4Cl saturated with iron (187 mg, 3.34 mmol) solution. The reaction was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was filtered and then poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and then purified by column chromatography to give the title compound (92 mg). MS (ESI, m / z): [M+H] + =590.7.

[0141] 3-3) Preparation of 3-(1-(3-(5-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] NaHCO (88.1 mg, 0.64 mmol) was added to (R)-3-(1-(3-(5-((4-(4-amino-2-fluorophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzonitrile-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (80 mg, 0.14 mmol) and 3-bromorpheridine-2,6-dione (73.4 mg, 0.38 mmol) in DMF (1 ml) at room temperature. The reaction was heated at 65 °C for 16 h and concentrated. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (65 mg). MS (ESI, m / z): [M+H] + =701.7.

number

[0142] Example E-4: Preparation of 3-(1-(3-(5-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydropetalazin-6-yl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(2,50 μl, 0.5 mmol) was added to a solution of 3-(6-oxo-1-(3-(5-(2-(piperazin-1-yl)ethoxy-pyrimidin-2-yl)benzyl)benzonitrile (50 mg, 0.1 mmol) and 3-(6-fluoro-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (27 mg, 0.1 mmol) in NMP (2 ml). The reaction was stirred at 140° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by MeOH / DCM (0-20%) column chromatography gave the title compound (38 mg). MS (ESI, m / z): [M+H] + =749.8.

number

[0143] Example E-5: Preparation of 3-(1-(3-(5-(2-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(2,50 μl, 0.5 mmol) was added to a solution of 3-(6-oxo-1-(3-(5-(2-(piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (50 mg, 0.1 mmol) and 3-(6-fluoro-4-methyl-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione (29 mg, 0.1 mmol) in NMP (2 ml). The reaction was stirred at 140° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification by column chromatography using MeOH / DCM (0-20%) gave the title compound (35 mg). MS (ESI, m / z): [M+H] + =763.8.

number

[0144] Example E-6: Preparation of 3-(1-(3-(5-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 6-1) Preparation of 3-(1-(3-(5-(2-(4-(2-(2-(2-(2-(2-(2-nitrophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethyl bis(224 mg, 1.73 mmol) was added to a solution of 3-(6-oxo-1-(3-(5-(2-(piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (180 mg, 0.35 mmol) and 1,2-difluoro-4-nitrobenzene (55.2 mg, 0.35 μmol) in acetonitrile (2 ml). The reaction was stirred at 100° C. for 2 hours. After cooling to room temperature, it was concentrated under reduced pressure and then purified by column chromatography and the compound of interest (110 mg) was obtained. MS (ESI, m / z): [M+H] + =633.7.

[0145] 6-2) Preparation of 3-(1-(3-(5-(2-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 2 ml of NH4Cl was saturated with a solution of 3-(1-(3-(5-(2-(4-(2-(2-(2-(2-(2-(2-fluoro-4-nitrophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (110 mg, 0.18 mmol) and iron (187 mg, 3.34 mmol) in THF (2 ml). The reaction was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was filtered, poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure and then purified by column chromatography to give the title compound (92 mg). MS (ESI, m / z): [M+H] + =603.7.

[0146] 6-3) Preparation of 3-(1-(3-(5-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] NaHCO (88.1 mg, 0.64 mmol) was added to a solution of 3-(1-(3-(5-(2-(4-(4-amino-2-fluorophenyl)piperazine-1-(4-amino-2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzonitrile (80 mg, 0.14 mmol) and 3-bromoperidine-2,6-dione (73.4 mg, 0.38 mmol) in 1 ml of DMF at room temperature. The reaction was concentrated at 65 °C for 16 h. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO, and concentrated under reduced pressure. The residue was purified by MPLC with MeOH / DCM (0-10%) to give the title compound (65 mg). MS (ESI, m / z): [M+H] + =714.7

number

[0147] Example E-7: Preparation of 3-(1-(3-(5-(4-((1-(4-(1-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 7-1) Preparation of t-butyl 3-({4-[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]piperazin-1-yl}methyl)azetidine-1-carboxylate [ka] Microwave at 100 °C for 2 h in a submicrowave oven to prepare a mixture of 3-(1-{[3-(5-bromopyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (0.3 g, 0.67 mmol), tert-butyl 3-[(piperazin-1-yl)methyl]azetidine-1-carboxylate (0.17 g, 0.67 mmol), Pd(dba) (19.4 mg, 33.8 μmol), Xantphos (39.1 mg, 67.5 μmol), and Na t-butoxide (162 mg, 1.69 mmol). After the reaction was complete, the reaction mixture was purified and concentrated under reduced pressure. The residue was purified by EA / Hex (50-100%) MPLC to give the title compound (310 mg). MS (ESI, m / z): [M+H] + =[619.7].

[0148] 7-2) Preparation of 3-(1-{[3-(5-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}pyrimidin-2-yl)phenyl]methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 30% TFA was added to a solution of t-butyl 4-(2-{[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}ethyl)piperazine-1-carboxylate (310 mg, 0.50 mmol) in DCM. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by DCM / MeOH (0-5%) amine column chromatography to give the title compound (270 mg). MS (ESI, m / z): [M+H] + =[519.6].

[0149] 7-3) Preparation of 3-[1-({3-[5-(4-{[1-(2-fluoro-4-nitrophenyl)azetidin-3-yl]methyl}piperazin-1-yl)pyrimidin-2-yl]phenyl}methyl)6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile [ka] Ethyl bis (224 mg, 1.73 mmol) was added to a solution of 3-(1-{3-(5-{4-[(azetidin-3-yl)methyl]piperazin-1-yl}pyrimidin-2-yl)phenyl}methyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (180 mg, 347 μmol) and 1,2-difluoro-4-nitrobenzene (55.2 mg, 347 μmol) in acetonitrile (2 ml). The reaction was stirred at 100° C. for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. Purification by column chromatography gave the title compound (110 mg). MS (ESI, m / z): [M+H] + =[658.7].

[0150] 7-4) Preparation of 3-[1-({3-[5-(4-{[1-(4-amino-2-fluorophenyl)azetidin-3-yl]methyl}piperazin-1-yl)pyrimidin-2-yl]phenyl}methyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile [ka] A solution of 3-[1-({3-[5-(4-{[1-(2-fluoro-4-nitrophenyl)azetidin-3-yl]methyl}piperazin-1-yl)pyrimidin-2-yl]phenyl}methyl)6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (110 mg, 167 μmol) and iron (187 mg, 3.34 mmol) in THF (2 ml) saturated with NH4Cl was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was purified, poured into purified water, and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (92 mg). MS (ESI, m / z): [M+H] + =[628.7].

[0151] 7-5) Preparation of 3-(1-(3-(5-(4-((1-(4-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] NaHCO3 (88.1 mg, 637 μmol) was added to a solution of 3-[1-({3-[5-(4-{[1-(4-amino-2-fluorophenyl)azetidin-3-yl]methyl}piperazin-1-yl]phenyl}methyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (80 mg, 127 μmol) and 3-bromoperidine-2,6-dione (73.4 mg, 382 μmol) in 1 ml of DMF at room temperature. The reaction was stirred at 65 °C for 16 h. The reaction was poured into water, extracted with ethyl acetate, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC in MeOH / DCM (0-10%) to give the title compound (65 mg). MS (ESI, m / z): [M+H] + =739.8.

number

[0152] Example E-8: Preparation of 3-(1-(3-(5-(4-((1-(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 8-1) Preparation of 3-(6-oxo-1-(3-(5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (144 mg, 158 μmol) and [5-(diphenylphosphony)9,9-dimethyl-9H-xanthen-4-yl]diphenylphospane (91.2 mg, 158 μmol) were added to a solution of 3-(1,5-diphenylphosphony)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphospane (91.2 mg, 158 μmol) in toluene (10 mL), followed by the addition of KCO (528 mg, 3.94 mmol). The reaction was stirred at 110 °C for 5 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by column chromatography to give the BOC-protected compound. The compound was treated with 4.0 M HCl in dioxane (5 mL) and stirred for 5 hours. The reaction was concentrated under reduced pressure and passed through a basic silica pad to give the target compound (521 mg). MS (ESI, m / z): [M+H] + =547.3.

[0153] 8-2) Preparation of 3-(1-(3-(5-(4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] Ethylbis(propan-2-yl)amine (47.3 mg, 366 μmol) was added to a solution of 3-(6-oxo-1-{{5-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}pyrimidin-2-yl)phenyl]methyl}-1,6-dihydropyridazin-3-yl)benzonitrile (100 mg, 183 μmol) and 1,2-difluoro-4-nitrobenzene (29.1 mg, 1839 μmol) in acetonitrile (2 ml). Ethylbis(propan-2-yl)amine (47.3 mg, 366 μmol) was added to the solution of 3-(6-oxo-1-{5-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}pyridin-2-yl}pyridin-2-yl} after cooling to room temperature and purified by column chromatography to give the title compound (110 mg). MS (ESI, m / z): [M+H] + =686.7.

[0154] 8-3) Preparation of 3-(1-(3-(5-(4-((1-(4-(4-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ka] 2 mL of saturated NH4Cl was added to a solution of 3-(1-(3-(5-(4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (100 mg, 146 μmol) and iron (40.7 mg, 729 μmol) in solution. The reaction was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography to give the title compound (79 mg). MS (ESI, m / z): [M+H] + =656.7.

[0155] 8-4) Preparation of 3-(1-(3-(5-(4-((1-(4-(1-((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 [ka] Ethylbis(propan-2-yl)amine (47.3 mg, 366 μmol) was added to a solution of 3-[1-({3-[5-(4-{[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)pyrimidin-2-yl]phenyl}methyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (100 mg, 146 μmol) and 3-bromorphidine-2,6-dione in acetonitrile (2 ml). The reaction was stirred at 100° C. for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by column chromatography to give the title compound (110 mg). MS (ESI, m / z): [M+H] + =767.9. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.72(s,1 H)8.52(s,3 H)8.32(s,2 H)8.28(s,1 H)8.18(d,J=8.09 Hz,1 H)8.09-8.14(m,3 H)7.87(d,J=7.78 Hz,1 H)7.65(t,J=7.93 Hz,1 H)7.36-7.40(m,2 H)7.10(d,J=9.61 Hz,1 H)6.76(t,J=9.31 Hz,1 H)6.40-6.48(m,1 H)6.35(d,J=8.70 Hz,1 H)5.72(d,J=7.78 Hz,1 H)5.37(s,3 H)4.15-4.23(m,1 H)2.99-3.09(m,2 H)2.58-2.73(m,1 H)2.48-2.53(m,3 H)2.17(br.s.,1 H)1.96-2.06(m,1 H)1.82-1.92(m,1 H)1.68-1.79(m,3 H)1.15-1.25(m,3 H)1.11(t,J=7.17 Hz,1 H)

[0156] Example 1: Cell line culture and compound preparation The c-MET-overexpressing human gastric cancer cell lines MKN45 and SNU638 were cultured in RPMI medium containing 10% fetal bovine serum, penicillin (100 U / ml), and streptomycin (100 mg / ml). The c-MET exon 14 skipping mutant human gastric cancer cell line Hs746T was cultured in DMEM medium. The c-MET-overexpressing human lung cancer cell line EBC-1 was cultured in MEM medium supplemented with 10% fetal bovine serum, penicillin (100 U / ml), and streptomycin (100 mg / ml). The human lung tissue-derived normal cell line WI-38 was cultured in EMEM medium supplemented with 10% fetal bovine serum, penicillin (100 U / ml), and streptomycin (100 mg / ml).

[0157] Compounds synthesized according to the present invention were prepared in 10 mM stock solutions in DMSO (dimethyl sulfoxide) and serially diluted and treated.

[0158] Example 2: Evaluation of the antiproliferative activity of cancer cells with ligand compounds targeting cMET To evaluate the inhibitory activity against cell growth, cells were distributed into a 96-well plate at a concentration of 5,000 cells / well and then treated with the compounds of the present invention prepared at various concentrations for 72 hours. The absorbance measurement at 450 nm was calculated using GraphicPad Prism 8.0 software. IC 50 The values ​​(concentration of the compound that achieves 50% cell suppression inhibition) are the average values ​​of the measurement results. The results are shown in Tables 1 and 2. As shown in the experimental results, the compounds of the present invention exhibit the effect of inhibiting the proliferation of cancer cells, and in particular, the embodiments of the effective degradation of c-MET are as follows: [Table 1] JPEG2025538555000211.jpg206147 [Table 2]

[0159] Example 3: Evaluation of c-MET proteolytic efficacy of PROTACs targeting cMET protein To evaluate the degradative efficacy of the compounds of the present invention against c-MET expressed in cells, cells were plated in 12-well plates at 2 × 10 5 The cells were distributed at a concentration of 1000 cells / well, and the gastric cancer cell line was then treated with the samples for 24 hours, and the lung cancer cell line was treated for 48 hours.

[0160] To perform Western blotting assays to confirm protein expression, cells were treated with compounds in 40 μL of RIPA buffer containing protease inhibitors for 30 min, and the cell lysates were collected using a scraper on ice and centrifuged at 15,000 rpm for 30 min at 4 °C to obtain the supernatant containing the proteins.

[0161] Protein expression was then measured using the Abby Simple Western Blot System (Abby) with 3 μg of protein from each sample. SDS- and heat-induced denatured proteins were separated by molecular weight, attached to capillaries, and reacted with anti-c-MET or anti-GAPDH primary antibodies, followed by HRP-conjugated secondary antibodies. Protein expression signals were analyzed using COMPASS software.

[0162] Protein expression was normalized based on the GAPDH expression value, and the protein expression level in each sample was measured as a percentage (%) based on 100% of the sample treated with 0.1% DMSO vehicle. DC values ​​were calculated from the changes in protein expression due to compound treatment. 50 (the concentration of compound at which 50% protein inhibition is achieved) was calculated.

[0163] The results are shown in Tables 3 and 4. [Table 3] [Table 4] [Industrial Applicability]

[0164] The PROTAC compounds according to the present invention can be used as anti-cancer agents.

Claims

1. A compound represented by the following chemical formula 1: [Chemical formula 1] cMET target protein binding portion (P)-{linker (L)}p-E3 ligase binding portion (E) During the ceremony, The E3 ligase binding moiety (E) is a compound represented by the following chemical formula 2: The cMET target protein binding moiety (P) is a compound represented by any one of formulas 3 to 7: p is an integer of 0 or 1; [Chemical formula 2] 【Chemistry 1】 [Chemical formula 3] 【Chemistry 2】 [Chemical formula 4] 【Transformation 3】 [Chemical formula 5] 【Chemistry 4】 [Chemical formula 6] 【Transformation 5】 [Chemical formula 7] 【Transformation 6】 [Chemical formula 8] 【Transformation 7】 During the ceremony, X is hydrogen, halogen, amino, nitro, hydroxy, C1-C6 straight or branched chain alkyl, or an oxygen- or nitrogen-containing heterocycle of 4-8 atoms; Q １ ~Q ４ are each independently C—F, C—Cl, C—H, C—X, or N, and Q １ ~Q ４ At least one of the following is C—X; Y is hydrogen, halogen, or C1-C6 straight, branched, or cyclic alkyloxy unsubstituted or substituted with halogen; R １ is hydrogen, nitro, amino, carbonyl, C1-C6 straight, branched or cyclic alkyl, or C1-C6 straight, branched or cyclic alkyl substituted with halogen; R ２ and R ３ are each independently hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, tosyl, or an unsubstituted or substituted C1-C6 straight, branched, or cyclic alkyl group; R ４ is hydrogen, a t-butoxycarbonyl group, or a benzyloxycarbonyl group.

2. The linker (L) is (i) is connected to a compound of formula 1 by replacing X in a compound of formula 2; or (ii) The compound according to claim 1, which is connected to the nitrogen atom or oxygen atom of X in the compound of formula 2.

3. The other end of the linker (L) is (i) any of the substituents R of the compounds of the chemical formulas 3 to 7 ２ , R ３ Or R ４ and connected to any one of the formulas 3 to 7; or (ii) The compound according to claim 2, wherein the compound is connected to the benzene ring of the structure of formula 8.

4. R ２ and R ３ are each independently a halogen or R ５ is a C1-C6 linear or cyclic alkyl group unsubstituted or substituted with R ５ is (i) a piperazine that is not substituted or substituted with a t-butoxycarbonyl, benzyloxycarbonyl, or tosyl group; (ii) R ６ C1-C6 alkoxy groups (R ６ is an amino substituted with a C1-C4 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

5. R ２ and R ３ are each independently a halogen or R ５ is a C1-C6 straight, branched or cyclic alkyl group unsubstituted or substituted with R ５ is (i) a piperazine that is unsubstituted or substituted with a t-butoxycarbonyl or benzyloxycarbonyl group; (ii) R ６ C1-C6 alkoxy groups (R ６ is an amino substituted with a C1-C4 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

6. R ２ is hydrogen or a C1-C6 straight or branched alkyl chain or cyclic alkyl group; R ３ But, R ５ is a C1-C4 linear, branched or cyclic alkyl group unsubstituted or substituted with R ５ (i) piperazine, (ii) R ６ C1-C4 alkoxy groups (R ６ is a C1-C4 alkoxy or amino group of, or (iii) a hydroxy group.

7. The linker (L) is 【Transformation 8】 wherein R ７ is piperazine, piperidine, azetidine, benzene, triazole or pyrrolidine; 2. The compound of claim 1, wherein m and n are each independently an integer selected from 0 to 5.

8. The linker (L) is 【Chemistry 9】 or 【change】 2. The compound of claim 1, wherein m and n are each independently an integer selected from 0 to 5.

9. The following compounds: 3-(6-(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)azetidin-3-yl)methyl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-(4-methyl-6-(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)azetidin-3-yl)methyl)piperazin-1-yl)1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-((3-fluoro-4-(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)azetidin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-(4-methyl-6-(4-((1-((1-(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)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazine-1-dei)-1-oxoptalazine-2(1H)-yl)piperidine-2,6-dione, 3-((3-fluoro-4-(4-((4-((1-(2-(((S)-2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-(1-(3-(5-(((2R)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(((2R)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(((2R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)morpholin-2-yl)methoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydroptaladin-6-yl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 3-(1-(3-(5-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)2-fluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, and 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, or a pharmaceutically acceptable salt thereof.

10. A compound represented by formula 3 or 4, or a pharmaceutically acceptable salt thereof, [Chemical formula 3] 【Chemistry 10】 [Chemical formula 4] 【Chemistry 11】 In the formula, R ２ and R ３ are each independently hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, tosyl, or a substituted or uninterrupted C1-C6 straight or branched or cyclic alkyl group, or a pharmaceutically acceptable salt thereof.

11. R ２ and R ３ are each independently a halogen or R ５ is a C1-C6 straight, branched or cyclic alkyl group unsubstituted or substituted with R ５ is (i) a substituted piperazine or non-t-butoxycarbonyl, benzyloxycarbonyl, or tosyl; (ii) R ６ C1-C6 alkoxy groups (R ６ is an amino substituted with a C1-C6 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

12. R ２ and R ３ are each independently a halogen or R ５ is a C1-C6 straight, branched or cyclic alkyl group unsubstituted or substituted with R ５ is (i) a substituted piperazine or a non-t-butoxycarbonyl or benzyloxycarbonyl; (ii) R ６ C1-C6 alkoxy groups (R ６ is an amino substituted with a C1-C6 alkoxy, amino, t-butoxycarbonyl group, benzyloxycarbonyl group, or tosyl group), or (iii) a hydroxy group.

13. R ２ is hydrogen, or a C1-C6 straight or branched alkyl chain or cyclic alkyl group; R ３ But, R ５ is a C1-C4 linear, branched or cyclic alkyl group unsubstituted or substituted with R ５ (i) piperazine, (ii) R ６ C1-C4 alkoxy groups (R ６ is a C1-C4 alkoxy group or an amino group), or (iii) a hydroxy group.

14. The following compounds: tert-butyl (S)-3-((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)piperazin-1-yl)methyl)azetidine-1-carboxylate, (S)-4-(5-(4-(azetidin-3-ylmethyl)piperazin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine, (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4-((1-methylazetidin-3-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)morpholine, (S)-benzyl 4-((1-(2-(2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methyl)piperazine-1-carboxylate, (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(3-(piperazin-1-ylmethyl)azetidin-1-yl)pyrimidin-2-yl)morpholine, (S)-4-(5-(3-((benzyloxy)methyl)azetidin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine, (S)-(1-(1-(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)azetidin-3-yl)methanol, (S)-(1-(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)azetidin-3-yl)methyl 4-methylbenzenesulfonate, tert-butyl (S)-4-((1-(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)azetidin-3-yl)methyl)piperazine-1-carboxylate, (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(3-((4-methylpiperazin-1-yl)methyl)azetidin-1-yl)pyrimidin-2-yl)morpholine, (S)-4-(5-(3-(((4-methoxybenzyl)oxy)methyl)azetidin-1-yl)pyrimidin-2-yl)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine, tert-butyl (S)-(4-(((1-(2-(2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methoxy)methyl)phenyl)carbamate, and tert-butyl (S)-(5-(((1-(2-(2-((5-(1-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)azetidin-3-yl)methoxy)methyl)pyridin-2-yl)carbamate, or a pharmaceutically acceptable salt thereof.

15. A compound represented by any one of the following chemical formulas 5 to 7, or a pharmaceutically acceptable salt thereof: [Chemical formula 5] 【Chemistry 12】 [Chemical formula 6] 【Chemistry 13】 [Chemical formula 7] 【Chemistry 14】 During the ceremony, R ４ is hydrogen, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, or a pharmaceutically acceptable salt thereof.

16. The following compounds: tert-butyl (2R)-2-(((2-(3-((3-(3-cyanophenyl)-6-oxopridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)oxy)methyl)morpholine-4-carboxylate, (S)-3-(1-(3-(5-(morpholin-2-ylmethoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, t-butyl-4-(2-{[2-(3-{[3-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-1-yl]methyl}phenyl)pyrimidin-5-yl]oxy}ethyl)piperazine-1-carboxylate, 3-(6-oxo-1-(3-(5-(2-(piperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, t-butyl 4-(2-(3-((3-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)methyl)phenyl)pyrimidin-5-yl)piperazine-1-carboxylate, and Preparation of 3-(6-oxo-1-(3-(5-(piperazin-1-yl)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.

17. An anti-cancer composition comprising a compound according to any one of claims 1 to 16.

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