A compound that targets and degrades CK1α protein and activates P53 protein and its applications.

Abstract

This invention relates to the field of medicinal chemistry, disclosing a compound that targets and degrades CK1α protein and activates P53 protein, and its applications. Specifically, it relates to a compound that can target ubiquitination and degrade CK1α protein and activate P53 protein, its pharmaceutically acceptable salts and hydrates, and pharmaceutical combinations with the compound as the active ingredient, as well as its use in the preparation of CK1α protein degraders and P53 protein agonists and their use in the treatment and / or prevention of cancer. The structures of the compound and its pharmaceutically acceptable salts and hydrates described in this invention are as follows: their variables are as described in the claims and specification.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a compound that can target and degrade CK1α protein and activate P53 protein, as well as pharmaceutically acceptable salts, hydrates and drug combinations with the compound as the active ingredient, and its use in the preparation of CK1α protein inhibitors and degraders and P53 protein agonists and their use in the treatment and / or prevention of tumors. Background Technology

[0002] Abnormal expression of CK1α is closely related to the occurrence and development of tumors. Studies have shown that inhibiting or knocking out CK1α protein can activate the tumor suppressor protein p53, thereby achieving the effect of treating tumors (Cell. 2018 Sep 20; 175(1):171-185.e25.).

[0003] PROTAC is a technique that uses bifunctional small molecules to bring target proteins closer to E3 in cells, thereby leading to ubiquitination and degradation of the target protein. Compared with traditional targeted drugs, it has advantages such as the ability to overcome undrugable targets and resistance to drug resistance. This invention designs and synthesizes a novel PROTAC compound, using a thalidomide analog as the binding site with the E3 ligase in the PROTAC, and using linker chains of different lengths and types to connect it to a structure with CK1α protein inhibitory activity to construct the PROTAC. In vitro antitumor activity tests and in vitro CK1α and P53 protein expression experiments show that the series of compounds can degrade CK1α protein and activate P53 protein, and have good antitumor activity. Summary of the Invention

[0004] The present invention aims to provide a compound that ubiquitinates and degrades CK1α protein and activates P53 protein, a method for preparing the same, and the application of such compounds as CK1α protein degraders and P53 protein activators in the prevention and / or treatment of tumors.

[0005] This invention relates to compounds represented by general formula I, and their pharmaceutically acceptable salts or hydrates:

[0006]

[0007] Each linker is independently selected from an alkyl chain. n is 1-20;

[0008] PEG chain n can be 1, 2, 3, 4, 5, or 6.

[0009] Furthermore, the present invention includes pharmaceutical compositions comprising a compound of general formula I and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The compounds of the present invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0010] The pharmaceutical combinations of the present invention can be formulated into several dosage forms, containing some excipients commonly used in the pharmaceutical field, such as oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders that can be used immediately after being added to water for injection before injection); and topical formulations (e.g., ointments or solutions).

[0011] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc., for oral formulations; preservatives, solubilizers, stabilizers, etc., for injectable formulations; and matrices, diluents, lubricants, preservatives, etc., for topical formulations. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets. Through in vitro screening, we found that this compound degrades CK1α protein and activates P53 protein activity. Therefore, the compounds of this invention can be used in diseases associated with abnormal expression of CK1α and P53 proteins, such as various cancers.

[0012] Through in vitro activity screening, we found that the compounds of this invention have antitumor activity. Therefore, the compounds of this invention can be used to prepare drugs for the treatment and / or prevention of various cancers, such as breast cancer, colon cancer, prostate cancer, pancreatic cancer, non-small cell lung cancer, papillary thyroid carcinoma, ovarian cancer, melanoma, or various leukemias.

[0013] The compounds of this invention can be used as the sole anticancer drug, or in combination with one or more other antitumor drugs. Combination therapy is achieved by administering the various therapeutic components simultaneously, sequentially, or separately.

[0014] The examples and preparation methods provided below further illustrate and demonstrate the compound and its preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the invention in any way.

[0015] The following synthetic routes describe the preparation of compounds of general formula I of the present invention. All starting materials are prepared by the methods described in these routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these routes or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these routes are as defined below or as defined in the claims.

[0016]

[0017] According to the general formula I compound of the present invention, each substituent in the synthetic route is as defined in the summary section of the invention.

[0018] The preparation method of this invention is simple to operate and mild under mild conditions. The resulting compounds all have CK1α protein degradation and P53 protein activation activities, and have significant anti-tumor effects.

[0019] Preparation of intermediate 2

[0020]

[0021] Compound 1 (12.0 g, 146.3 mmol), 240 mL of tetrahydrofuran, and 70 mL of n-butyllithium were added at -78 °C. After stirring for 1 h, 120 mL of a tetrahydrofuran solution of cyclopropaneformaldehyde (12.3 g, 175.6 mmol) was added. The mixture was stirred overnight, and 500 mL of a saturated ammonium chloride aqueous solution was added. The aqueous phase was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 2 (17.5 g, 79% yield), a colorless oil.

[0022] 1 H NMR (400MHz, CDCl3) δ: 7.21 (d, J=2.0Hz, 1H), 6.19 (d, J=2.0Hz, 1H), 4.46 (s, 1H), 4.02 (d, J=8.0H z, 1H), 3.76 (s, 3H), 1.29-1.23 (m, 1H), 0.64-0.50 (m, 2H), 0.44-0.38 (m, 1H), 0.29-0.23 (m, 1H).

[0023] Preparation of intermediate 3

[0024]

[0025] Compound 2 (15.2 g, 100 mmol), trifluoroacetic acid (68.4 g, 600 mmol), and Et3SiH (70.0 g, 600 mmol) were dissolved in 1200 mL of dichloromethane and stirred at room temperature for 36 h. The pH was adjusted to 8 with NaHCO3 aqueous solution, and the mixture was extracted three times with dichloromethane. After drying to anhydrous sodium sulfate, the solution was evaporated to dryness and subjected to column chromatography (petroleum ether:ethyl acetate = 50:1) to give compound 3 (7.0 g, 51%) as a colorless oil.

[0026] 1 H NMR (400MHz, CDCl3) δ: 7.39 (s, 1H), 6.19 (s, 1H), 3.79 (s, 3H), 2.52 (d, J = 8.0Hz, 2H), 1.06-0.96 (m, 1H), 0.60-0.55 (m, 2H), 0.20-0.18 (m, 2H).

[0027] Preparation of intermediate 4

[0028]

[0029] Compound 3 (7.0 g, 51.5 mmol) was added to 100 mL of dichloromethane, followed by NBS (11.0 g, 61.8 mmol), and reacted at room temperature for 2 h. Evaporation and column chromatography (petroleum ether: ethyl acetate = 50:1) yielded compound 4 (8.0 g, 73%).

[0030] 1 H NMR (400MHz, CDCl3) δ: 7.39 (s, 1H), 3.86 (s, 3H), 2.52 (d, J = 8.0Hz, 2H), 1.00-0.91 (m, 1H), 0.54-0.49 (m, 2H), 0.28-0.24 (m, 2H).

[0031] Preparation of intermediate 5

[0032]

[0033] Compound 4 (8.0 g, 37.2 mmol) was added to 150 mL of tetrahydrofuran, followed by the addition of n-butyllithium (28.0 mL, 56.0 mmol) at -78 °C. After reacting for 0.5 h, 20 mL of a tetrahydrofuran solution of isopropanol pinacol boronic acid ester (15.0 g, 74.4 mmol) was added. The reaction was allowed to proceed at room temperature for 1.0 h. 300 mL of saturated NH4Cl aqueous solution was added, followed by extraction three times with ethyl acetate, drying to anhydrous sodium sulfate, and column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 5 (8.8 g, 90%).

[0034] 1H NMR (400MHz, CDCl3) δ: 7.67 (s, 1H), 3.86 (s, 3H), 2.78 (d, J=8.0Hz, 2H), 1.29 (s, 12H), 0.97-0.89 (m, 1H), 0.46-0.41 (m, 2H), 0.29-0.25 (m, 2H).

[0035] Preparation of intermediate 6

[0036]

[0037] Compound 5 (8.00 g, 30.5 mmol), 2,4-dichloro-5-fluoropyrimidine (6.1 g, 36.6 mmol), Na₂CO₃ (7.1 g, 33.6 mmol), and Pd(amphos)Cl₂ 0.3 g were added to 150 mL of ethylene glycol dimethyl ether and reacted at 85 °C for 2 h under nitrogen protection. 150 mL of water was added, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 6 (6.0 g, 75%).

[0038] 1 H NMR (400MHz, CDCl3) δ: 8.36 (d, J=4.0Hz, 1H), 8.06 (d, J=4.0Hz, 1H), 3.94 (s, 3H) , 3.21 (d, J=8.0Hz, 2H), 1.12-1.03 (m, 1H), 0.52-0.47 (m, 2H), 0.39-0.35 (m, 2H).

[0039] Preparation of intermediate 7

[0040]

[0041] Compound 6 (0.5 g, 1.9 mmol), with a diamine linkage of 2.3 mmol, was reacted with 10 mL of n-butanol at 160 °C for 8 h. The reaction was then carried out under reduced pressure and purified by column chromatography (dichloromethane:methanol = 1:1) to yield a series of compounds 7.

[0042]

[0043] Compound 7a: 1H NMR (400MHz, CD3OD) δ: 8.11 (d, J = 4.0Hz, 1H), 7.93 (d, J = 4.0Hz, 1H), 3.90 (s, 3H), 3.45 (t, J = 8.0Hz, 2H), 3.32-3 .30(m,2H),2.74(t,J=8.0Hz,2H),1.81-1.74(m,2H),1.15-1.11(m,1H),0.50-0.45(m,2H),0.30-0.25(m,2H).

[0044]

[0045] Compound 7b: 1 H NMR (400MHz, CDCl3) δ: 8.05 (d, J = 4.0Hz, 1H), 7.94 (d, J = 4.0Hz, 1H), 3.86 (s, 3H), 3.38 (d, J = 4.0Hz, 2H), 3.11 (d,J=4.0Hz,2H),2.96(brs,2H),1.76-1.69(m,4H),1.06-1.03(m,1H),0.44-0.40(m,2H),0.21-0.17(m,2H).

[0046]

[0047] Compound 7c: 1 H NMR (400MHz, CD3OD) δ: 8.11 (d, J = 4.0Hz, 1H), 7.94 (d, J = 4.0Hz, 1H), 3.91 (s, 3H), 3.41-3.35 (m, 2H), 2.82 (t, J=4.0Hz,2H),1.67-1.58(m,4H),1.45-1.29(m,6H),1.16-1.12(m,1H),0.49-0.45(m,2H),0.30-0.26(m,2H).

[0048]

[0049] Compound 7d: 1H NMR (400MHz, CD3OD) δ: 8.08 (d, J = 4.0Hz, 1H), 7.92 (d, J = 4.0Hz, 1H), 3.91 (s, 3H), 3.36 (t, J = 8.0Hz, 2H), 3.27 (d, J = 8.0Hz ,2H),2.94(t,J=8.0Hz,2H),1.70-1.58(m,4H),1.39(brs,8H),1.16-1.08(m,1H),0.48-0.44(m,2H),0.30-0.26(m,2H).

[0050]

[0051] Compound 7e: 1 H NMR (400MHz, CD3OD) δ: 8.13 (d, J = 4.0Hz, 1H), 7.94 (d, J = 4.0Hz, 1H), 3.91 (s, 3H), 3.66-3.59 (m, 4H), 3.52 (t, J = 4 .0Hz,2H),3.27(d,J=4.0Hz,2H),2.79(t,J=4.0Hz,2H),1.16-1.10(m,1H),0.50-0.45(m,2H),0.30-0.26(m,2H).

[0052]

[0053] Compound 7f: 1 H NMR (400MHz, CD3OD) δ: 8.11 (d, J = 4.0Hz, 1H), 7.92 (d, J = 4.0Hz, 1H), 3.90 (s, 3H), 3.69-3.62 (m, 8H), 3.53 (t, J = 4 .0Hz,2H),3.24(d,J=4.0Hz,2H),2.80(t,J=4.0Hz,2H),1.15-1.08(m,1H),0.48-0.46(m,2H),0.29-0.27(m,2H).

[0054]

[0055] Compound 7g: 1H NMR (400MHz, CD3OD) δ: 8.09 (d, J = 4.0Hz, 1H), 7.91 (d, J = 4.0Hz, 1H), 3.88 (s, 3H), 3.65-3.55 (m, 12H), 3.49 (t, J = 4 .0Hz,2H),3.23(d,J=8.0Hz,2H),2.76(t,J=4.0Hz,2H),1.13-1.06(m,1H),0.47-0.42(m,2H),0.27-0.23(m,2H).

[0056] Preparation of compound 8

[0057]

[0058] 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (0.1 g, 0.36 mmol), compound 7 (0.36 mmol), and 0.1 mL of DIPEA were added to 5 mL of DMF and reacted at 100 °C for 10 h. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure for silica gel column chromatography (methanol:dichloromethane = 1:20) to give compound 8. Detailed Implementation

[0059] Example 1: Compound 4-((3-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)propyl)amino)-2-(2,6-dioxanidin-3-yl)isoindoline-1,3-dione (8a)

[0060]

[0061] 1 H NMR (400MHz, DMSO) δ: (11.10, s, 1H), 8.26 (d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1 H),7.54(t,J=8.0Hz,1H),7.16-6.99(m,3H),6.70(s,1H),5.07-5.03(m,1H),3. 84(s,3H),3.17-3.15(m,2H),2.93-2.83(m,2H),2.60-2.50(m,3H),2.03-1.99( m,2H),1.86-1.82(m,2H),1.06-1.00(m,1H),0.35-0.33(m,2H),0.18(brs,2H). LC-MS: [M+H] + 561.4.

[0062] Example 2: 4-((4-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)butyl)amino)-2-(2,6-dioxanil-3-yl)isoindoline-1,3-dione (8b)

[0063]

[0064] 1 H NMR (400MHz, DMSO) δ: 11.08 (s, 1H), 8.24 (d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1H), 7. 55(t,J=8.0Hz,1H),7.09-7.00(m,3H),6.56-6.54(t,J=4.0Hz,1H),5.06-5.02(m,1H ),3.84(s,3H),3.10-3.17(m,2H),2.93-2.84(m,2H),2.61-2.53(m,1H),2.03-1.97 (m,2H),1.64-1.63(m,4H),1.09-1.02(m,1H),0.39-0.34(m,2H),0.23-0.19(m,2H). LC-MS:[M+H] + 575.4

[0065] Example 3: 4-((6-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)hexyl)amino)-2-(2,6-dioxanidin-3-yl)isoindoline-1,3-dione (8c)

[0066]

[0067] 1 H NMR (400MHz, DMSO) δ: 11.09 (s, 1H), 8.23 ​​(d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1H), 7.55 ( t, J=8.0Hz, 1H), 7.07-7.00 (m, 3H), 6.51 (t, J=4.0Hz, 1H), 5.07-5.02 (m, 1H), 3.85 (s, 3 H),3.29-3.19(m,6H),2.93-2.83(m,1H),2.61-2.52(m,1H),2.04-1.96(m,2H),1.58-1 .53(m,4H),1.39-1.36(m,4H),1.08-1.04(m,1H),0.39-0.35(m,2H),0.23-0.19(m,2H). LC-MS:[M+H] +603.4

[0068] Example 4: 4-((8-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)octyl)amino-2-(2,6-dioxanidin-3-yl)isoindoline-1,3-dione (8d)

[0069]

[0070] 1 H NMR (400MHz, DMSO) δ: 11.08 (s, 1H), 8.23 ​​(d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1H), 7.56 (t,J=8.0Hz,1H),7.08-6.99(m,3H),6.50(t,J=4.0Hz,1H),5.06-5.02(m,1H),3.85(s, 3H),3.34-3.19(m,6H),2.93-2.83(m,1H),2.61-2.52(m,1H),2.04-1.99(m,2H),1.58 -1.51(m,4H),1.31(brs,8H),1.07-1.03(m,1H),0.40-0.35(m,2H),0.23-0.20(m,2H). LC-MS:[M+H] + 631.7.

[0071] Example 5: 4-((2-(2-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethyl)amino)-2-(2,6-dioxanil-3-yl)isoindoline-1,3-dione (8e)

[0072]

[0073] 1H NMR (400MHz, DMSO) δ: 11.10 (s, 1H), 8.23 ​​(d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1H), 7.54 (t , J=8.0Hz, 1H),7.12-6.94(m,3H),6.61(t, J=4.0Hz, 1H),5.07-5.03(m,1H),3.84(s,3H) ,3.65-3.58(m,4H),3.49-3.44(m,4H),3.15(d,J=4.0Hz,2H),2.93-2.84(m,1H),2.63-2 .48(m,2H),2.04-1.99(m,2H),1.07-1.00(m,1H),0.37-0.34(m,2H),0.21-0.20(m,2H). LC-MS:[M+H] + 591.3.

[0074] Example 6: 4-((2-(2-(((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethyl)amino)-2-(2,6-dioxindoline-1,3-dione) (8f)

[0075]

[0076] 1 H NMR (400MHz, DMSO) δ: 11.09 (s, 1H), 8.23 ​​(d, J = 4.0Hz, 1H), 7.83 (d, J = 4.0Hz, 1H), 7.55 (t , J=8.0Hz, 1H),7.12-6.89(m,3H),6.59(t, J=4.0Hz, 1H),5.07-5.02(m,1H),3.84(s,3H) ,3.63-3.54(m,8H),3.43-3.36(m,4H),3.17(d,J=8.0Hz,2H),2.91-2.82(m,1H),2.60-2 .51(m,2H),2.04-1.97(m,2H),1.07-1.01(m,1H),0.40-0.35(m,2H),0.24-0.20(m,2H). LC-MS:[M+H] + 635.3.

[0077] Example 7: 4-((2-(2-(-2-(2-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethoxyoxy)ethyl)amino)-2-(2,6-dioxanidin-3-yl)isoindoline-1,3-di(8g)

[0078]

[0079] 1 H NMR (400MHz, DMSO) δ: 11.06 (s, 1H), 8.22 (d, J = 4.0Hz, 1H), 7.81 (d, J = 4.0Hz, 1H), 7. 53(t,J=8.0Hz,1H),7.10-6.88(m,3H),6.56(t,J=4.0Hz,1H),5.04-5.00(m,1H),3. 83(s,3H),3.60-3.37(m,16H),3.15(d,J=8.0Hz,2H),2.90-2.80(m,1H),2.58-2.51 (m,2H),2.02-1.95(m,2H),1.06-1.00(m,1H),0.37-0.34(m,2H),0.21-0.19(m,2H). LC-MS:[M+H] + 679.3.

[0080] Example 8: MTT assay for tumor cell proliferation inhibition activity

[0081] Tumor cells (MM1S cells or A549 cells) in the logarithmic growth phase to be used in the experiment were seeded into culture plates at a certain cell volume and cultured for 24 hours. Different concentrations of inhibitors were added, and the cells were cultured for another 72 hours at 37°C and 5% CO2. 20 μL of MTT solution was added to each well and the cells were cultured for another 4 hours. The cells were then dissolved and crystallized with DMSO, and the OD value was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader to calculate the IC50. 50 .

[0082] Compound numbering <![CDATA[MM1S IC 50 (nM)]]> <![CDATA[A549 IC 50 (nM)]]> 1 >1000 >1000 2 >1000 >1000 3 658 532 4 350 462 5 532 480 6 164 182 7 84 96

[0083] Example 9: Western blot determination of CK1α and P53 protein degradation

[0084] MM 1S cells treated with 1 μM of the drug for 12 h were collected, washed twice with pre-cooled PBS, and lysed with PMSF and RIPA lysis buffer at a ratio of 1:100. Cells were lysed on ice for 20 min, centrifuged at 12000 rpm for 20 min at 4 °C, and the supernatant (total cellular protein) was collected. Protein levels were quantified using the BCA method. Proteins were diluted with 5× protein loading buffer and denatured at 100 °C for 5 min. Proteins were separated by SDS-PAGE electrophoresis, transferred to a membrane, blocked for 2 h, and incubated overnight with primary antibody at 4 °C. The membrane was washed with TBST, incubated with secondary antibody at a 1:1000 ratio for 2 h, and then developed using chemiluminescence and X-ray film. The grayscale value of each band was analyzed using ImageJ software. The expression levels of CK1α and P53 proteins were calculated, with 0 nM drug concentration as 100%.

[0085]

[0086]

Claims

1. A compound of the following general formula I, and pharmaceutically acceptable salts thereof: （I）， wherein each linker is independently selected from an alkyl chain n is 1-20; PEG chain n is 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, and pharmaceutically acceptable salts thereof: selected from, 4-((3-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((8-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)octyl)amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-((2-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-((2-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((2-((2-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

3. A pharmaceutical combination, characterized in that: A compound according to any one of claims 1, 2, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

4. Use of a compound according to any one of claims 1, 2, and pharmaceutically acceptable salts thereof, and a pharmaceutical composition according to claim 3, in the manufacture of a medicament for treating a disease associated with abnormal expression of CK1α protein and P53 protein activity.

5. Use of a compound according to any one of claims 1, 2, and pharmaceutically acceptable salts thereof, and a pharmaceutical composition according to claim 3, in the manufacture of an antitumor medicament for treating a disease associated with abnormal expression of CK1α protein and P53 protein activity.

6. Use of a compound according to any one of claims 1, 2, and pharmaceutically acceptable salts thereof, and a pharmaceutical composition according to claim 3, in the manufacture of a medicament for treating and / or preventing breast cancer, colon cancer, prostate cancer, pancreatic cancer, non-small cell lung cancer, papillary thyroid cancer, ovarian cancer, melanoma, or various leukemias.

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