PPM1d degradation-inducing compound and use thereof

Abstract

The present invention relates to a novel PPM1D degradation-inducing compound, a production method therefor, and a use thereof. The compound of the present invention exhibits an effect of inducing PPM1D degradation. Therefore, the compound of the present invention can be effectively used for preventing or treating PPM1D-related diseases.

Description

PPM1D degradation-inducing compounds and uses thereof

[0001] The present invention relates to a novel PPM1D degradation-inducing compound and its use. The present invention can specifically target abnormal cells and the like through effective degradation of PPM1D, and can be usefully applied to the treatment of various diseases.

[0002] PPM1D (or WIP1, PP2Cδ) encodes a phosphatase enzyme that plays a crucial role in regulating cell division, DNA damage repair, and apoptosis. Its function is to separate a phosphate group from the amino acids serine / threonine. This gene is located on chromosome 17q23, a region frequently amplified in various types of cancer, and mutations in the gene have been identified at a high frequency in various solid cancers, including breast cancer, ovarian cancer, lung cancer, hepatocellular carcinoma, neuroblastoma, and pancreatic cancer. In addition, PPM1D is frequently mutated in hematological malignancies (AML) and myelodysplasia spondylitis (MDS), and is also associated with the development of hematological malignancies (t-AML / t-MN) induced by chemotherapy. Overexpression or mutation-induced enzymatic activity of PPM1D is associated with poor prognosis and the development of resistance to chemotherapy and radiotherapy.

[0003] Despite significant advances in cancer research, finding effective treatments for patients with PPM1D mutations remains an unmet need. While therapeutics that selectively inhibit PPM1D activity are being studied, no drugs have yet been developed. Therefore, continued research into the mechanisms and impact of PPM1D mutations in cancer is crucial to identify new therapeutic targets and develop personalized treatment options for patients with these mutations.

[0004] Recent studies have shown that PPM1D mutations are associated with cancer recurrence in blood cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PPM1D mutations in blood cancers can lead to overactivation of the PPM1D protein, promoting cancer cell growth and survival. PPM1D overactivation is associated with poor prognosis and chemotherapy resistance in AML patients. Therefore, understanding the impact of PPM1D mutations in blood cancers is essential for developing new treatments and improving patient prognosis.

[0005] The physiological significance of PPM1D mutations in hematological cancers lies in their role as regulators of the p53 pathway. p53 is a tumor suppressor protein that plays a crucial role in preventing the development and growth of cancer cells. PPM1D mutations lead to inactivation of the p53 pathway, allowing cancer cells to evade normal growth control mechanisms. Therefore, studying PPM1D mutations in hematological cancers can provide valuable insights into cancer growth mechanisms and help identify novel therapeutic targets to improve patient outcomes.

[0006] Recently, a small-molecule platform technology called PROTAC (Proteolysis Targeting Chimera) has been proposed to induce proteolysis of target proteins in vivo. A PROTAC is a bifunctional compound consisting of a ligand molecule that binds to a disease-associated target protein and an E3 ubiquitin ligase binding moiety, linked by a chemical linker. Theoretically, PROTAC compounds can induce target protein degradation by positioning the disease-associated target protein near the E3 ubiquitin ligase. Based on this novel mechanism, different from existing inhibitors, many PROTAC compounds are being developed as therapeutics for cancer, inflammatory diseases, and other diseases, and are being studied with diverse potential (e.g., as payloads for antibody-drug conjugates (ADCs). However, PROTACs do not exhibit activity across all binding moieties or linkers, and it has been known through several studies that each binding moiety and linker must have an appropriately linked structure for PROTACs to exhibit the desired level of efficacy (literature [US2020-0325130A]). In particular, for moieties targeting CRBN (cereblon) E3 ligase, there is a concern that they may degrade CRBN's neo-substrates (GSPT1, IKZF1 / 3, etc.) or exhibit off-target toxicity depending on the type of binding moiety or the structure of the compound linked to it. Therefore, when developing PROTAC drugs, it is important to select an appropriate binding moiety and optimize the structure of the entire compound to avoid unexpected toxicity.

[0007] Therefore, there is an unmet need for effective PPM1D degradation-inducing compounds that have no or minimal side effects (e.g., off-target toxicity).

[0008] The purpose of the present invention is to provide a novel PPM1D degradation-inducing compound.

[0009] Another object of the present invention is to provide a method for preparing a novel PPM1D degradation-inducing compound.

[0010] Another object of the present invention is to provide a use of a novel PPM1D degradation-inducing compound.

[0011] To achieve the above purpose, the inventors of the present invention have discovered a novel PROTAC compound that specifically acts on abnormal cells overexpressing PPM1D, inducing effective degradation of PPM1D and minimizing side effects through appropriate structural combination and optimization of an E3 ligase binder, a target binding moiety, and a linker, thereby completing the present invention.

[0012] PPM1D selective degradation-inducing compounds

[0013] The present invention provides novel compounds that induce effective degradation of PPM1D. Specifically, the present invention provides bifunctional compounds in which a PPM1D binding moiety and an E3 ubiquitin ligase binding moiety are linked by a chemical linker.

[0014] One embodiment of the present invention is a compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula I]

[0016]

[0017] In the above chemical formula I,

[0018] PTM is a moiety represented by the following chemical formula 1;

[0019] [Chemical Formula 1]

[0020]

[0021] ULM is a CRBN or VHL E3 ligase moiety;

[0022] Linker is a group that chemically connects ULM and PTM;

[0023] R1 and R2 are each independently -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 Alkoxy, or -halo;

[0024] R3 is cycloalkyl or heterocycloalkyl {wherein, at least one H of the cycloalkyl or heterocycloalkyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 {which may be substituted with alkoxy or -halo}.

[0025] According to a specific example of the present invention, the compound represented by chemical formula I may be in the following range:

[0026] R1 is -C 1-4 It is alkyl;

[0027] R2 is -halo;

[0028] R3 is a 5-6 membered cycloalkyl {wherein at least one H of the 5-6 membered cycloalkyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, or -halo}

[0029] According to a specific example of the present invention, the PTM is It could be.

[0030] According to a specific example of the present invention, the CRBN E3 ligase moiety

[0031] and;

[0032] X1 is -CH2- or -C(=O)-;

[0033] X2 is -H, -C 1-4 Alkyl, -C1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 It can be alkoxy, or -halo.

[0034] According to a specific example of the present invention, the CRBN E3 ligase moiety It could be.

[0035] According to a specific embodiment of the present invention, the VHL E3 ligase moiety and;

[0036] Y1 is a 5-6 membered heteroaryl, and {wherein, at least one H of the 5-6 membered heteroaryl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, or -halo};

[0037] Y2 is -C 1-4 alkyl or phenyl {wherein at least one H of the phenyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 {which may be substituted with alkoxy or -halo}.

[0038] According to a specific embodiment of the present invention, the VHL E3 ligase moiety

[0039] It could be.

[0040] According to a specific example of the present invention, the Linker is -(CH2) a -, -(CH2) b -NH(C=O)-(CH2) c -O-, -[(CH2CH2)O] d -, -(CH2) e -Cycloalkyl-(CH2) f -, or -(CH2) e-Heterocycloalkyl-(CH2) f - and {above -(CH2) e -Cycloalkyl-(CH2) f - or -(CH2) e -Heterocycloalkyl-(CH2) f - One or more H in the ring is -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 which may be substituted with alkoxy, -OH, or -halo;

[0041] a is an integer from 1 to 10;

[0042] b to d are each independently integers from 1 to 5;

[0043] e and f can each independently be an integer from 0, 1 to 4.

[0044] According to a specific embodiment of the present invention, the compound represented by formula I is a compound selected from the group consisting of compounds 1 to 6 below.

[0045]

[0046]

[0047] In the present invention, "alkyl" may mean a straight or branched chain acyclic, cyclic or saturated hydrocarbon with a combination thereof, unless otherwise specified. For example, "C 1-6 "Alkyl" may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, or tert-butyl, as examples. Cyclic alkyl may be used interchangeably herein with "cycloalkyl" and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples.

[0048] In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-6 "Alkoxy" of C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6 Alkoxy may mean, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, but is not limited thereto.

[0049] In the present invention, “halo” may be F, Cl, Br, or I.

[0050] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more carbon atoms substituted with halo as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0051] As used herein, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with hydroxy (OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with -OH.

[0052] In this specification, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"). Here, R' and R" are each independently hydrogen, C 1-6alkyl, and N protecting groups (e.g., Boc), wherein the selected R' and R" may each be independently substituted or unsubstituted.

[0053] As used herein, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0054] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain a heteroatom (such as N, O, P, P(=O), or S) within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as cycloalkenyl. Unless otherwise stated, a cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.

[0055] In the present invention, "heterocycloalkyl" may mean a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. Also, "heterocycloalkyl having 3 to 12 atoms" may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, and as an example, the heterocycloalkyl is pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, It may include, but is not limited to, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0056] In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternary benzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl."

[0057] In the present invention, "heteroarene" may be a ring containing at least one of O, N, P, Si, and S as a heteroatom. The number of ring-forming carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, Benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran, but are not limited thereto. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. As used herein, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as a "heteroaryl".

[0058] In the present invention, "stereoisomer" means a compound having the same chemical formula or molecular formula but sterically different. In the present specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention. For example, since the chemical formula I of the present invention does not specify the stereochemical structure, it may include the stereoisomers of the chemical formula I. Unless otherwise stated, the solid bond ( ) is a wedge-shaped solid line combination representing the absolute arrangement of the stereocenter ( ) or wedge-shaped dotted line join ( ) may be included.

[0059] The compound represented by the chemical formula I of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by the chemical formula I. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects due to the salt do not reduce the beneficial effects of the compound represented by the chemical formula I.

[0060] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0061] Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0062] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula I in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0063] In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, a corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate), and can be prepared through a salt preparation method known in the art.

[0064] Uses of compounds that selectively induce PPM1D degradation

[0065] The present invention provides a use of a compound represented by the following chemical formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0066] [Chemical Formula I]

[0067]

[0068] The above chemical formula I is as defined above.

[0069] The present invention relates to a compound represented by the above chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which effectively induces PPM1D protein degradation.

[0070] According to one specific example of the present invention, the PPM1D degradation-inducing PROTAC compound of the present invention can degrade the target protein PPM1D at the source from the viewpoint of the mechanism of action, and thus achieves a superior PPM1D inhibitory effect compared to conventional PPM1D small molecule inhibitors that simply inhibit the activity of PPM1D.

[0071] Therefore, a composition comprising a compound represented by chemical formula I of the present invention or a pharmaceutically acceptable salt thereof can be usefully used for selective decomposition of PPM1D.

[0072] One embodiment of the present invention is a pharmaceutical composition for preventing or treating a PPM1D-related disease, comprising a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a method for preventing or treating a PPM1D-related disease by administering such a composition. Chemical Formula I is as defined above.

[0073] In the present invention, a PPM1D-related disease refers to any disease or condition that can be treated, alleviated, delayed, inhibited, or prevented by inducing degradation or inhibiting the activity of PPM1D. In one embodiment, the PPM1D-related disease may be cancer (malignant tumor).

[0074] The above cancer includes all cancers that may exhibit preventive or therapeutic efficacy due to inhibition of the activity of PPM1D, and may be solid cancer or hematological cancer. The type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, It may be at least one selected from the group consisting of renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. There is. In addition, the cancer includes not only primary cancer but also metastatic cancer.

[0075] According to one specific embodiment of the present invention, the present invention provides a pharmaceutical composition for treating or preventing a PPM1D-related disease, comprising a compound represented by the above chemical formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the PPM1D-related disease may be cancer. The type of cancer is as mentioned above.

[0076] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0077] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral and parenteral dosage forms.

[0078] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a PPM1D-related disease. Specifically, the PPM1D-related disease may be cancer. The type of cancer is as mentioned above.

[0079] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing cancer. The type of cancer is as mentioned above.

[0080] In addition, according to one specific embodiment of the present invention, the present invention provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as mentioned above.

[0081] In addition, according to one specific example of the present invention, the present invention provides a method for decomposing PPM1D protein, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0082] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by the above formula (I) that is effective in treating or preventing a PPM1D-related disease. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in amounts exceeding the determined dosage.

[0083] As used herein, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the compound.

[0084] In addition, according to one specific embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0085] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.

[0086] The above pharmaceutical composition may be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0087] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0088] Additionally, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0089] In addition, the compound represented by chemical formula I of the present invention or a pharmaceutically acceptable salt thereof may have a synergistic effect when administered in combination with other effective ingredients.

[0090] For example, the compound represented by Chemical Formula I of the present invention or a pharmaceutically acceptable salt thereof may be administered in combination with a "second anticancer agent" in the present invention. In the present invention, the scope of the second anticancer agent is not particularly limited, and a person skilled in the art may select an appropriate type and use it depending on the type and degree of progression of the cancer, and for the purpose of complete cure, control, symptom relief, etc. of the cancer. The second anticancer agent may be, for example, a cytotoxic anticancer agent, a targeted anticancer agent, an immune anticancer agent, or a metabolic anticancer agent, but is not limited thereto.

[0091] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0092] The compound of the present invention exhibits an effect of inducing the degradation of PPM1D. Therefore, the compound of the present invention can be useful for the prevention or treatment of PPM1D-related diseases.

[0093] Figure 1 shows the results of a Western blot analysis of the PPM1D protein degradation assay of example compounds in A549 cells.

[0094] Figure 2 shows the results of a Western blot analysis of the PPM1D protein degradation assay of example compounds in HCT116 cells.

[0095] Figure 3 is a graph showing the survival rate of cells after treating MOLT4 cells with an example compound.

[0096] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0097] Example 4. Synthesis of (2R,4S)-1-((S)-2-(11-((S)-2-(5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamido)-3-cyclohexylpropanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0098] Step 1: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid

[0099]

[0100] To a solution of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoate (200 mg, 0.668 mmol) in methanol / water (150 mL, 3:2) was added sodium hydroxide (80.16 mg, 2.00 mmol), and the reaction mixture was stirred at room temperature for 24 h. After removing the methanol under reduced pressure, the residual solution was acidified with 1 N aqueous hydrochloric acid. After adding more water, the aqueous solution was extracted with ethyl acetate, and the extracted organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (130 mg, 72%).

[0101] Step 2: Synthesis of tert-butyl ((S)-3-cyclohexyl-1-((11-(((S)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl)amino)-1-oxopropan-2-yl)carbamate

[0102]

[0103] (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (22.95 mg, 0.085 mmol), EDCI (22.11 mg, 0.115 mmol), (2R,4S)-1-((S)-2-(11-aminoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (50 mg, 0.077 mmol), HOBt (10.39 mg, 0.077 mmol), and DIPEA (14.91 mg, 0.115 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed with brine, the organic layer was dehydrated with anhydrous sodium sulfate, and the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (56 mg).

[0104] Step 3: Synthesis of (2R,4S)-1-((S)-2-(11-((S)-2-amino-3-cyclohexylpropanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride

[0105]

[0106] To a solution of tert-butyl ((S)-3-cyclohexyl-1-((11-(((S)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl)amino)-1-oxopropan-2-yl)carbamate was added a dioxane solution containing 4 M HCl, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added dropwise. The resulting solid was filtered to obtain the title compound (44 mg, 71%).

[0107] Step 4: Synthesis of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-2-thiophene carboxylic acid

[0108]

[0109] 5-Chloro-2-methylpyridin-3-amine (183 mg, 1.281 mmol) was added to a solution of 5-formylthiophene-2-carboxylic acid (200 mg, 1.281 mmol) in methanol under nitrogen. The reaction mixture was heated to 50°C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid compound. The solid compound was dissolved in methanol, and the solution was cooled to 0°C, and sodium cyanoborohydride (96 mg, 1.537 mmol) was added dropwise over 10 minutes. The mixture was then warmed to room temperature and stirred for 12 hours. The reaction mixture was acidified to pH 4 by adding 1 N HCl aqueous solution, and concentrated under reduced pressure. The residue was diluted with water, and the precipitated solid was filtered and washed with ethyl acetate to obtain a pale yellow solid compound. The obtained solid was used in the next reaction without further purification.

[0110] Step 5: Synthesis of (2R,4S)-1-((S)-2-(11-((S)-2-(5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxamido)-3-cyclohexylpropanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0111]

[0112] (2R,4S)-1-((S)-2-(11-((S)-2-amino-3-cyclohexylpropanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (44 mg, 0.055 mmol), EDCI (15.75 mg, 0.082 mmol), 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)thiophene-2-carboxylic acid (15.48 mg, 0.055 mmol), HOBt (7.4 mg, 0.055 mmol) and DIPEA (10.62 mg, 0.082 mmol) were dissolved in dichloromethane (20 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (11 mg, 19%).

[0113] Example 5. Synthesis of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[0114] Step 1: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid

[0115]

[0116] To a solution of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoate (200 mg, 0.668 mmol) in methanol / water (150 mL, 3:2) was added sodium hydroxide (80.16 mg, 2.00 mmol), and the reaction mixture was stirred at room temperature for 24 h. After removing the methanol under reduced pressure, the residual solution was acidified with 1 N aqueous hydrochloric acid. After adding more water, the aqueous solution was extracted with ethyl acetate, and the extracted organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (130 mg, 72%).

[0117] Step 2: Synthesis of tert-butyl ((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)carbamate

[0118]

[0119] (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (100 mg, 0.479 mmol), EDCI (36.94 mg, 0.193 mmol), 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (143 mg, 0.405 mmol), HOBt (49.79 mg, 0.369 mmol), and DIPEA (71.45 mg, 0.553 mmol) were dissolved in dichloromethane. The mixture reaction solution was stirred at room temperature for 24 h. The reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (95 mg, 47%).

[0120] Step 3: Synthesis of (2S)-2-amino-3-cyclohexyl-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)propanamide hydrochloride

[0121]

[0122] To a solution of tert-butyl ((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)carbamate in ethyl acetate was added dropwise 4M HCl dioxane solution (4 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added dropwise. The resulting solid was filtered to obtain the title compound (65 mg, 34%).

[0123] Step 4: Synthesis of N-((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)-5-formylthiophene-2-carboxamide

[0124]

[0125] (2S)-2-Amino-3-cyclohexyl-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)propanamide hydrochloride (65 mg, 0.128 mmol), EDCI (36.94 mg, 0.193 mmol), 5-formylthiophene-2-carboxylic acid (24.07 mg, 0.154 mmol), HOBt (17.36 mg, 0.128 mmol), and DIPEA (24.9 mg, 0.193 mmol) were dissolved in dichloromethane. The mixed reaction solution was stirred at room temperature for 24 h. The reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (49 mg, 62%).

[0126] Step 5: Synthesis of 5-(((5-chloro-2-methylpyridin-3-yl)amino)methyl)-N-((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)thiophene-2-carboxamide

[0127]

[0128] To a solution of N-((2S)-3-cyclohexyl-1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)-5-formylthiophene-2-carboxamide (49 mg, 0.081 mmol) in dichloromethane, NaBH3CN (7.6 mg, 0.121 mmol) and 5-chloro-2-methylpyridin-3-amine (12.65 mg, 0.089 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (11 mg, 18%).

[0129] <Example 1> to <Example 6>

[0130] All other example compounds of the present invention (compounds of Examples 1, 2, 3, and 6) were prepared in a similar manner to the above Example 4 or 5, and the compound name, chemical structural formula, NMR, and LCMS analysis results of each example compound are summarized and shown in [Table 1] below.

[0131] [Table 1]

[0132]

[0133]

[0134]

[0135] Experimental Example 1: PPM1D protein degradation test

[0136] In this experiment, PPM1D protein degradation was monitored in A549 (human lung cancer cell) and HCT116 (human colon cancer cell) cell lines using example compounds. Cells were cultured in RPMI medium supplemented with FBS. 3 × 10 5Cells were seeded in 60 mm dishes and allowed to grow. Compounds used were Examples 1, 2, 3, 4, and 6, and treatment was performed for 24 hours at the following concentrations: 0, 0.1, 1, 5, 10, and 20 μM.

[0137] Western blot techniques were used to assess target protein degradation. For each sample, 20 μg of protein was loaded onto the gel. Target protein detection was performed using a specific Wip1 antibody, sc-376257, a mouse monoclonal antibody that recognizes amino acids 306-605 of the C-terminus of human Wip1. The predicted size of the Wip1 protein is 64 kDa, but the actual blot showed a size between 70-90 kDa. Cell lysates were subjected to Western blot analysis and Wip1 antibody probing to measure changes in protein levels or potential degradation in response to compound treatment at various concentrations and time points. To quantify the band-like appearance of the Western blot, gel images were saved and then imageJ (imagej.net / downloads) was used to designate a region of equal size defined by the analyst. The pixel counts of the images constituting each band were calculated and output. The quantitative values ​​for each band and the compound concentration were used to determine the DC, the concentration of the compound at 50% of the maximum degradation concentration. 50 It was calculated through regression analysis (Rstudio, drc package).

[0138] Western blot analysis results are shown in Figures 1 and 2. DC 50 The results are shown in Table 2 below.

[0139] [Table 2]

[0140]

[0141] Experimental Example 2: Cell Death Test of the Example Compound

[0142] The Promega CellTiter-Glo assay was used to assess cell death. This assay is a luminescent assay that quantitatively measures the number of viable cells using intracellular ATP concentration as an indicator. A higher luminescent signal indicates a higher number of viable cells, and it can sensitively detect changes in cell viability following drug treatment.

[0143] (1) Cell line preparation

[0144] 3 x 10 MOLT-4 cell lines were seeded in 96-well plates. 3 Dispensed at a concentration of cells / well.

[0145] The cell suspension volume in each well was adjusted to a total of 80 μL to allow cells to attach and stabilize.

[0146] (2) Treatment of the compound of the present invention

[0147] Starting from a concentration of 10 μM, the compound was serially diluted in 1 / 2 steps to create 10 concentration points (10, 5, 2.5, 1.3, 0.6, 0.3, 0.16, 0.08, 0.04, 0 μM).

[0148] 20 μL of each compound solution was treated to the corresponding well so that the final volume of each well was 100 μL, and the cells were cultured for 72 hours.

[0149] (3) Cell viability analysis

[0150] After incubation, 100 μL of CellTiter-Glo (Promega) reagent prepared according to the manufacturer's protocol was dispensed onto the plate and vortexed.

[0151] The luminescence signal from viable cells was measured using a luminometer, and the relative cell viability at each concentration was calculated compared to the concentration at which the compound was not treated (0 μM).

[0152] The results of confirming cell viability in the MOLT4 cell line are shown in Fig. 3. As can be seen in Fig. 3, when the example compound was treated, the change in cell viability and IC50 The value was confirmed.

[0153] Experimental Example 3: Metabolic Stability Test

[0154] (1) Microsome assay

[0155] To evaluate the drug metabolism profile, a microsomal assay was performed on compound Example 6. This assay indirectly determines how rapidly a drug candidate is metabolized in the body and what metabolites are produced. Furthermore, by comparing differences in metabolic profiles between different species (e.g., humans and mice), information can be obtained for extrapolating animal study results to humans. In this experiment, microsomal assays were performed on the compounds listed in Table 3 below.

[0156] [Table 3]

[0157]

[0158] The procedure for performing the microsome assay is as follows.

[0159] Working solutions of the example compounds and the control compound were prepared at a concentration of 10 μM, and a working solution of 10 unit / mL was prepared using NADPH tetrasodium salt powder (BONTAC, Cat. No. BT04) as an NADPH auxiliary. Human liver microsomes (Cat No. 452117, Lot No. 38298) from Corning and mouse liver microsomes (Cat No. M1000, Lot No. 2210246) from Xenotech were used, each suspended at a concentration of 0.5 mg protein / mL. A 4°C acetonitrile solution containing 200 ng / mL of tolbutamide and labetalol as internal standards was used as a reaction stopping solution. 10 μL of the compound solution and 80 μL of the microsome suspension were dispensed into a 96-well plate using an automated device, and the pre-reaction was performed at 37°C for 10 minutes. The reaction was initiated by adding 10 μL of NADPH regeneration system and incubated at 37°C for 30 minutes. To stop the reaction, 300 μL of reaction stop solution was added, followed by centrifugation to collect the supernatant. The collected supernatant was diluted threefold with water and analyzed by LC-MS / MS.

[0160] The results of human and mouse microsome assays are shown in Table 4 below.

[0161] [Table 4]

[0162]

[0163] As shown in Table 4 above, the metabolic stability of the compound of Example 6 was confirmed. It was confirmed that the compound of Example 6 was metabolized in human liver microsomes at a level similar to that of the control group, thereby ensuring stability.

[0164] The embodiments of the present invention may be modified in various ways, and the scope of the present invention is not limited to the embodiments described below. Furthermore, the embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Furthermore, throughout the specification, the term "including" a certain component does not exclude other components, but rather implies the inclusion of other components, unless specifically stated otherwise.

Claims

1. A compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, PTM is a moiety represented by the following chemical formula 1; [Chemical Formula 1] ULM is a CRBN or VHL E3 ligase moiety; Linker is a group that chemically connects ULM and PTM; R1 and R2 are each independently -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 Alkoxy, or -halo; R3 is cycloalkyl or heterocycloalkyl {wherein, at least one H of the cycloalkyl or heterocycloalkyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 {which may be substituted with alkoxy or -halo}.

2. In paragraph 1, R1 is -C 1-4 It is alkyl; R2 is -halo; R3 is a 5-6 membered cycloalkyl {wherein at least one H of the 5-6 membered cycloalkyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, or -halo}; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. In paragraph 2, The above PTM is person; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, The above CRBN E3 ligase moiety is and; X1 is -CH2- or -C(=O)-; X2 is -H, -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 Alkoxy, or -haloine; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. In paragraph 4, The above CRBN E3 ligase moiety is person; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, The above VHL E3 ligase moiety is and; Y1 is a 5-6 membered heteroaryl, and {wherein, at least one H of the 5-6 membered heteroaryl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, or -halo}; Y2 is -C 1-4 Alkyl or phenyl {wherein at least one H of the phenyl ring is -C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Aminoalkyl, -C 1-4 Haloalkyl, -C 1-4 alkoxy, or -halo}; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. In paragraph 6, The above VHL E3 ligase moiety is person; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, Linker is -(CH2) a -, -(CH2) b -NH(C=O)-(CH2) c -O-, -[(CH2CH2)O] d -, -(CH2) e -Cycloalkyl-(CH2) f -, or -(CH2) e -Heterocycloalkyl-(CH2) f - and {above -(CH2) e -Cycloalkyl-(CH2) f - or -(CH2) e -Heterocycloalkyl-(CH2) f - One or more H in the ring is -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 which may be substituted with alkoxy, -OH, or -halo; a is an integer from 1 to 10; b to d are each independently integers from 1 to 5; e and f are each independently an integer from 0 to 4; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, A compound represented by the above chemical formula I, a compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for preventing or treating a PPM1D-related disease, comprising a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. In paragraph 11, The above PPM1D-related disease is cancer, pharmaceutical composition.

13. In paragraph 12, A pharmaceutical composition wherein the cancer is a solid cancer or a blood cancer.

14. A method for treating or preventing a PPM1D-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. In paragraph 14, A method for treating or preventing a PPM1D-related disease, wherein the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof induces degradation of the PPM1D protein.

16. Use of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. Use of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of a disease associated with PPM1D.

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