Compounds inhibiting or degrading CDK2 and / or CDK9 and medical uses thereof

Abstract

The present invention provides: a compound having a specific chemical structure and having an activity of inhibiting or degrading CDK2 and / or CDK9, or a pharmaceutically acceptable salt thereof; and a preparation method thereof. The present invention provides a composition comprising the compound or a pharmaceutically acceptable salt thereof. The present invention provides: the use of a compound according to the invention, a salt thereof or a composition comprising the same for inhibiting or degrading CDK2 and / or CDK9; and medical uses for the prevention or treatment of diseases associated therewith. The present invention also provides a method for preventing or treating a CDK2 and / or CDK9 related disease comprising administering to an individual in need thereof an effective amount of a compound according to the present invention, a salt thereof, or a composition comprising the same.

Description

Technical Field

[0001] The present invention relates to a group of compounds having inhibitory or degrading activity against cyclin-dependent kinase 2 (CDK2) and / or cyclin-dependent kinase 9 (CDK9), and methods for preparing the same. The present invention also relates to a pharmaceutical composition comprising these compounds. The present invention relates to an effective method for treating diseases related to CDK2 or CDK9 using these compounds. In other words, the present invention relates to the medical use of the compounds according to the present invention in the treatment or prevention of diseases related to CDK2 or CDK9. Background Art

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that are activated by binding to cyclins. CDKs have multiple isoforms, and 21 CDK isoforms are expressed in humans. Each CDK plays a different role within the cell; however, in terms of function, CDKs can be broadly classified into CDKs involved in the cell cycle and CDKs involved in transcriptional regulation.

[0003] CDK2 is one of the CDKs that regulate the cell cycle and is activated by binding to cyclin E or cyclin A. The CDK2-cyclin E complex regulates the entry of cells into the S phase, while the CDK2-cyclin A complex plays a role in regulating DNA synthesis during the S phase. Uncontrolled activation of CDK2 induces cells to enter the S phase even in the absence of growth factors, leading to chromosomal instability and increased cell proliferation, thus contributing to the development of cancer. In fact, CDK2 has been reported to be overexpressed in various types of cancer (prostate cancer, B-cell lymphoma, glioblastoma; Cell Cycle, 2007, 6:2982-2989, Future Oncol., 2018, 14:709-718, Transl. Oncol., 2016, 9:548-556) and cyclin E1 (ovarian cancer, TNBC, hepatocellular carcinoma; Oncotarget, 2015, 6:20801-20812, Clin. Cancer Res., 2017, 23:1862-1874, Oncol. Rep., 2015, 33:990-996, Gynecol. Oncol., 2018, 151:327-336, Oncotarget, 2017, 8:14897-14911). These research findings suggest that therapeutic effects can be expected in cancer types with CDK2 overexpression through the selective degradation of CDK2. In addition, International Patent Publication No. WO 2006 / 040036 discloses that CDK2 inhibitors can be used to treat breast cancer, colon cancer, lung cancer, and prostate cancer.

[0004] CDK9 is one of the CDKs that regulate transcription, and CDK9 binds to cyclin T1, cyclin T2, or cyclin K to form the positive transcription elongation factor (P-TEFb) complex. The P-TEFb complex phosphorylates RNA polymerase II, promoting transcription elongation. CDK9 regulates the expression of the transcription factor Myc in cancer (Mol. Cancer Ther., 2019, 18:1520-32) and the anti-apoptotic protein MCL-1 (Am. J. Manag. Care, 2018, 24: S356-S365). Therefore, it has been found that inhibiting CDK9 can inhibit cell proliferation in various cancers, including prostate cancer, pancreatic cancer, breast cancer, multiple myeloma, and chronic lymphocytic leukemia (CLL) (Endocr Relat Cancer, 2016, 23, T211-T226). In addition, since human immunodeficiency virus (HIV) utilizes the host's P-TEFb for viral replication, CDK9 has been used as a candidate target protein for inhibiting HIV replication (Cancer Biol. Ther., 2002, 1:342-347). Furthermore, International Patent Publication WO 2017 / 001354 discloses that CDK9 inhibitors can be used to treat cancers such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, breast cancer, lung cancer, neuroblastoma, and colorectal cancer, as well as other diseases, including cardiovascular diseases, viral diseases, inflammation, and pain.

[0005] Meanwhile, the proteolysis-targeting chimera (PROTAC) technology for degrading target proteins has recently been actively used in drug development (PNAS, 2001, 98(15):8554-8559, Cell, 2020, 2:1-3). PROTACs are novel therapeutic agents that are manufactured by linking an inhibitor or binder compound that specifically binds to certain proteins and a ligand compound that specifically binds to an E3 ubiquitin ligase with various types of linkers. Since PROTAC compounds selectively degrade the target proteins that cause diseases, the possibility of drug resistance is low, and there is no high binding affinity for the target proteins, so sufficient therapeutic effects are achieved through protein degradation. In addition, they can be applied to undruggable targets that are difficult to inhibit with conventional drugs. Therefore, PROTAC compounds are attracting attention as a new therapeutic technology.

[0006] However, not every inhibitor (i.e., binding factor) becomes an effective PROTAC compound by binding to an E3 ubiquitin ligase ligand. The effectiveness of PROTAC compounds varies depending on the binding moieties (such as inhibitors, E3 ubiquitin ligase ligands, and linkers). SUMMARY OF THE INVENTION

[0007] [Technical Problem]

[0008] One object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that exhibits activity for inhibiting or degrading CDK2 and / or CDK9.

[0009] Another object of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to provide a composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] Another object of the present invention is to provide a pharmaceutical composition for inhibiting or degrading CDK2, CDK9 or both, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer or HIV infection, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] Another object of the present invention is to provide a method for preventing or treating cancer or HIV infection, comprising administering the pharmaceutical composition to a subject in need thereof.

[0014] [Advantageous Effects]

[0015] The present invention provides a compound or a pharmaceutically acceptable salt thereof that can exhibit various pharmacological activities by inhibiting or degrading CDK2 and / or CDK9, a pharmaceutical composition comprising the same as an active ingredient, its medical use (particularly for treating or preventing cancer or HIV infection), and a treatment method comprising administering the same to a subject in need of treatment or prevention. The compound or a pharmaceutically acceptable salt thereof according to the present invention is excellent in various aspects (including safety and stability), and has high selectivity in inhibiting or degrading CDK2 and / or CDK9 activity, thereby providing excellent medical effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A graph for illustrating the evaluation results of the CDK protein degradation activity of certain compounds according to the present invention.

[0017] Figure 2 A graph for illustrating the evaluation results of the cytotoxicity of certain compounds according to the present invention.

[0018] Figures 3 to 13 A graph summarizing the analysis results of 479 compounds synthesized according to the present invention obtained using a mass spectrometer and / or an NMR spectrometer. DETAILED DESCRIPTION

[0019] Each description and embodiment described herein can be applied to other descriptions and embodiments separately. That is, all combinations of the various elements described herein fall within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific descriptions set forth below.

[0020] In addition, those of ordinary skill in the art can recognize or identify numerous equivalents of the specific embodiments of the present invention described herein through the use of routine experimentation. In addition, these equivalents are intended to be included within the present invention.

[0021] Furthermore, throughout the specification of the present invention, when a portion is stated to "comprise" a certain component, it means that the portion may further include other components, rather than excluding all other components, unless otherwise explicitly stated.

[0022] The following description is merely illustrative and is not intended to limit the present invention, its applications, or uses.

[0023] Hereinafter, the present invention will be described in more detail.

[0024] A first aspect of the present invention provides a compound of the following formula 1 or a pharmaceutically acceptable salt thereof to achieve the above object:

[0025] [Formula 1]

[0026]

[0027] Wherein, in the above formula 1:

[0028] R 1 is C 1-10 alkyl, aryl, -C 1-3 alkyl-C 6-10 aryl, 5-10 membered heteroaryl, -C 1-3 alkyl-5-10 membered heteroaryl, C 3-10 cycloalkyl, -C 1-3 alkyl-C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl or -C 1-3 alkyl-3-10 membered heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or more selected from the group consisting of: halogen, cyano, tert-butoxycarbonyl (-Boc), amino, nitro, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, -OR a , -C(=O)R a , -C(=O)OR a , -C(O)NR a R b -SO 2 R a, -S(O)R a , -SO(N)R a , C 1-2 alkyl-C 6-10 aryl and C 6-10 aryl, wherein, R a and R b are the same or different and independently are hydrogen, halogen, amino, C 1-6 alkyl, halo-C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl;

[0029] A is a moiety that functions as an export carrier;

[0030] L is a linker; and

[0031] ELB is an E3 ubiquitin ligase binder.

[0032] For example, in Formula 1 above, ELB can have a structure represented by the following Formula 2:

[0033] [Formula 2]

[0034]

[0035] wherein, in Formula 2 above:

[0036] Cy is C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl;

[0037] k is an integer selected from 0-2;

[0038] X is N or C;

[0039] R 2 is absent, hydrogen, deuterium (D) or C 1 -C 3 alkyl; and

[0040] the aryl, heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more selected from the group consisting of: oxo, halogen, nitro, amino, hydroxy, carboxy, C 1-6 alkyl and C 1-6 alkoxy.

[0041] Specifically, Formula 2 above can have any of the following structures, but the structure is not limited thereto:

[0042]

[0043] (R 3 is hydrogen or halogen, and X2 is CH or N).

[0044] More specifically, Formula 2 above may have any of the following structures, but the structures are not limited thereto.

[0045]

[0046] For example, R in Formula 1 above 1 is C 1-6 alkyl, -C 1-3 alkyl-phenyl, phenyl, -C 1-3 alkyl-pyridyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, halogen, cyano and halo-C 1-3 alkyl, but is not limited thereto.

[0047] Specifically, R 1 may have any of the following structures, but the structures are not limited thereto:

[0048]

[0049] For example, A in Formula 1 above may have the structure of Formula 3 below, but the structure is not limited thereto.

[0050] [Formula 3]

[0051]

[0052] wherein, in Formula 3 above:

[0053] Cy 1 is unsubstituted or C 1-3 alkyl-substituted C 6-10 aryl or 5-10 membered heteroaryl;

[0054] Cy 2 is 3-10 membered heterocycloalkyl; and

[0055] L is an integer selected from 0-4, and m, n and p are independently 0 or 1, but the case where l, m, n and p are all 0 is excluded.

[0056] Specifically, A may have any of the following structures, but the structures are not limited thereto:

[0057]

[0058] For example, in Formula 1 above, the linker may be represented by -L1-L2-.

[0059] In particular, L2 may be a direct linker

[0060]

[0061] and L1 can be

[0062] In the above, q, t, v, and y can each independently be 0 or 1; r, s, u, and x can each independently be an integer selected from 0 - 6; and Cy 3 and Cy 4 can each independently be absent, a 3 - to 10 - membered heterocycloalkyl, or a C 3-10 cycloalkyl. However, they are not limited thereto.

[0063] Specifically, L1 can have any of the following structures, but the structures are not limited thereto:

[0064]

[0065] In one embodiment of the present invention, the ELB part of Formula 1 above refers to an E3 ligase ligand and degrades or inhibits CDK2 and / or CDK9 through the following steps: binding the CDK2 and / or CDK9 binder part of Formula 1 according to the present invention to CDK2 and / or CDK9 (i.e., the target protein), and then binding CDK2 and / or CDK9 to an E3 ligase (Step 1); using ubiquitin from the E2 complex formed with the E3 ligase to polyubiquitinate the lysine residues of the target protein (Step 2); and degrading the target protein via the proteasome (Step 3). The degrading agent can be recycled using the same method (Step 4).

[0066] In one embodiment of the present invention, the linker in Formula 1 above refers to a linker connecting a CDK2 and / or CDK9 inhibitor and an E3 ligase ligand compound. These linkers can be bound to the CDK2 and / or CDK9 inhibitor compound via chloride, bromide, iodide, or tosylate through an alkyl bond, or via an acid or amine through an amide bond. Such linkers can include, for example, the linkers disclosed in the existing patents US20180353501 A1, WO2019199816A1, WO2019023553A1, US20180125821A1, US20190192668A1, WO 2017197056 A1, WO 2019186358 A1, and / or WO 2018089736 A1. The disclosures in the above - mentioned existing patent applications are incorporated herein by reference in their entirety.

[0067] In a typical embodiment, the linker has a chain of 2 - 14, 15, 16, 17, 18, or 20 or more carbon atoms, and one or more of the carbon atoms may be replaced by a heteroatom such as O, N, S, or P. In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive atoms in the chain. For example, the chain may comprise one or more ethylene glycol units (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units), which may be consecutive, partially consecutive, or non - consecutive. In certain embodiments, the chain includes at least 1, 2, 3, 4, 5, 6, 7, or 8 consecutive chains, which may have branches independently being alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl, cycloalkyl, or heterocycloalkyl.

[0068] In another embodiment, the linker may comprise one or more ethylene glycols, propylene glycols, lactic acid, and / or glycolic acid, or consist of these units. Generally, propylene glycol increases hydrophobicity, while ethylene glycol increases hydrophilicity. The lactic acid fragment exhibits a longer half - life than the glycolic acid fragment. In addition to ethylene glycol and propylene glycol, block and random lactic acid - glycolic acid moieties are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half - life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties (such as alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl) as needed to achieve appropriate drug properties.

[0069] The names and chemical structural formulas of non - limiting examples of the compounds of Formula 1 according to the present invention are disclosed in Tables 1 to 14 below.

[0070] [Table 1]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] [Table 2]

[0103]

[0104]

[0105]

[0106]

[0107] [Table 3]

[0108]

[0109]

[0110]

[0111]

[0112] [Table 4]

[0113]

[0114]

[0115]

[0116]

[0117] [Table 5]

[0118]

[0119]

[0120]

[0121]

[0122] [Table 6]

[0123]

[0124]

[0125]

[0126]

[0127] [Table 7]

[0128]

[0129]

[0130]

[0131]

[0132] [Table 8]

[0133]

[0134]

[0135]

[0136]

[0137] [Table 9]

[0138]

[0139]

[0140]

[0141]

[0142] [Table 10]

[0143]

[0144]

[0145]

[0146]

[0147] [Table 11]

[0148]

[0149]

[0150]

[0151]

[0152] [Table 12]

[0153]

[0154]

[0155]

[0156]

[0157] [Table 13]

[0158]

[0159]

[0160]

[0161]

[0162] [Table 14]

[0163]

[0164]

[0165]

[0166]

[0167] Among the compounds according to the present disclosure above, compounds 25, 31, 33, 34, 35, 38, 41, 45, 74, 75, 88, 89, 90, 91, 92, 93, 96, 108, 109, 114, 115, 116, 117, 122, 123, 124, 125, 134, 135, 137, 145, 148, 149, 150, 151, 152, 153, 162, 163, 164, 165, 166, 167, 169, 170, 171, 174, 176, 178, 179, 182, 185, 189, 191, 193, 202, 204, 205, 217, 226, 236, 258, 259, 301, 307, 330, 353, 354, 378, 379, 393, 428, 429, etc. may be more preferred for the purposes of the present invention, but the compounds are not limited thereto.

[0168] The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. Useful salts include acid addition salts formed from pharmaceutically acceptable free acids. As used herein, the term "pharmaceutically acceptable salt" refers to a salt form that is relatively non-toxic and harmless to a patient at effective concentrations, and refers to any organic or inorganic addition salt, wherein the side effects of the salt do not reduce the beneficial effects of the compound represented by Formula 1.

[0169] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent (such as methanol, ethanol, acetone or acetonitrile). The compound and an equimolar amount of acid are heated in water or an alcohol (such as ethylene glycol monomethyl ether), and subsequently, the mixture can be evaporated to dryness, or the precipitated salt can be filtered off.

[0170] In particular, as free acids, organic acids and inorganic acids can be used; inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid and hydroiodic acid can be used, but the free acids are not limited thereto.

[0171] In addition, pharmaceutically acceptable metal salts can be prepared using bases. For example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salts, and evaporating and drying the filtrate, an alkali metal salt or alkaline earth metal salt is obtained. In particular, as metal salts, sodium salts, potassium salts or calcium salts are pharmaceutically suitable, but the metal salts are not limited thereto. Additionally, the corresponding silver salts can be obtained by reacting the alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

[0172] Unless otherwise indicated, the pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of formula 1 above. For example, pharmaceutically acceptable salts can include sodium salts, calcium salts and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups can include hydrobromide salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, acetate salts, succinate salts, citrate salts, tartrate salts, lactate salts, mandelate salts, mesylate salts and tosylate salts; these salts can be prepared by salt preparation methods known in the art.

[0173] Any salt of the compound of formula 1 can be used as the salt of the compound of the present invention without limitation, as long as the salt is pharmaceutically acceptable and exhibits pharmacological activity comparable to that of the compound of formula 1.

[0174] In addition, the compounds represented by formula 1 according to the present invention include not only their pharmaceutically acceptable salts, but also solvates, such as hydrates, that can be prepared therefrom, as well as all possible stereoisomers, but are not limited thereto. The solvates and stereoisomers of the compounds represented by formula 1 can be prepared from the compounds represented by formula 1 using methods known in the art.

[0175] In addition, the compounds represented by formula 1 according to the present invention can be prepared in crystalline or amorphous form, and if prepared in crystalline form, the compound can optionally be hydrated or solvated. In the present invention, in addition to the stoichiometric hydrates of the compounds represented by formula 1, compounds containing various amounts of water can also be included. The solvates of the compounds represented by formula 1 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0176] The second aspect of the present invention provides a method for preparing the compound of the first embodiment or a pharmaceutically acceptable salt thereof, which comprises the following steps: In the first step, reacting a compound of formula 4 below with a derivative of part A containing an amino group at one end and a protecting group at the other end, and deprotecting the compound to prepare a compound of formula 5; In the second step, reacting the compound of formula 5 with a derivative of part L1 containing a reactive functional group X 2 at one end and a protecting group at the other end, and deprotecting the compound to prepare a compound of formula 6; and In the third step, reacting the compound of formula 5 with a CRBN binder, the CRBN binder containing a reactive functional group X 3 .

[0177] [Formula 4]

[0178]

[0179] [Formula 5]

[0180]

[0181] [Formula 6]

[0182]

[0183] Wherein, in the above formulas 4 to 6:

[0184] X 1 、X 2 and X 3 are independently halogen or hydroxyl;

[0185] The protecting group is tert-butoxycarbonyl;

[0186] And A' and L1' can be the same as A and L1 respectively, or can be in the form of their salts.

[0187] R 1 、A and L1 not defined above are as defined in the first aspect.

[0188] Specifically, the CRBN binder can be any one selected from the group consisting of:

[0189] but not limited thereto.

[0190] For example, the first step can be carried out by: heating in a lower alcohol solvent at a temperature of 70°C - 100°C to react a compound in which X 1 is halogen; and deprotecting by treating with a strong acid solution in an organic solvent, but not limited thereto.

[0191] For example, the second step can be carried out through the following steps:

[0192] i) React a compound in which X 2 is a hydroxyl group with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in an organic solvent at a temperature of 15°C - 40°C;

[0193] ii) React a compound in which X 2 is a halogen with a base at a temperature of 40°C - 80°C under basic conditions in an organic solvent;

[0194] iii) React a compound in which X 2 is an oxo group with DIPEA and sodium triacetoxyborohydride (NaBH(OAc) 3 ) at a temperature of 15°C to 40°C; or

[0195] iv) React a compound in which X 2 is an oxo group with sodium cyanoborohydride (NaBH 3 CN) at a temperature of 15°C - 40°C in the presence of acetic acid in a lower alcohol solvent, and

[0196] deprotect the compound by treatment with a strong acid solution in an organic solvent, but not limited to this.

[0197] In addition, according to the type of linker to be introduced, the second step can be carried out in a sequential manner using two or more of the same or different reactions selected from the above four reactions, but not limited to this.

[0198] For example, the third step can be carried out through the following steps:

[0199] i) React a compound in which X3 is a hydroxyl group with EDCL, HOBt, and DIPEA in an organic solvent at a temperature of 15°C - 40°C; or

[0200] ii) React a compound in which X3 is a halogen with DIPEA in an organic solvent at a temperature of 70°C - 100°C, but not limited to this.

[0201] As described above, the reactions in each step can be carried out in a lower alcohol or an organic solvent. For example, the lower alcohol solvent refers to a C 1-4 alkyl alcohol, and can be methanol or ethanol, but not limited to this. In addition, the organic solvent can be dimethylformamide (DMF), dichloromethane (DCM), dimethyl sulfoxide (DMSO), etc., which can be used alone or in combination, but not limited to this.

[0202] As a strong acid solution, a solution containing hydrochloric acid can be used, and an alkaline condition can be achieved by using potassium carbonate (K 2 CO 3 ), but is not limited thereto.

[0203] The specific reactions for the first to third steps are merely illustrative and are not intended to limit the scope of the present invention. Any similar reactions known in the art can be used without limitation. In addition, the preparation method of the present invention may further include processes after each step, such as separation, purification, and / or washing processes, but is not limited thereto.

[0204] The third aspect of the present invention provides a composition comprising the compound of the first embodiment or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0205] The fourth aspect of the present invention provides a pharmaceutical composition for inhibiting or degrading cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 9 (CDK9), or both, comprising the compound of the first embodiment or a pharmaceutically acceptable salt thereof as an active ingredient.

[0206] The fifth aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer or HIV infection, comprising the compound of the first aspect or a pharmaceutically acceptable salt thereof as an active ingredient.

[0207] As used herein, the terms "compound of the first embodiment" and "pharmaceutically acceptable salt" are as described above.

[0208] In a specific embodiment of the present invention, the effects of degrading CDK2, CDK9, or both or inhibiting their activities have been confirmed. This finding indicates that the composition containing the compound of the present invention can effectively inhibit or degrade CDK2, CDK9, or both, and further indicates that it can be effectively used for preventing or treating diseases caused by these enzymes.

[0209] As used herein, the term "prevention" refers to any activity of inhibiting or delaying the occurrence, spread, and recurrence of cancer or viral infection by administering the composition of the present invention, and the term "treatment" refers to any active improvement or beneficial change of the disease symptoms by administering the composition of the present invention.

[0210] Diseases that can be prevented or treated by administering the pharmaceutical composition of the present invention include cancer or human immunodeficiency virus (HIV) infection. The cancer can be, for example, one or more selected from the group consisting of: pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colorectal 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, diffuse large B-cell lymphoma, hepatopancreatic ampulla, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, non-Hodgkin lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal pelvic 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, gastric cancer, gastric carcinoid, 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, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi 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 and thymic cancer. Specifically, the cancer can be prostate cancer, lymphoma (such as B-cell lymphoma, Burkitt lymphoma or follicular lymphoma), glioblastoma, neuroblastoma, ovarian cancer, hepatocellular carcinoma, liver cancer, breast cancer, leukemia (such as chronic lymphocytic leukemia (CLL) or acute myeloid leukemia), pancreatic cancer, colon cancer, lung cancer, colorectal cancer or multiple myeloma, but not limited thereto. At the same time, the HIV infection can be acquired immunodeficiency syndrome (AIDS), but not limited thereto. In addition, HIV can refer to human immunodeficiency virus-1 (HIV-1), the most common and pathogenic variant, but not limited thereto.

[0211] Preferably, based on the total weight of the composition, the pharmaceutical composition of the present invention may contain 0.1 wt% - 75 wt%, more preferably 1 wt% - 50 wt% of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0212] The composition of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into various forms by conventional methods, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., for various intended uses. The composition may be administered orally or by various routes, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Examples of suitable carriers, excipients or diluents that may be included in such a composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate and mineral oil. In addition, the composition of the present invention may further comprise fillers, anticoagulants, lubricants, humectants, fragrances, emulsifiers, preservatives, etc.

[0213] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are formulated by mixing at least one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin) in the composition. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

[0214] Examples of oral liquid preparations may include suspensions, solutions, emulsions, syrups, etc., and in addition to common simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents and preservatives may also be included.

[0215] Preparations for non-oral administration include sterile aqueous solvents, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used. As the matrix of suppositories, Witepsol, Macrogol, Tween 61, cocoa butter, lauric acid, glycerogelatin, etc. may be used. At the same time, injections may contain conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0216] The sixth aspect of the present invention provides a method for preventing or treating cancer or HIV infection, comprising administering the pharmaceutical composition of the fifth aspect to a subject in need thereof.

[0217] As used herein, the terms "compound of the first embodiment" and "pharmaceutically acceptable salt" are as described above.

[0218] As used herein, the term "subject" refers to any animal that can contract or be infected with a viral infection, including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, cats, dogs, mice, rats, rabbits, or guinea pigs. The pharmaceutical compositions of the present invention can be effectively used to prevent or treat diseases by administering them to a subject. The pharmaceutical compositions of the present invention can be administered simultaneously with existing therapeutic agents.

[0219] As used herein, the term "administer" means providing a specified substance to a patient by any suitable means, and the route of administration of the compositions of the present invention can be any general route that can reach the target tissue. It can be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, topically, intranasally, intrapulmonary, and rectally, but the route of administration is not limited thereto. In addition, the pharmaceutical compositions of the present invention can also be administered by any device capable of transporting the active substance to the target cells. The required methods of administration and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, infusion, etc. Injectables can be manufactured using aqueous solvents such as saline solutions and Ringer's solutions, and non-aqueous solvents such as vegetable oils, higher fatty acid esters (such as ethyl oleate), alcohols (such as ethanol, benzyl alcohol, propylene glycol, or glycerol). Injectables can also contain pharmaceutical carriers such as stabilizers (such as ascorbic acid, sodium metabisulfite, sodium pyrosulfite, BHA, tocopherol, or EDTA), emulsifiers, buffers for pH adjustment, and preservatives for inhibiting the growth of microorganisms (such as phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

[0220] In the present invention, the term "therapeutically effective amount" used in combination with the active ingredient refers to the amount of the triazolylmethylurea derivative compound or its pharmaceutically acceptable salt that is effective in preventing or treating the target disease.

[0221] In addition to the compounds of the present invention or their pharmaceutically acceptable salts, the pharmaceutical compositions of the present invention can also contain known drugs for preventing or treating each disease as active ingredients, depending on the type of disease to be prevented or treated. For example, when used for preventing or treating a viral infection, in addition to the compounds of the present invention or their pharmaceutically acceptable salts, known drugs can also be included, and the pharmaceutical compositions of the present invention can be used in combination with other known therapeutic agents for infections.

[0222] In particular, the compositions of the present invention are administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease and having a reasonable benefit-risk ratio applicable to medical therapy and not causing significant side effects. The effective dose level can be determined based on factors including the health condition of the patient, the type and severity of the disease, the drug activity, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the elimination rate, the duration of treatment, and the combination or simultaneous use of drugs, as well as other well-known factors in the medical field. The compositions of the present invention can be administered as a sole therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. The compositions of the present invention can be administered in single or multiple doses. Considering all the above factors, it is important to administer the minimum amount that can achieve the maximum effect without side effects. This can be easily determined by those of ordinary skill in the art.

[0223] For example, the administered dose can vary according to factors such as the route of administration, the severity of the disease, gender, body weight, and age, etc., and thus the administered dose does not limit the scope of the present invention in any way.

[0224] Specifically, the effective amount of the compound in the composition of the present invention can vary according to the age, gender, and body weight of the patient, and can be administered daily or every other day in the range of 1 mg - 100 mg per kg body weight, preferably 5 mg - 60 mg, or divided into 1 - 3 administrations per day. However, the administered dose can vary according to factors such as the route of administration, the severity of the disease, gender, body weight, and age, etc., and thus the administered dose does not limit the scope of the present invention in any way.

[0225] [Ways of Implementing the Present Invention]

[0226] Hereinafter, the present invention will be described in detail with reference to examples and the like for easy understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. The embodiments of the present invention are provided to more comprehensively describe the present invention to those of ordinary skill in the art to which the present invention pertains.

[0227] Preparation of the Compounds of the Invention

[0228] The synthetic procedures of certain compounds of the present invention are described as follows, and the compounds not mentioned below can be prepared in a similar manner by replacing the starting materials, intermediates, and / or reactants.

[0229] Certain intermediates, especially the CDK inhibitor moiety, can be prepared by the method disclosed in Korean Patent No. 1893879, the entire disclosure of which is incorporated herein by reference.

[0230] <Substance>

[0231] The structural formulas and names of the exemplary CRBN binder compounds used in the embodiments of the present invention are listed below.

[0232]

[0233] CRBN binder - 1: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine

[0234] CRBN binder - 2: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine

[0235] CRBN binder - 3: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid

[0236] CRBN binder - 4: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0237] CRBN binder - 5: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

[0238] CRBN binder - 6: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

[0239] CRBN binder - 7: 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

[0240] CRBN binder - 8: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid

[0241] CRBN binder - 9: 2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetic acid

[0242] CRBN binder - 10: 2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetic acid

[0243] CRBN binder - 11: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carboxylic acid

[0244] CRBN binder - 12: 2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetic acid

[0245] CRBN binder-13: 1-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperidine-4-carboxylic acid

[0246] Example 1: Synthesis of N-((1r,3r)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 1)

[0247]

[0248] Step 1: Synthesis of tert-butyl 4-((9-((1s,3s)-3-(6-methylpicolinamido)cyclobutyl)-9H-purin-6-yl)amino)piperidine-1-carboxylate (Intermediate A-1)

[0249] Dissolve N-((1s,3s)-3-(6-chloro-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Intermediate A, 583 mg, 1.70 mmol) in ethanol (7 mL). Then, add tert-butyl 4-aminopiperidine-1-carboxylate (680 mg, 3.40 mmol), and subsequently stir at 90 °C for 3 hours. After completion of the reaction, concentrate the reaction product under reduced pressure, and separate and purify by silica gel column chromatography to obtain the desired Intermediate A-1 (698 mg, 1.19 mmol, 81%) as a white solid.

[0250] 1 1H NMR (300 MHz, chloroform-d) δ 8.84 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.68 (d, J = 8.1 Hz, 1H), 4.79 (t, J = 8.2 Hz, 1H), 4.60 (q, J = 8.1 Hz, 1H), 4.39 (s, 1H), 4.23 - 3.98 (m, 2H), 3.26 - 3.09 (m, 2H), 3.07 - 2.89 (m, 4H), 2.64 (s, 3H), 2.18 - 2.06 (m, 2H), 1.54 (s, 2H), 1.48 (s, 9H).

[0251] Step 1-1: Synthesis of 6-methyl-N-((1s,3s)-3-(6-(piperidin-4-ylamino)-9H-purin-9-yl)cyclobutyl)picolinamide hydrochloride (Intermediate A-2)

[0252] Intermediate A-1 (100 mg, 0.43 mmol) was dissolved in DCM (2 mL). Then 4N hydrochloric acid / 1,4-diene (1.08 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the desired Intermediate A-2 (143 mg, 0.35 mmol, total weight) as a white solid.

[0253] 1 1H NMR (300 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 9.14 (d, J = 9.0 Hz, 1H), 8.46 (s, 2H), 7.97 - 7.89 (m, 2H), 7.52 (dd, J = 5.8, 3.0 Hz, 1H), 4.93 (p, J = 8.4 Hz, 1H), 4.62 - 4.49 (m, 1H), 3.57 (s, 3H), 3.35 (s, 2H), 2.97 - 2.86 (m, 4H), 2.12 - 2.04 (m, 2H), 2.00 - 1.85 (m, 2H), 1.85 - 1.73 (m, 2H).

[0254] Step 2: Synthesis of tert-butyl (6-(4-((9-((1s,3s)-3-(6-methylpyridinamido)cyclobutyl)-9H-purin-6-yl)amino)piperidin-1-yl)-6-oxohexyl)carbamate (Intermediate A-3)

[0255] Intermediate A-2 (156 mg, 0.25 mmol), 6-((tert-butoxycarbonyl)amino)hexanoic acid (82 mg, 0.25 mmol), EDCI·HCl (53 mg, 0.28 mmol), and HOBt·H 2 2O (40 mg, 0.28 mmol) were dissolved in DMF (1 mL). Then DIPEA (0.2 mL, 1.25 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, and the residue was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography to obtain the desired Intermediate A-3 (78 mg, 0.13 mmol, 51%) as a white solid.

[0256] 11H NMR (300 MHz, chloroform-d) δ 8.85 (d, J = 8.5 Hz, 1H), 8.48 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.92 (s, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.0 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.67 - 4.57 (m, 3H), 4.50 (s, 1H), 3.97 - 3.85 (m, 1H), 3.19 - 3.10 (m, 4H), 3.06 - 2.92 (m, 3H), 2.66 (s, 3H), 2.38 (t, J = 7.5 Hz, 2H), 2.23 - 2.12 (m, 2H), 1.68 - 1.65 (m, 2H), 1.56 - 1.48 (m, 4H), 1.46 (s, 9H), 1.44 - 1.38 (m, 2H), 1.32 - 1.21 (m, 2H).

[0257] Step 2-2: Synthesis of N-((1s,3s)-3-(6-((1-(6-Aminohexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide hydrochloride (Intermediate A-4)

[0258] Dissolve Intermediate A-3 (77 mg, 0.11 mmol) in DCM (2 mL). Then add 4N hydrochloric acid / 1,4-diene (0.27 mL), and subsequently stir at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain the desired Intermediate A-4 as a white solid.

[0259] 1 1H NMR (500 MHz, methanol-d 4 ) δ 8.75 (s, 1H), 8.57 - 8.41 (m, 3H), 8.00 (d, J = 8.3 Hz, 1H), 5.14 - 5.01 (m, 1H), 4.68 - 4.57 (m, 1H), 3.63 - 3.57 (m, 1H), 3.28 (s, 2H), 3.22 (t, J = 8.5 Hz, 2H), 3.20 - 3.14 (m, 2H), 3.09 - 3.01 (m, 3H), 2.98 (t, J = 7.7 Hz, 2H), 2.88 (s, 3H), 2.47 - 2.36 (m, 2H), 2.24 - 2.16 (m, 2H), 1.88 (s, 2H), 1.77 - 1.69 (m, 2H), 1.62 (s, 2H).

[0260] ​Step 3: Synthesis of N-((1r,3r)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 1)

[0261] Dissolve intermediate A-4 (10 mg, 0.019 mmol), (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (6 mg, 0.019 mmol), EDCI.HCl (4 mg, 0.021 mmol) and HOBt.H 2 O (3 mg, 0.021 mmol) in DMF (1 mL). Then add DIPEA (0.02 mL, 0.095 mmol), and subsequently stir at room temperature for 12 hours. Dilute the reaction mixture with water and then extract with ethyl acetate. Wash the organic layer with brine, and dry and filter the residue over anhydrous magnesium sulfate. Concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography to obtain the desired compound 1 as a yellow solid (6.6 mg, 41%).

[0262] Example 2: Synthesis of N-((1r,3r)-3-(6-(((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 2)

[0263]

[0264] Compound 2 was synthesized in a similar manner to Example 1, except that (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (CRBN binder 2) was used instead of CRBN binder 1.

[0265] Example 3: Synthesis of N-((1r,3r)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 3)

[0266]

[0267] Compound 3 was synthesized in a similar manner to Example 1, except that 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (CRBN binder 3) was used instead of CRBN binder 1.

[0268] Example 4: Synthesis of N-((1r,3r)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 4)

[0269]

[0270] Compound 4 was synthesized in a similar manner to Example 1, except that 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (CRBN binder 4) was used instead of CRBN binder 1.

[0271] Example 5: Synthesis of N-((1r,3r)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 5)

[0272]

[0273] Intermediate A-4 (40 mg, 0.08 mmol) was dissolved in DMSO (1 mL). Then 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (22 mg, 0.08 mmol) and DIPEA (0.04 mL, 0.23 mmol) were added, and the mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, and the residue was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and then separated and purified by silica gel column chromatography to obtain the desired Compound 5 (6.7 mg, 11%) as a yellow solid.

[0274] Example 6: Synthesis of N-((1r,3r)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide (Compound 6)

[0275]

[0276] Compound 6 was synthesized in a similar manner to Compound 5, except that 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (CRBN binder 6) was used instead of CRBN binder 5.

[0277] Compounds 7 to 153 were synthesized using the corresponding linkers in the same or a similar manner as in Examples 1 to 6 above. Hereinafter, the synthesis methods of the intermediates and compounds used additionally are described exemplarily, and other compounds for which specific methods are not provided were synthesized using the corresponding intermediates and appropriate reactions.

[0278] Example 7: Synthesis of N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 154)

[0279]

[0280] Step 1: Synthesis of (1s,3s)-3-(6-chloro-9H-purin-9-yl)cyclobutan-1-amine hydrochloride (Intermediate B-1)

[0281] Intermediate B (tert-butyl (1s,3s)-3-(6-chloro-9H-purin-9-yl)cyclobutylcarbamate; 5.7 g, 17.6 mmol) was dissolved in DCM (20 mL). Then 4N hydrochloric acid / 1,4-di ene (53 mmol) was added, and the mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the desired Intermediate B-1 (3.9 g) as a white solid.

[0282] 1H H NMR (300 MHz, DMSO) δ 9.21 (s, 1H), 8.79 (s, 1H), 8.57 (s, 3H), 5.04 (p, J = 8.5 Hz, 1H), 3.80 - 3.62 (m, 1H), 3.42 - 2.85 (m, 4H).

[0283] Step 2: Synthesis of N-((1s,3s)-3-(6-chloro-9H-purin-9-yl)cyclobutyl)acetamide (Intermediate B-2)

[0284] Intermediate B-1 (650 mg, 2.4988 mmol) was dissolved in DCM (10 mL). Then TEA (1.044 mL) was added, followed by acetic anhydride (0.354 mL), and then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, and the residue was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and then separated and purified by silica gel column chromatography to obtain the desired intermediate B-2 (170 mg, 22%).

[0285] 1 H NMR (500 MHz, chloroform-d) δ 8.78 (s, 1H), 8.25 (s, 1H), 6.34 (d, J = 8.2 Hz, 1H), 4.85 - 4.76 (m, 1H), 4.50 - 4.40 (m, 1H), 3.15 - 3.08 (m, 2H), 2.96 - 2.89 (m, 2H), 2.07 (s, 3H).

[0286] Step 3: Synthesis of tert-butyl 4-(((9-((1s,3s)-3-acetamidocyclobutyl)-9H-purin-6-yl)amino)methyl)piperidine-1-carboxylate (Intermediate B-3)

[0287] The reaction was carried out in a similar manner to Step 1 of Example 1 above, except that Intermediate B-2 (170 mg, 0.6398 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (136 mg, 0.9597 mmol) were used as reactants. The reaction mixture was separated and purified to obtain the desired Intermediate B-3 (256 mg, 90%) as a white solid.

[0288] 1 H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 7.76 (s, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.85 (s, 1H), 4.73 - 4.63 (m, 1H), 4.53 - 4.42 (m, 1H), 4.15 (s, 2H), 3.59 (s, 2H), 3.54 - 3.50 (m, 1H), 3.13 - 3.05 (m, 2H), 2.91 - 2.83 (m, 2H), 2.72 (s, 2H), 2.07 (s, 3H), 1.83 - 1.78 (m, 2H), 1.47 (s, 9H), 1.30 - 1.20 (m, 2H).

[0289] Step 4: Synthesis of N-((1s,3s)-3-(6-((piperidin-4-ylmethyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate B-4)

[0290] The reaction was carried out in a manner similar to Step 1-1 of Example 1 above, except that intermediate B-3 (250 mg, 0.5636 mmol) was used as the reactant, to obtain the desired intermediate B-4 (214 mg) as a white solid.

[0291] 1 H NMR (500 MHz, methanol-d 4 ) δ 8.54 (d, J = 4.3 Hz, 1H), 8.44 (d, J = 13.8 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.19 - 4.13 (m, 1H), 3.64 - 3.58 (m, 1H), 3.51 - 3.44 (m, 2H), 3.10 - 3.01 (m, 4H), 2.84 - 2.75 (m, 2H), 2.16 - 2.09 (m, 2H), 2.03 (s, 3H), 1.63 - 1.62 (m, 3H), 1.62 - 1.57 (m, 1H).

[0292] Step 5: Synthesis of tert-butyl 4-((4-(((9-((1s,3s)-3-acetamidocyclobutyl)-9H-purin-6-yl)amino)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (intermediate B-5)

[0293] Intermediate B-4 (210 mg, 0.5527 mmol) was dissolved in DCM (20 mL). Then DIPEA (144 μL) and tert-butyl 4-formylpiperidine-1-carboxylate (188 mg, 0.8291 mmol) were added, and then stirred. Then NaBH(OAC) 3 (152 mg, 0.7185 mmol) was added, and the mixture was then stirred at room temperature overnight. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the reaction mixture was separated and purified by silica gel column chromatography to obtain the desired intermediate B-5 (0.264 g).

[0294] 11H NMR (500 MHz, methanol-d4) δ 8.26 (d, J = 8.5 Hz, 2H), 4.83 - 4.74 (m, 1H), 4.33 - 4.24 (m, 1H), 4.08 (d, J = 13.2 Hz, 2H), 3.79 - 3.71 (m, 1H), 3.60 - 3.51 (m, 2H), 3.46 (d, J = 12.0 Hz, 2H), 3.28 - 3.21 (m, 1H), 3.02 - 2.94 (m, 2H), 2.82 (d, J = 6.9 Hz, 2H), 2.80 - 2.68 (m, 5H), 2.00 (s, 3H), 1.98 (s, 1H), 1.94 (s, 2H), 1.85 - 1.78 (m, 2H), 1.72 - 1.61 (m, 2H), 1.44 (s, 9H), 1.21 - 1.11 (m, 2H).

[0295] Step 6: Synthesis of N-((1s,3s)-3-(6-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate B-6)

[0296] The reaction was carried out in a manner similar to Step 2-1 of Example 1 above, except that Intermediate B-5 (260 mg, 0.48 mmol) was used as the reactant, to obtain the desired Intermediate B-6 (211 mg) as a white solid.

[0297] 1 1H NMR (500 MHz, methanol-d4) δ 8.52 (s, 1H), 8.44 (d, J = 13.9 Hz, 1H), 4.31 - 4.22 (m, 1H), 3.78 - 3.71 (m, 2H), 3.61 (d, J = 6.7 Hz, 1H), 3.46 (d, J = 12.8 Hz, 2H), 3.16 - 3.00 (m, 8H), 2.81 - 2.73 (m, 2H), 2.32 (s, 1H), 2.15 (d, J = 15.0 Hz, 4H), 2.01 (s, 3H), 1.90 - 1.80 (m, 2H), 1.62 (s, 2H), 1.61 - 1.52 (m, 2H), 1.42 - 1.38 (m, 1H).

[0298] Step 7: Synthesis of N-((1s,3s)-3-(6-(((1-((1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 154)

[0299] The reaction was carried out in a similar manner to Step 3 of Example 1 above, except that intermediate B-6 (20 mg, 0.0419 mmol) and a CRBN binder (16 mg, 0.0503 mmol) were used as reactants. The reaction mixture was separated and purified to give the desired compound 154 (6 mg, 20%) as a white solid.

[0300] Example 8: Synthesis of N-((1s,3s)-3-(6-(((1-((1-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 155)

[0301]

[0302] Compound 155 was synthesized in a similar manner to Compound 154, except that CRBN binder 4 was used instead of CRBN binder 3.

[0303] Example 9: Synthesis of N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 156)

[0304]

[0305] Compound 156 was synthesized in a similar manner to Compound 154, except that CRBN binder 1 was used instead of CRBN binder 3.

[0306] Example 10: Synthesis of N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 157)

[0307]

[0308] Compound 157 was synthesized in a similar manner to Compound 154, except that CRBN binder 2 was used instead of CRBN binder 3.

[0309] Synthesis of N-((1S,3S)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 158) in Example 11

[0310]

[0311] Compound 158 was synthesized in a similar manner to Example 5, except that Intermediate B-6 was used instead of Intermediate A-4.

[0312] Synthesis of N-((1S,3S)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide (Compound 159) in Example 12

[0313]

[0314] Compound 159 was synthesized in a similar manner to Compound 154, except that CRBN binder 6 was used instead of CRBN binder 3.

[0315] Compounds 160 to 185 were synthesized in the same or similar manner as Compounds 155 to 160 above, using the corresponding linkers.

[0316] Preparation Example 1: Synthesis of 2-phenyl-N-((1S,3S)-3-(6-((4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate C-6)

[0317]

[0318] Step 1: Synthesis of N-((1S,3S)-3-(6-chloro-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide (Intermediate C-2)

[0319] Intermediate B-1 (500 mg, 1.92 mmol) was dissolved in dichloroethane (15 mL). Then, 2-phenylacetyl chloride (508 μL, 3.84 mmol) and DIPEA (1.4 mL, 7.68 mmol) were added, and the mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, and the residue was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and then separated and purified by silica gel column chromatography to obtain the desired intermediate C-2 (265 mg, 40%).

[0320] 1 H NMR (500 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.18 (s, 1H), 7.50 - 7.32 (m, 5H), 6.34 - 6.19 (m, 1H), 4.78 (p, J = 8.3 Hz, 1H), 4.48 (q, J = 8.2 Hz, 1H), 3.67 (s, 2H), 3.11 (m, 2H), 2.81 (m, 2H).

[0321] Step 2: Synthesis of tert-butyl 4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazine-1-carboxylate (Intermediate C-3)

[0322] The reaction was carried out in a similar manner to Step 1 of Example 1 above, except that intermediate C-2 (750 mg, 2.194 mmol) and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.1 g, 3.949 mmol) were used as reactants. The reaction mixture was separated and purified to obtain the desired intermediate C-3 (1.0 g) as an off-white solid.

[0323] 1 H NMR (500 MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.78 (s, 1H), 7.71 - 7.54 (m, 3H), 7.42 - 7.37 (m, 5H), 7.01 - 6.92 (m, 2H), 6.69 (d, J = 8.6 Hz, 1H), 4.66 (p, J = 8.1 Hz, 1H), 4.46 (h, J = 8.1 Hz, 1H), 3.63 (s, 2H), 3.59 (t, J = 5.2 Hz, 4H), 3.11 (t, J = 5.2 Hz, 4H), 3.09 - 3.00 (m, 2H), 2.84 - 2.72 (m, 2H), 1.49 (s, 9H).

[0324] Step 3: Synthesis of 2-phenyl-N-((1s,3s)-3-(6-((4-(piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate C-4)

[0325] The reaction was carried out in a similar manner to Step 1-1 of Example 1 above, except that Intermediate C-3 (1.0 g, 1.71 mmol) was used as the reactant, to obtain the desired Intermediate C-4 (850 mg) as a light green solid.

[0326] 1 H NMR (500 MHz, CD3OD) δ 8.58 (s, 1H), 8.29 (s, 1H), 7.49 - 7.43 (m, 2H), 7.34 (m, 4H), 7.30 - 7.24 (m, 3H), 4.99 - 4.93 (m, 1H), 4.36 - 4.21 (m, 1H), 3.56 (m, 6H), 3.44 (m, 4H), 3.05 (m, 2H), 2.80 (m, 2H).

[0327] Step 4: Synthesis of tert-butyl 4-((4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Intermediate C-5)

[0328] Intermediate C-4 (100 mg, 0.192 mmol) was dissolved in DCM (10 mL). Then DIPEA (100 μL, 0.576 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (82 mg, 0.385 mmol) were added, and then stirred. Then NaBH(OAC) 3 (142 mg, 0.672 mmol) was added, and then stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the reaction mixture was separated and purified by silica gel column chromatography to obtain the desired Intermediate C-5 (90 mg).

[0329] 11H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.70 - 7.56 (m, 2H), 7.41 - 7.18 (m, 5H), 7.10 - 6.96 (m, 2H), 4.81 (q, J = 8.5 Hz, 1H), 4.31 (p, J = 8.2 Hz, 1H), 4.09 (d, J = 13.1 Hz, 2H), 3.55 (s, 2H), 3.21 (t, J = 5.0 Hz, 4H), 3.00 (m, 2H), 2.76 (m, 2H), 2.65 (t, J = 5.1 Hz, 4H), 2.31 (d, J = 6.6 Hz, 2H), 1.81 (d, J = 12.1 Hz, 3H), 1.48 (s, 9H), 1.21 - 1.01 (m, 1H).

[0330] Step 5: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (piperidin - 4 - ylmethyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 6)

[0331] The reaction was carried out in a similar manner to Step 2 - 1 of Example 1 above, except that Intermediate C - 5 (90 mg, 0.132 mmol) was used as the reactant, to obtain the desired Intermediate C - 6 (75 mg) as a white solid.

[0332] 1 1H NMR (500 MHz, CD3OD) δ 8.59 (s, 1H), 8.30 (s, 1H), 7.54 - 7.42 (m, 2H), 7.36 - 7.33 (m, 4H), 7.31 - 7.23 (m, 3H), 4.99 - 4.94 (m, 1H), 4.34 - 4.24 (m, 1H), 3.99 (d, J = 13.0 Hz, 2H), 3.83 (d, J = 11.7 Hz, 2H), 3.56 (s, 2H), 3.52 - 3.36 (m, 6H), 3.28 (d, J = 6.7 Hz, 2H), 3.13 (m, 2H), 3.09 - 3.01 (m, 2H), 2.81 (m, 2H), 2.45 - 2.35 (m, 1H), 2.21 (d, J = 13.8 Hz, 2H), 1.70 - 1.58 (m, 2H).

[0333] Preparation Example 2: Synthesis of N - ((1s,3s) - 3 - (6 - ((4 - (4 - (7 - azaspiro[3.5]nonan - 2 - yl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl) - 2 - phenylacetamide hydrochloride (Intermediate C - 8)

[0334]

[0335] Step 1: Synthesis of tert-butyl 2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate C-7)

[0336] Intermediate C-7 was synthesized in a similar manner to Step 4 of Preparation Example 1 above.

[0337] 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.34 - 7.20 (m, 5H), 6.91 (d, J = 9.0 Hz, 2H), 4.76 (p, J = 8.6 Hz, 1H), 4.16 (h, J = 8.2 Hz, 1H), 3.43 (s, 2H), 3.29 (t, J = 5.7 Hz, 2H), 3.20 (m, 2H), 3.09 (m, 4H), 2.85 (m, 2H), 2.71 (t, J = 7.7 Hz, 1H), 2.67 - 2.57 (m, 2H), 2.38 (m, 4H), 1.98 (t, J = 9.4 Hz, 2H), 1.57 (t, J = 9.9 Hz, 2H), 1.49 (t, J = 5.6 Hz, 2H).

[0338] Step 2: Synthesis of N-((1s,3s)-3-(6-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-8)

[0339] Intermediate C-7 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0340] 1 H NMR (500 MHz, DMSO-d 6)δ 11.71 (s, 1H), 10.33 (s, 1H), 8.79 (s, 2H), 8.68 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.35 - 7.28 (m, 4H), 7.24 (t, J = 6.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.80 (p, J = 8.5 Hz, 1H), 4.17 (h, J = 8.1 Hz, 1H), 3.81 (d, J = 12.9 Hz, 4H), 3.44 (s, 3H), 3.41 (m, 1H), 3.18 (t, J = 12.4 Hz, 2H), 3.08 - 2.93 (m, 6H), 2.92 - 2.83 (m, 2H), 2.65 (m, 2H), 2.34 (m, 2H), 2.22 (t, J = 10.1 Hz, 2H), 1.82 (t, J = 5.7 Hz, 2H), 1.75 (t, J = 5.7 Hz, 2H).

[0341] Preparation Example 3: Synthesis of 2-Phenyl-N-((1s,3s)-3-(6-((4-(4-(2-(piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide Hydrochloride (Intermediate C-10)

[0342]

[0343] Step 1: Synthesis of tert-Butyl 4-(2-oxo-2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (Intermediate C-9) The reaction was carried out in a similar manner to Step 2-1 of Example 1 above, except that Intermediate C-4 (100 mg, 0.192 mmol) and 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (56 mg, 0.231 mmol) were used as reactants. The reaction mixture was separated and purified to obtain the desired Intermediate C-9 (105 mg, 79%) as a white solid.

[0344] 11H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.67 (d, J = 9.0 Hz, 2H), 7.34 (m, 4H), 7.31 - 7.22 (m, 1H), 7.11 - 7.03 (m, 2H), 4.83 (m, 1H), 4.31 (m, 1H), 4.09 (d, J = 13.2 Hz, 2H), 3.77 (m, 4H), 3.55 (s, 2H), 3.18 (dt, J = 16.0, 5.2 Hz, 4H), 3.01 (m, 2H), 2.77 (m, 2H), 2.42 (d, J = 7.0 Hz, 2H), 2.00 (m, 1H), 1.82 - 1.70 (m, 2H), 1.47 (s, 9H), 1.19 (m, 2H).

[0345] Step 2: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (2 - (piperidin - 4 - yl)acetyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 10)

[0346] Intermediate C - 7 was synthesized in a manner similar to Step 5 of Preparation Example 1 above.

[0347] 1 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.36 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.34 (m, 4H), 7.30 - 7.24 (m, 1H), 4.98 - 4.93 (m, 1H), 4.28 (m, 1H), 3.91 (m, 4H), 3.54 (m, 4H), 3.48 (t, J = 5.1 Hz, 1H), 3.42 (m, 2H), 3.12 - 2.99 (m, 4H), 2.80 (m, 2H), 2.53 (d, J = 6.8 Hz, 2H), 2.24 - 2.13 (m, 1H), 2.06 (d, J = 14.0 Hz, 2H), 1.61 - 1.45 (m, 2H).

[0348] Preparation Example 4: Synthesis of N - ((1s,3s) - 3 - (6 - ((4 - (4 - (((1r,4r) - 4 - (aminomethyl)cyclohexyl)methyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl) - 2 - phenylacetamide hydrochloride (Intermediate C - 12)

[0349]

[0350] Step 1: Synthesis of tert-butyl (((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)carbamate (Intermediate C-11)

[0351] Dissolve Intermediate C-4 (30 mg, 0.0577 mmol) in DMF (5 mL). Then add tert-butyl (((1r,4r)-4-(iodomethyl)cyclohexyl)methyl)carbamate (24 mg, 0.0693 mmol) and potassium carbonate (20 mg, 0.144 mmol), and then stir at 70 °C for 12 h. Dilute the reaction mixture with water and then extract with ethyl acetate. Wash the organic layer with brine, and dry and filter the residue over anhydrous magnesium sulfate. Concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography to obtain the desired Intermediate C-11 as a white solid (17 mg, 34%).

[0352] 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 7.83 (s, 1H), 7.70 - 7.60 (m, 3H), 7.46 - 7.31 (m, 5H), 6.97 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 1H), 4.67 (m, 2H), 4.47 (p, J = 8.1 Hz, 1H), 3.64 (s, 2H), 3.42 (m, 3H), 3.17 - 2.73 (m, 10H), 2.52 (s, 2H), 2.02 (m, 3H), 1.87 - 1.56 (m, 4H), 1.46 (s, 9H), 1.16 - 0.85 (m, 4H).

[0353] Step 2: Synthesis of N-((1s,3s)-3-(6-((4-(4-(((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-12)

[0354] Synthesize Intermediate C-7 in a manner similar to Step 5 of Preparation Example 1 above.

[0355] 11H NMR (500 MHz, CD3OD) δ 8.57 (s, 1H), 8.29 (m, 1H), 7.55 - 7.23 (m, 9H), 4.28 (m, 1H), 3.98 (d, J = 10.3 Hz, 2H), 3.84 - 3.59 (m, 5H), 3.55 (s, 2H), 3.41 (m, 3H), 3.17 (d, J = 6.8 Hz, 2H), 3.05 (m, 2H), 2.82 (m, 4H), 2.00 (m, 4H), 1.69 (m, 1H), 1.26 (m, 5H).

[0356] Preparation Example 5: Synthesis of 6-methyl-N-((1s,3s)-3-(6-((3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide hydrochloride (Intermediate D-4)

[0357]

[0358] Step 1: Synthesis of tert-butyl 4-(3-((9-((1s,3s)-3-(6-methylpicolinamido)cyclobutyl)-9H-purin-6-yl)amino)propyl)piperazine-1-carboxylate (Intermediate D-1)

[0359] The reaction was carried out in a similar manner to Step 1 of Example 1 above, except that tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate was used as the reactant to obtain the desired Intermediate D-1.

[0360] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 8.6 Hz, 1H), 8.37 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.80 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.00 (s, 1H), 4.71 (p, J = 8.3 Hz, 1H), 4.53 (h, J = 8.2 Hz, 1H), 3.67 (m, 2H), 3.52 (t, J = 5.1 Hz, 4H), 3.18 - 3.03 (m, 2H), 2.88 (m, 2H), 2.57 (m, 5H), 2.51 - 2.38 (m, 4H), 1.87 (p, J = 6.5 Hz, 2H), 1.40 (s, 9H).

[0361] Step 2: Synthesis of 6-methyl-N-((1s,3s)-3-(6-((3-(piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide (Intermediate D-2)

[0362] Intermediate D-2 was synthesized in a similar manner to Step 1-1 of Example 1 above.

[0363] 1H NMR (300 MHz, CD3OD) δ 8.33 (s, 1H), 8.29 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.46 (dd, J = 7.6, 1.2 Hz, 1H), 4.88 (m, 1H), 4.61 (p, J = 8.2 Hz, 1H), 3.68 (m, 2H), 3.15 - 3.03 (m, 2H), 2.98 (m, 2H), 2.89 (t, J = 5.0 Hz, 4H), 2.66 (s, 3H), 2.61 - 2.41 (m, 6H), 1.93 (p, J = 6.9 Hz, 2H).

[0364] Step 3: Synthesis of tert-butyl 4 - ((4-(3 - ((9 - ((1s,3s)-3-(6 - methylpyridinecarboxamido)cyclobutyl)-9H - purin - 6 - yl)amino)propyl)piperazin - 1 - yl)methyl)piperidine - 1 - carboxylate (Intermediate D-3)

[0365] Intermediate D-2 (150 mg, 0.333 mmol) was dissolved in methanol (25 mL). Then tert-butyl 4 - formylpiperidine - 1 - carboxylate (106 mg, 0.50 mmol) and acetic acid (0.5 mL) were added, and then stirred for 30 minutes. Then NaBH 3 CN (125 mg, 1.98 mmol) was slowly added to the reaction solution, and then stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography to obtain the desired Intermediate D-3 (138 mg, 90%) as a white solid (138 mg, 90% yield).

[0366] 1 1H NMR (500 MHz, CD3OD) δ 8.34 (s, 1H), 8.30 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 4.89 (m, 1H), 4.61 (m, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.67 (m, 2H), 3.14 - 3.05 (m, 3H), 2.97 (m, 3H), 2.62 (m, 14H), 2.25 (d, J = 6.5 Hz, 2H), 1.94 (m, 2H), 1.77 (d, J = 12.2 Hz, 3H), 1.47 (s, 9H), 1.15 - 0.99 (m, 2H).

[0367] Step 4: Synthesis of 6-methyl-N-((1s,3s)-3-(6-((3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide hydrochloride (Intermediate D-4)

[0368] Intermediate D-4 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0369] 1 H NMR (500 MHz, CD3OD) δ 8.88 (s, 0.5H), 8.73 (s, 0.5H), 8.64 - 8.43 (m, 3H), 8.07 (d, J = 7.8 Hz, 1H), 5.17 - 5.01 (m, 1H), 4.64 (m, 1H), 4.29 (m, 1H), 3.84 (m, 9H), 3.58 - 3.42 (m, 4H), 3.21 - 3.02 (m, 6H), 2.91 (s, 3H), 2.37 (m, 3H), 2.24 (d, J = 14.2 Hz, 2H), 1.59 (m, 2H).

[0370] Preparation Example 6: Synthesis of 2-phenyl-N-((1s,3s)-3-(6-((4-(4-(3-(piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate C-14)

[0371]

[0372] Step 1: Synthesis of tert-butyl 4-(3-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)propyl)piperazine-1-carboxylate (Intermediate C-13)

[0373] Intermediate C-13 was synthesized in a similar manner to Step 1 of Preparation Example 4 above.

[0374] 11H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.38 - 7.19 (m, 5H), 7.13 - 6.97 (m, 2H), 4.81 (q, J = 8.6 Hz, 1H), 4.31 (p, J = 8.2 Hz, 1H), 3.55 (s, 2H), 3.47 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 5.0 Hz, 4H), 3.06 - 2.94 (m, 2H), 2.84 - 2.64 (m, 6H), 2.47 (m, 8H), 1.80 (m, 2H), 1.48 (s, 9H).

[0375] Step 2: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (3 - (piperazin - 1 - yl)propyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 14)

[0376] Intermediate C - 14 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0377] 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.29 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.33 (m, 4H), 7.27 (m, 3H), 5.00 - 4.93 (m, 1H), 4.28 (m, 1H), 4.02 (s, 3H), 3.87 - 3.65 (m, 14H), 3.62 - 3.58 (m, 2H), 3.55 (s, 2H), 3.47 (m, 5H), 3.05 (m, 2H), 2.80 (m, 2H), 2.55 - 2.37 (m, 2H).

[0378] Preparation Example 7: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (2 - (piperidin - 4 - yloxy)ethyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 16)

[0379]

[0380] Step 1: Synthesis of tert - butyl 4 - (2 - (4 - (4 - ((9 - ((1s,3s) - 3 - (2 - phenylacetamido)cyclobutyl) - 9H - purin - 6 - yl)amino)phenyl)piperazin - 1 - yl)ethoxy)piperidine - 1 - carboxylate (Intermediate C - 15)

[0381] Intermediate C - 13 was synthesized in a similar manner to Step 1 of Preparation Example 4 above.

[0382] 1 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.41 - 7.23 (m, 5H), 7.04 (d, J = 9.1 Hz, 2H), 4.82 (m, 1H), 4.31 (m, 1H), 3.83 - 3.67 (m, 6H), 3.55 (s, 3H), 3.23 (t, J = 5.1 Hz, 4H), 3.17 (m, 2H), 3.07 - 2.92 (m, 2H), 2.82 - 2.65 (m, 8H), 1.95 - 1.82 (m, 2H), 1.54 (m, 2H), 1.48 (s, H).

[0383] Step 2: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (2 - (piperidin - 4 - yloxy)ethyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 16)

[0384] Intermediate C - 14 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0385] 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.29 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.33 (m, 4H), 7.28 - 7.22 (m, 3H), 4.95 (q, J = 8.2, 7.7 Hz, 1H), 4.28 (h, J = 7.8, 7.4 Hz, 1H), 3.99 (t, J = 5.0 Hz, 4H), 3.89 - 3.74 (m, 4H), 3.69 (m, 1H), 3.55 (m, 4H), 3.48 - 3.38 (m, 5H), 3.16 (m, 2H), 3.09 - 2.98 (m, 2H), 2.79 (m, 2H), 2.12 (m, 2H), 1.99 (m, 2H).

[0386] Preparation Example 8: Synthesis of 2 - phenyl - N - ((1s,3s) - 3 - (6 - ((4 - (4 - (3 - (piperidin - 4 - yl)propyl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl)acetamide hydrochloride (Intermediate C - 18)

[0387]

[0388] Step 1: Synthesis of tert-butyl 4-(3-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)propyl)piperidine-1-carboxylate (Intermediate C-17)

[0389] Intermediate C-17 was synthesized in a similar manner to Step 1 of Preparation Example 4 above.

[0390] 1H NMR (300 MHz, CD3OD) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.34 (m, 4H), 7.31 - 7.22 (m, 1H), 7.05 (d, J = 9.1 Hz, 2H), 4.81 (q, J = 8.1 Hz, 1H), 4.29 (q, J = 8.2 Hz, 1H), 4.08 (d, J = 12.9 Hz, 2H), 3.55 (s, 2H), 3.24 (t, J = 5.0 Hz, 4H), 3.01 (m, 2H), 2.86 - 2.67 (m, 8H), 2.53 - 2.43 (m, 2H), 1.74 (d, J = 13.0 Hz, 2H), 1.68 - 1.57 (m, 3H), 1.47 (s, 8H), 1.31 (m, 2H), 1.09 (m, 2H).

[0391] Step 2: Synthesis of 2-phenyl-N-((1s,3s)-3-(6-((4-(4-(3-(piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate C-18)

[0392] Intermediate C-18 was synthesized in a similar manner to Step 1 of Preparation Example 4 above.

[0393] 1 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.30 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.33 (m, 4H), 7.27 (m, 3H), 4.95 (m, 1H), 4.29 (p, J = 8.2 Hz, 1H), 4.00 (d, J = 9.7 Hz, 2H), 3.76 (m, 3H), 3.69 (m, 1H), 3.64 - 3.58 (m, 1H), 3.56 (s, 2H), 3.43 (d, J = 12.9 Hz, 2H), 3.31 (m, 1H), 3.26 (m, 2H), 3.09 - 2.97 (m, 4H), 2.80 (m, 2H), 2.03 (d, J = 14.1 Hz, 2H), 1.93 (m, 2H), 1.73 (m, 1H), 1.47 (m, 4H).

[0394] Preparation Example 9: Synthesis of N-((1s,3s)-3-(6-((4-(4-(6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-20)

[0395]

[0396] Step 1: Synthesis of tert-butyl 2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate (Intermediate C-19)

[0397] Intermediate C-19 was synthesized in a similar manner to Step 2 of Preparation Example 5 above.

[0398] 1 H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.34 (m, 4H), 7.27 (m, 1H), 7.04 (d, J = 8.7 Hz, 2H), 4.81 (m, 1H), 4.31 (p, J = 8.2 Hz, 1H), 3.55 (s, 2H), 3.37 (m, 3H), 3.24 (m, 5H), 3.07 - 2.95 (m, 2H), 2.87 (m, 1H), 2.77 (m, 2H), 2.59 (t, J = 4.9 Hz, 4H), 2.16 (m, 2H), 1.98 (m, 3H), 1.89 (m, 1H), 1.48 (m, 9H).

[0399] Step 2: Synthesis of N-((1s,3s)-3-(6-((4-(4-(6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-20)

[0400] Intermediate C-20 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0401] 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.29 (s, 1H), 7.48 - 7.42 (m, 2H), 7.33 (m, 4H), 7.27 (d, J = 9.0 Hz, 2H), 5.00 - 4.92 (m, 1H), 4.28 (p, J = 8.2 Hz, 1H), 4.07 - 3.86 (m, 4H), 3.62 (m, 2H), 3.55 (s, 2H), 3.42 - 3.35 (m, 4H), 3.16 (t, J = 11.8 Hz, 2H), 3.09 - 2.99 (m, 2H), 2.83 - 2.59 (m, 5H), 2.54 (t, J = 10.1 Hz, 1H), 2.21 (q, J = 7.2 Hz, 2H).

[0402] Preparation Example 10: Synthesis of N-((1s,3s)-3-(6-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-24)

[0403]

[0404] Step 1: Synthesis of tert-butyl 2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate C-21)

[0405] Intermediate C-21 was synthesized in a similar manner to Step 2 of Preparation Example 5 above.

[0406] 1 1H NMR (500 MHz, DMSO-d 6)δ 9.65 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.34 - 7.20 (m, 5H), 6.91 (d, J = 9.0 Hz, 2H), 4.76 (p, J = 8.6 Hz, 1H), 4.16 (h, J = 8.2 Hz, 1H), 3.43 (s, 2H), 3.29 (t, J = 5.7 Hz, 2H), 3.20 (m, 2H), 3.09 (m, 4H), 2.85 (m, 2H), 2.71 (t, J = 7.7 Hz, 1H), 2.67 - 2.57 (m, 2H), 2.38 (m, 4H), 1.98 (t, J = 9.4 Hz, 2H), 1.57 (t, J = 9.9 Hz, 2H), 1.49 (t, J = 5.6 Hz, 2H).

[0407] Step 2: Synthesis of N - ((1s,3s) - 3 - (6 - ((4 - (4 - (7 - azaspiro[3.5]nonan - 2 - yl)piperazin - 1 - yl)phenyl)amino) - 9H - purin - 9 - yl)cyclobutyl) - 2 - phenylacetamide hydrochloride (Intermediate C - 22)

[0408] Intermediate C - 22 was synthesized in a manner similar to Step 5 of Preparation Example 1 above.

[0409] 1 H NMR (500 MHz, DMSO - d 6 )δ 11.71 (s, 1H), 10.33 (s, 1H), 8.79 (s, 2H), 8.68 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.35 - 7.28 (m, 4H), 7.24 (t, J = 6.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.80 (p, J = 8.5 Hz, 1H), 4.17 (h, J = 8.1 Hz, 1H), 3.81 (d, J = 12.9 Hz, 4H), 3.44 (s, 3H), 3.41 (m, 1H), 3.18 (t, J = 12.4 Hz, 2H), 3.08 - 2.93 (m, 6H), 2.92 - 2.83 (m, 2H), 2.65 (m, 2H), 2.34 (m, 2H), 2.22 (t, J = 10.1 Hz, 2H), 1.82 (t, J = 5.7 Hz, 2H), 1.75 (t, J = 5.7 Hz, 2H).

[0410] Step 3: Synthesis of tert-Butyl 3-(2-(4-(4-((9-((1s,3s)-3-(2-Phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidine-1-carboxylate (Intermediate C-23)

[0411] Intermediate C-23 was synthesized in a similar manner to Step 4 of Preparation Example 1 above.

[0412] 1 H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.40 - 7.18 (m, 5H), 7.04 (d, J = 8.8 Hz, 2H), 4.81 (q, J = 8.3 Hz, 1H), 4.31 (m, 1H), 3.97 (m, 2H), 3.78 (m, 2H), 3.55 (s, 2H), 3.24 (m, 4H), 3.13 - 2.95 (m, 3H), 2.90 (t, J = 8.0 Hz, 1H), 2.76 (m, 2H), 2.62 (m, 4H), 2.47 - 2.21 (m, 2H), 2.09 (m, 2H), 1.73 (m, 4H), 1.65 (t, J = 5.5 Hz, 2H), 1.46 (s, 9H), 1.39 (d, J = 6.4 Hz, 2H).

[0413] Step 4: Synthesis of N-((1s,3s)-3-(6-((4-(4-(7-(Azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide Hydrochloride (Intermediate C-24)

[0414] Intermediate C-24 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0415] 11H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.28 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.38 - 7.18 (m, 7H), 4.95 (m, 2H), 4.71 (m, 2H), 4.47 - 4.35 (m, 3H), 4.28 (p, J = 8.4 Hz, 1H), 4.00 (d, J = 13.4 Hz, 2H), 3.89 (m, 1H), 3.76 (t, J = 5.7 Hz, 1H), 3.72 - 3.58 (m, 6H), 3.55 (s, 2H), 3.19 - 2.99 (m, 5H), 2.79 (m, 2H), 2.58 (m, 1H), 2.39 (m, 2H), 2.23 - 2.05 (m, 4H).

[0416] Preparation Example 11: Synthesis of N-((1s,3s)-3-(6-((4-(4-(7-(azetidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate C-25)

[0417]

[0418] Step 1: Synthesis of tert-butyl 3-((2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)azetidine-1-carboxylate (Intermediate C-25)

[0419] Intermediate C-25 was synthesized in a similar manner to Step 1 of Preparation Example 4 above.

[0420] 1 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.34 (m, 4H), 7.27 (m, 1H), 7.04 (d, J = 9.0 Hz, 2H), 4.83 (m, 1H), 4.63 (s, 4H), 4.31 (p, J = 8.5 Hz, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.69 - 3.59 (m, 2H), 3.55 (s, 2H), 3.23 (m, 4H), 3.01 (m, 2H), 2.89 - 2.66 (m, 6H), 2.59 (m, 4H), 2.46 (m, 2H), 2.16 - 2.00 (m, 2H), 1.74 (m, 3H), 1.66 (t, J = 5.8 Hz, 2H), 1.45 (s, 9H).

[0421] Step 2: Synthesis of N-((1s,3s)-3-(6-((4-(4-(7-(azetidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide (Intermediate C-26)

[0422] Intermediate C-26 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0423] 1 H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.28 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.33 (m, 4H), 7.26 (d, J = 8.6 Hz, 3H), 4.89 (m, 2H), 4.26 (m, 4H), 4.15 - 3.95 (m, 4H), 3.90 (m, 1H), 3.76 (m, 1H), 3.72 - 3.60 (m, 5H), 3.54 (m, 4H), 3.45 (m, 2H), 3.10 (m, 6H), 2.79 (m, 2H), 2.61 (m, 1H), 2.40 (m, 3H), 2.08 (m, 4H).

[0424] Preparation Example 12: Synthesis of 2-phenyl-N-((1s,3s)-3-(6-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate E-4)

[0425]

[0426] Step 1: Synthesis of tert-butyl 4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperidine-1-carboxylate (Intermediate E-1)

[0427] Intermediate E-1 was synthesized in a similar manner to Step 2 of Preparation Example 1 above.

[0428] 1 H NMR (500 MHz, DMSO-d 6)δ 9.83 (s, 1H), 8.48 (d, J = 7.7 Hz, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.39 - 7.15 (m, 7H), 4.78 (p, J = 8.6 Hz, 1H), 4.16 (q, J = 8.1 Hz, 1H), 4.08 (m, 2H), 3.44 (s, 2H), 2.92 - 2.74 (m, 4H), 2.72 - 2.59 (m, 3H), 1.76 (d, J = 12.8 Hz, 2H), 1.50 (m, 2H), 1.43 (s, 9H).

[0429] Step 2: Synthesis of 2-phenyl-N-((1s,3s)-3-(6-((4-(piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate E-2)

[0430] Intermediate E-2 was synthesized in a similar manner to Step 3 of Preparation Example 1 above.

[0431] 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.26 (s, 1H), 7.77 - 7.68 (m, 2H), 7.38 - 7.22 (m, 7H), 4.85 - 4.74 (m, 1H), 4.30 (p, J = 8.3 Hz, 1H), 3.54 (s, 2H), 3.21 - 3.13 (m, 2H), 3.00 (m, 2H), 2.76 (m, 4H), 2.71 - 2.62 (m, 1H).

[0432] Step 3: Synthesis of tert-butyl 4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (Intermediate E-3)

[0433] Intermediate E-3 was synthesized in a similar manner to Step 4 of Preparation Example 1 above.

[0434] 11H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.28 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.34 (m, 4H), 7.28 (m, 3H), 4.85 - 4.76 (m, 1H), 4.30 (h, J = 7.9 Hz, 1H), 4.11 (d, J = 13.2 Hz, 2H), 3.55 (s, 2H), 3.19 (d, J = 11.5 Hz, 2H), 3.08 - 2.98 (m, 2H), 2.77 (m, 2H), 2.64 (m, 1H), 2.44 (d, J = 6.7 Hz, 2H), 2.31 (m, 2H), 1.93 - 1.74 (m, 7H), 1.48 (s, 9H), 1.14 (m, 2H).

[0435] Step 4: Synthesis of 2-phenyl-N-((1S,3S)-3-(6-((4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide hydrochloride (Intermediate E-4)

[0436] Intermediate E-4 was synthesized in a manner similar to Step 5 of Preparation Example 1 above.

[0437] 1 1H NMR (500 MHz, CD3OD) δ 8.61 (s, 1H), 8.32 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.34 (m, 4H), 7.30 - 7.23 (m, 1H), 4.99 - 4.93 (m, 1H), 4.33 - 4.23 (m, 1H), 3.82 (d, J = 12.0 Hz, 2H), 3.56 (s, 2H), 3.49 (d, J = 12.9 Hz, 2H), 3.28 - 3.18 (m, 4H), 3.16 - 2.99 (m, 5H), 2.81 (m, 2H), 2.41 - 2.29 (m, 3H), 2.19 (t, J = 16.3 Hz, 4H), 1.61 (m, 2H).

[0438] Preparation Example 13: Synthesis of N-((1S,3S)-3-(6-((4-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate E-6)

[0439]

[0440] Step 1: tert-Butyl 2-(4-(4-((9-((1s,3s)-3-(2-phenylacetamido)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate E-5)

[0441] Intermediate E-5 was synthesized in a similar manner to Step 4 of Preparation Example 1 above.

[0442] 1 H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.28 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.34 (m, 4H), 7.32 - 7.24 (m, 3H), 4.85 - 4.78 (m, 1H), 4.36 - 4.25 (m, 1H), 3.55 (s, 2H), 3.42 (m, 1H), 3.37 (m, 2H), 3.26 (d, J = 11.3 Hz, 2H), 3.06 - 2.96 (m, 2H), 2.77 (m, H), 2.33 (m, 2H), 2.21 (t, J = 10.1 Hz, 2H), 2.06 - 1.77 (m, 7H), 1.63 (t, J = 5.6 Hz, 2H), 1.59 - 1.54 (m, 2H), 1.47 (s, 9H).

[0443] Step 2: Synthesis of N-((1s,3s)-3-(6-((4-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide hydrochloride (Intermediate E-6)

[0444] Intermediate E-6 was synthesized in a similar manner to Step 5 of Preparation Example 1 above.

[0445] 1 H NMR (500 MHz, CD3OD) δ 8.55 (s, 1H), 8.27 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.30 (m, 4H), 7.23 (m, 1H), 4.91 (m, 1H), 4.24 (p, J = 8.3 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.61 (d, J = 11.9 Hz, 2H), 3.51 (s, 2H), 3.18 (t, J = 5.9 Hz, 2H), 3.12 (t, J = 5.7 Hz, 2H), 3.06 - 2.93 (m, 5H), 2.76 (m, 2H), 2.41 (t, J = 10.3 Hz, 2H), 2.34 (t, J = 10.6 Hz, 2H), 2.17 (m, 4H), 1.92 (m, 4H).

[0446] Example 13: Synthesis of N-((1s,3s)-3-(6-(4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)phenylamino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide (Compound 186)

[0447]

[0448] The reaction was carried out in a similar manner to Step 3 of Example 1 above, except that intermediate C-6 (10 mg, 0.0162 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (CRBN binder 8; 5.2 mg, 0.0194 mmol) were used as reactants. The reaction mixture was separated and purified to give the desired compound 186 (9 mg, 69%) as a white solid.

[0449] 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 9.86 (s, 2H), 8.56 - 8.40 (m, 2H), 8.35 (s, 0.5H), 8.23 (d, J = 2.5 Hz, 0.5H), 7.78 (d, J = 8.5 Hz, 1H), 7.43 - 7.15 (m, 8H), 7.02 (d, J = 8.6 Hz, 1H), 4.85 - 4.68 (m, 1H), 4.4 (m, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 3.76 (d, J = 10.9 Hz, 2H), 3.61 (t, J = 6.8 Hz, 4H), 3.15 (m, 7H), 2.93 - 2.81 (m, 2H), 2.73 - 2.60 (m, 5H), 2.18 (m, 1H), 1.88 (m, 3H), 1.23 (m, 4H).

[0450] Compounds 187 to 479 were synthesized in the same or similar manner to Compound 186, using the corresponding starting materials and CRBN binders.

[0451] Experimental Example 1: Compound Identification

[0452] To identify the 479 compounds synthesized according to the above examples, the compounds were analyzed using mass spectrometry and NMR spectrometry, and the results were summarized and shown in the following Figures 3 to 13 as follows.

[0453] Experimental Example 2: Evaluation of CDK Protein Degradation Activity

[0454] To evaluate the CDK protein degradation activity of the compounds of the present invention, the following experiments were conducted.

[0455] MDA-MB-231 cells were seeded in 6-well plates at 5×10 5 cells / well. The next day, the compounds were treated in each well to achieve final concentrations of 100 nM, 1 μM, and 10 μM. For the control group, an equal volume of DMSO to the compound was treated in the wells. After 16 hours of treatment, the cells were collected and cell lysates were prepared using Triton X-100 lysis buffer (50 mM HEPES, pH 7.5, 40 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 10 mM pyrophosphate, 10 mM β-glycerophosphate, 50 mM NaF, 1 mM NaVO 4 4, protease inhibitor). The cell lysates were quantified and separated by size using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Then, Western blotting was performed using antibodies that specifically recognize CDK2, CDK9, and tubulin. The results obtained by Western blotting were quantitatively analyzed using the ImageJ program, and representative images of the experimental results are shown in Figure 1 . In addition, the residual rates calculated based on the enzymatic degradation ability of CDK2 and CDK9 are shown in Table 15 below.

[0456] [Table 15]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] Experimental Example 3: Cytotoxicity Evaluation

[0465] To evaluate the cytotoxicity of the compounds of the present invention, the following experiments were conducted.

[0466] MDA-MB-231 cells were seeded at 3×10 3Cells were seeded at a density of 50 per well in a 96-well plate. The next day, compounds were treated in each well to achieve final concentrations of 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, and 10 μM. For the control group, an equal volume of DMSO as the compound was treated in the wells. After 72 hours of compound treatment, the number of viable cells was analyzed using the CellTiter-Glo luminescent cell viability assay (Promega). Luminescence was measured using a VICTOR X3 multilabel plate reader (PerkinElmer). The GI Figure 2 values of the compounds were implemented using Prism software (GraphPad Prism 5.01), and images of representative experimental results are presented in

[0467] Experimental Example 4: Evaluation of CDK Protein Inhibition

[0468] To evaluate the inhibition of the compounds according to the present invention on the activities of CDK2 and CDK9 proteins, the compounds were tested using the KINOMEscan technology provided by Eurofins Scientific, and the results of some selected compounds are shown in Tables 16 and 17 below.

[0469] [Table 16]

[0470]

[0471]

[0472] [Table 17]

[0473] Compound Number CDK2 / Cyclin A Inhibition CDK9 / Cyclin T1 Inhibition 74 ＞10000 25 91 613 17 125 1295 28 176 439 57

[0474] After examining the above tables, it can be found that most of the compounds of the present invention exhibit high degradation activity against CDK2 and / or CDK9. Specifically, it is confirmed that relatively high degradation activity, especially in the case of certain compounds. This indicates that a pharmaceutical composition for treating CDK2 and / or CDK9-mediated diseases can be provided, which composition contains the compounds according to the embodiments of the present invention as active ingredients.

[0475] Based on the above description, those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical concept or basic features. In this regard, the above embodiments should be understood as illustrative and not limiting in any way. The scope of the present invention should be construed to include the meanings and scopes derived from the following claims and equivalent concepts rather than all modifications or modified forms detailed above.

Claims

1. A compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] in, In the above formula 1: R 1 It is C 1-10 Alkyl, aryl, -C 1-3 Alkyl-C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-3 Alkyl-5-10 membered heteroaryl, C 3-10 Cycloalkyl, -C 1-3 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -C 1-3 Alkyl-3-10 membered heterocycloalkyl, wherein The aryl, heteroaryl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted by one or more selected from the group consisting of halogen, cyano, tert-butyloxycarbonyl (-Boc), amino, nitro, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, -OR a 、-C(=O)R a 、-C(=O)OR a 、-C(O)NR a R b 、-SO 2 R a 、-S(O)R a 、-SO(N)R a , C 1-2 Alkyl-C 6-10 Aryl and C 6-10 Aryl, wherein R a and R b are the same or different and are independently hydrogen, halogen, amino, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; A is the part that acts as an export carrier; L is a connector; and ELB is an E3 ubiquitin ligase binder.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The ELB has a structure represented by the following Formula 2: [Formula 2] Wherein, in the above formula 2: Cy is C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; k is an integer selected from 0-2; X is N or C; R 2 is absent, hydrogen, deuterium (D), or C 1 -C 3 Alkyl; and The aryl, heteroaryl or heterocycloalkyl group is unsubstituted or substituted by one or more selected from the group consisting of: oxo, halogen, nitro, amino, hydroxyl, carboxyl, C 1-6 Alkyl and C 1-6 Alkoxy.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, in, Formula 2 is represented by any of the following structures: R 3 is hydrogen or a halogen, and X 2 It is CH or N.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, in, Formula 2 is represented by any of the following structures:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The R 1 C 1-6 Alkyl, -C 1-3 Alkyl-phenyl, phenyl, -C 1-3 Alkyl-pyridyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or selected from C 1-3 Alkyl, halogen, cyano and halo-C 1-3 The alkyl group is substituted with one or more substituents selected from the group consisting of the alkyl group.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The R 1 Represented by any of the following structures:

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The A has a structure represented by the following Formula 3: [Formula 3] Wherein, in the above formula 3: Cy 1 is unsubstituted or replaced by C 1-3 Alkyl substituted C 6-10 Aryl or 5-10 membered heteroaryl; Cy 2 is a 3-10 membered heterocycloalkyl group; and l is an integer selected from 0-4, and m, n and p are independently 0 or 1, wherein all l, m, n and p are not 0 at the same time.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, in, The A is represented by any of the following structures:

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The connector is -L1-L2-; L2 is a direct connector. as well as L1 is in: q, t, v, x and z are independently 0 or 1; r, s, u and y are independently integers selected from 0-6; Ch is C 1-4 Alkenyl or C 1-4 Alkynyl; and Cy 3 and Cy 4 are independently absent, 3-10 membered heterocycloalkyl or C 3-10 Cycloalkyl.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, in, L 1 Represented by any of the following structures:

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The compound is: N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperidin-4-yl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-(((1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propoxy)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1r,3r)-3-(6-((3-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)benzyl)amino)-9H-purin-9-yl)cyclobutyl)acetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-(((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carbonyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperidine-4-carbonyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)benzamide, 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)benzofuran-6-carboxamide, 2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, 1-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidine-4-carboxamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, N-((1s,3s)-3-(6-((4-(4-(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(((1r,4r)-4-((4-(4-((9-((1s,3s)-3-(2-phenylacetylamino)cyclobutyl)-9H-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)acetamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((3-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((3-(4-((1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)propyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclohexyl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(6-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-6-azaspiro[3.4]oct-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)azetidin-3-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)azetidin-3-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)azetidin-3-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)azetidin-3-yl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)azetidin-3-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)azetidin-3-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)azetidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)azetidine-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((2-(1-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)butyl)piperidin-4-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-(7-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)acetyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-chloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)propyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, N-((1s,3s)-3-(6-((2-(1-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-fluoropicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-(trifluoromethyl)picolinamide, 6-cyano-N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)picolinamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, 2,6-dichloro-N-((1s,3s)-3-(6-((4-(4-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)benzamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, N-((1s,3s)-3-(6-((4-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)amino)-9H-purin-9-yl)cyclobutyl)-6-methylpicolinamide, or N-((1s,3s)-3-(6-((4-(4-(7-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)but-2-en-1-yl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)phenyl)amino)-9H-purin-9-yl)cyclobutyl)-2-phenylacetamide.

12. A method for preparing a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, include: In the first step, a compound of the following formula 4 is reacted with a derivative of the A moiety comprising an amine group at one end and a protecting group at the other end, and the compound is deprotected to prepare a compound of formula 5; In the second step, the compound of formula 5 is reacted with a reactive functional group X at one end. 2 and reacting a derivative of the L1 moiety comprising a protecting group at the other end, and deprotecting the compound to prepare a compound of formula 6; as well as The third step is to react the compound of formula 5 with a CRBN binder, wherein the CRBN binder comprises a reactive functional group X at one end. 3 , [Formula 4] [Formula 5] [Formula 6] Wherein, in the above formula 4 to formula 6: X 1 , X 2 and X 3 are each independently halogen or hydroxy; The protecting group is tert-butyloxycarbonyl; and A' and L1' are the same as A and L1, respectively, or are in the form of a salt thereof.

13. The method according to claim 12, in, The CRBN binding agent is any one selected from the group consisting of:

14. The method according to claim 12, in, The first step is to make X 1 The compound which is a halogen is reacted by heating at a temperature of 70°C to 100°C in a lower alcohol solvent, and deprotected by treating with a strong acid solution in an organic solvent.

15. The method according to claim 12, in, The second step is performed by the following steps: i) Make X 2 A hydroxyl compound is reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt) and N,N-diisopropylethylamine (DIPEA) in an organic solvent at a temperature of 15° C. to 40° C.; ii) Make X 2 A halogen compound is reacted in an organic solvent under alkaline conditions at a temperature of 40°C to 80°C; iii) Make X 2 The oxo-substituted compound was reacted with DIPEA and sodium triacetoxyborohydride (NaBH(OAc) 3 ) at a temperature of 15°C to 40°C; or iv) Make X 2 The oxo-substituted compound reacts with sodium cyanoborohydride (NaBH(OAc) 3 ) in a lower alcohol solvent in the presence of acetic acid at a temperature of 15°C to 40°C, and Deprotection is carried out by treatment with a strong acid solution in an organic solvent.

16. The method according to claim 12, in, The third step is performed by the following steps: i) Make X 3 A hydroxy compound is reacted with EDCL, HOBt and DIPEA in an organic solvent at a temperature of 15°C to 40°C; or ii) Make X 3 The compound which is a halogen is reacted with DIPEA at a temperature of 70°C to 100°C in an organic solvent.

17. A compound comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition for inhibiting or degrading cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 9 (CDK9), or both, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

19. A pharmaceutical composition for preventing or treating cancer or human immunodeficiency virus (HIV) infection, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

20. The pharmaceutical composition according to claim 19, in, The cancer is prostate cancer, lymphoma, glioblastoma, neuroblastoma, ovarian cancer, hepatocellular carcinoma, liver cancer, breast cancer, leukemia, pancreatic cancer, colon cancer, lung cancer, colorectal cancer, or multiple myeloma.

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