Compounds for suppressing EGFR-mutated cancer and their pharmaceutical applications

Abstract

The present disclosure provides compounds of a specific chemical structure or pharmaceutically acceptable salts thereof that have the activity of inhibiting and / or degrading mutant EGFR proteins. The present disclosure also provides compositions containing such compounds or pharmaceutically acceptable salts thereof. The present disclosure also provides pharmaceutical uses of the compounds according to the present invention, salts thereof, and compositions containing them for the treatment or prevention of cancers with EGFR mutations, particularly lung cancer. The present disclosure also provides methods for treating or preventing EGFR mutant cancers, particularly lung cancer, comprising administering an effective amount of a compound according to the present invention, a salt thereof, or a composition containing them to an individual in need of treatment.

Description

[Technical Field]

[0001] This application claims priority based on Korean Patent Application No. 10-2020-0117186, filed on 11 September 2020, and all contents disclosed in the specification and drawings of said application are incorporated herein by reference.

[0002] This disclosure relates to a group of compounds for suppressing, i.e., treating or preventing cancers with EGFR mutations. This disclosure also relates to pharmaceutical compositions comprising such compounds. Furthermore, this disclosure relates to useful methods for treating or preventing cancers with EGFR mutations, particularly those with one or more EGFR mutations among del19, T790M, C797S, and L858R, using such compounds. In other words, this disclosure relates to pharmaceutical uses of the compounds according to the present invention for treating or preventing such cancers. [Background technology]

[0003] The epidermal growth factor receptor (EGFR) is a protein consisting of a receptor moiety and a tyrosine kinase moiety, and it plays a role in transmitting signals from outside the cell to inside the cell across the cell membrane. EGFR plays an essential role in normal cell regulation through intracellular signal transduction. However, EGFR overexpression or activated EGFR mutations characterized by ligand-independent tyrosine kinase activity are known to abnormally activate the cellular signaling system, inducing cancer cell growth, differentiation, angiogenesis, metastasis, and resistance development. Abnormal EGFR overexpression or frequent mutations have been reported in most solid cancer cells, and this is associated with a poor prognosis. For example, lung cancer, liver cancer, esophageal cancer, stomach cancer, intestinal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma are known to be associated with EGFR mutations (Cancer Communications. 2020;40:43-59).

[0004] Among these, EGFR-activating mutations, such as the L858R point mutation in exon 21 of the EGFR tyrosine kinase domain or the in-frame deletion in exon 19, are known to be important causes of non-small cell lung cancer. Therefore, based on the prediction that blocking signal transduction by cancer cells via the epidermal growth factor receptor should produce excellent anticancer effects, research is actively being conducted to develop anticancer drugs that target the epidermal growth factor receptor.

[0005] Among small molecule substances, the first drug developed as an EGFR tyrosine kinase inhibitor was gefitinib, a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among the EGFR subtypes. Another drug with similar characteristics is erlotinib, and such EGFR-targeted therapies are mainly used in patients with EGFR-activating mutations, primarily for non-small cell lung cancer (NSCLC).

[0006] However, it has been reported that NSCLC patients with EGFR-activating mutations who were treated with gefitinib or erlotinib developed drug resistance after approximately 8 to 16 months, with about 60% of these resistances being due to the EGFR T790M mutation (Helena A. Yu et al., Clin Cancer Res. 19(8), 2240, 2013).

[0007] To overcome resistance to conventional EGFR inhibitors such as gefitinib or erlotinib, irreversible inhibitors have been proposed. However, irreversible EGFR inhibitors still exhibit high activity against EGFR WT (wild-type), which is also present in normal cells. Therefore, when doses are administered to overcome resistance caused by the EGFR T790M mutation, they can cause serious side effects, thus limiting their clinical applicability.

[0008] As an alternative, numerous drugs, including EGFR mutation-selective inhibitors such as osimertinib, olmutinib, naquotinib, and avitinib, are currently under development for clinical trials. However, clinical results of osimertinib in non-small cell lung cancer patients with EGFR-resistant mutations show that drug resistance develops after about 10 months due to the activation of other resistance mechanisms, with C797S mutations appearing in a high proportion of over 20% of these cases. The C797S mutation is a point mutation in which cysteine ​​773 (Cys773), which forms a covalent bond with irreversible EGFR inhibitors, is replaced with serine. This mutation prevents the formation of a covalent bond with irreversible EGFR inhibitors, leading to decreased responsiveness to the drug.

[0009] Thus, the development of EGFR-targeted therapies has limitations, such as the inability to maintain drug efficacy for a certain period due to the development of primary and secondary resistance. In particular, research on the EGFR C797S mutation is limited to reports from early-stage preclinical studies; there are no substances even in clinical trials, and there is an urgent need for effective therapeutic therapies for it. [Overview of the project] [Problems that the invention aims to solve]

[0010] Therefore, the problem that this disclosure seeks to solve is to provide compounds having inhibitory, deterrent, and / or degradative activity against cancers with EGFR mutations, pharmaceutical compositions containing these as active ingredients, and pharmaceutical uses for the treatment or prevention of cancers with EGFR mutations.

[0011] Another problem that this disclosure seeks to solve is to provide a method for treating or improving cancer with EGFR mutations, characterized by administering a compound according to the present invention, which is characterized by inhibiting cancer cells having EGFR mutations, to a patient who needs treatment, improvement, or prevention of cancer with EGFR mutations. [Means for solving the problem]

[0012] <Abstract> To solve the above problems, one aspect of the present invention provides a compound having the structure of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0013] <Chemical Formula>

[0014] In Chemical Formula 1, R1 and R2 are each independently hydrogen, a C1-C6 alkyl group, CD3, or a C1-C6 haloalkyl group, R3 to R6 are each independently hydrogen, a halogen group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyloxy, a C3-C6 heterocycloalkyloxy, or -C(=O)OR7, where R7 is a C1-C5 alkyl group, m and n are each independently 0, 1, 2, 3 or 4, A is a divalent 4- to 7-membered heterocyclic ring, a 4- to 7-membered spiroheterocyclic ring, or an 8- to 10-membered bicyclic heterocyclic ring, L is a group that covalently links A and B, B is

[0015] <Chemical Formula>

[0016] and X is a direct bond, (CH2) 13 , , 13 , , , 13 , , 0-6 , 13 , , ,

[0015] , , 0-6 , 0-6 , 0-6 ,

[0016] , 0-6 , , , 1-6 , , , , 、O-(CH2) 0-6 、C(O)-(CH2) 0-6 、N(R 13 )-(CH2) 0-6 、C(O)-N(R 13 )-(CH2) 0-6 、N(R 13 )-C(O)-(CH2) 0-6 、N(R 13 )、N(R13 )-(CHR 14 ), or O-(CHR 14 ) and W is C(R 14 )2 or C(O), R8 is hydrogen, OH, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, or C1-C6 haloalkoxy group. R9 and R 10 Each of these is independently either hydrogen or a C1-C6 alkyl group. R 13 and R 14 Each of these is independently either hydrogen or a C1-C6 alkyl group. o and p are independent of each other, in 1, 2, or 3. be.

[0017] The compounds disclosed herein exhibit excellent degradation capabilities of EGFR mutant proteins in cancers with EGFR mutations. Therefore, they can be expected to have preventive or therapeutic effects on cancers with EGFR mutations.

[0018] In particular, the compounds of this disclosure have the advantage of selectively degrading mutant EGFR proteins, including C797S, rather than EGFR proteins in cells with normal EGFR.

[0019] The compounds disclosed herein are particularly useful for the degradation of EGFR mutant proteins having one or more mutations among Del19, T790M, C797S, and L858R, and especially for the degradation of Del19 / T790M / C797S and L858R / T790M / C797S mutant proteins. Mutant EGFR, including C797S, is a resistance mutation that appears after treatment with the third-generation therapeutic agent Tagrisso (osimertinib), but the compounds disclosed herein have the advantage of being useful for suppressing and degrading lung cancer cells with the EGFR C797S mutation, particularly non-small cell lung cancer (NSCLC) cells.

[0020] The compounds disclosed herein are predicted to have a right-side moisture in their chemical structure that binds to and / or inhibits mutant EGFR proteins, and a left-side moisture that acts as an E3 ligase binder, inducing the ubiquitin-proteasome system (UPS) and further promoting the degradation and / or inhibition of the relevant proteins. However, the present invention is not limited to such theoretically predicted mechanisms.

[0021] In another embodiment, the disclosure provides a pharmaceutical composition comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0022] In yet another embodiment, the disclosure provides a method for treating cancer having an EGFR mutation, comprising the step of administering to an individual a therapeutically effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof. The cancer having the EGFR mutation may be, for example, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, small intestinal cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, psoriasis, fibroadenoma, etc. Preferably, the cancer having the EGFR mutation is lung cancer. More preferably, the cancer having the EGFR mutation is non-small cell lung cancer.

[0023] In other words, this disclosure provides pharmaceutical applications characterized by using a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. In one embodiment, the pharmaceutical applications of the present invention are for the treatment or prevention of diseases or conditions described herein.

[0024] The aforementioned compounds, pharmaceutical compositions containing such compounds, and their pharmaceutical uses will be described in detail later in the detailed description.

[0025] <Detailed explanation> The following description is illustrative only and does not limit the invention, application, or use.

[0026] <Definition> The terms used herein are defined as follows:

[0027] In this specification, the terms "substituent," "radical," "group," "moiety," and "fragment" may be used interchangeably.

[0028] As used herein, the term "alkyl" means a saturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms (unless otherwise specified). "Lower alkyl" means a linear or branched alkyl having 1 to 4 carbon atoms. Typical saturated linear alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, and 2,4-dimethylbutyl This product contains diethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.

[0029] In this specification, "C 1-6 When written as "C1-6" or "C1-C6", it means that the number of carbon atoms is between 1 and 6. For example, C1-C6 alkyl means an alkyl group with 1 to 6 carbon atoms.

[0030] As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine, or iodine.

[0031] As used herein, the terms “haloalkyl,” “haloalkoxy,” “haloalkenyl,” or “haloalkynyl” each mean an alkyl, alkoxy, alkenyl, or alkynyl group in which one or more hydrogen atoms are substituted with halogen atoms. For example, haloalkyls include -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and similar groups. In one embodiment of the present invention, the haloalkyl is CF3. Here, alkyl and halogen are defined as described above.

[0032] As used herein, the term "alkoxy" means -O-(alkyl), including -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and similar thereof, where alkyl is as defined above. As used herein, the term "lower alkoxy" means -O-(lower alkyl), where lower alkyl is as defined above.

[0033] The terms “aryloxy,” “cycloalkyloxy,” or “heterocycloalkyloxy” are RO-, where R is aryl, cycloalkyl, or heterocycloalkyl, respectively, as defined herein. “Arylthio” is RS-, where R is aryl, as defined herein.

[0034] As used herein, the term "aryl" refers to a carbocyclic aromatic group containing 3 to 10 ring atoms. Typical examples include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, and azulenyl. Carbocyclic aromatic groups can be selectively substituted.

[0035] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7) cycloalkyls (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Examples of polycyclic rings include, but are not limited to, fused bicyclic rings (bicyclic hydrocarbon rings) such as octahydropentalene and decahydronaphthalene; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, and spiro[5.5]undecane; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.2.2]octane. Cycloalkyl groups can be selectively substituted. In one embodiment, the cycloalkyl group is a monocyclic ring. In one embodiment, the cycloalkyl group is a cyclopropyl group. In one embodiment of the present invention, the “spirohydrocarbon ring” or “spiro ring” is spiro[3.3]heptane, spiro[3.4]octane, spiro[4.3]octane, spiro[4.5]decane, spiro[4.4]decane, or spiro[5.5]undecane.

[0036] As used herein, "heteroaryl" refers to a 3- to 10-membered aromatic heterocyclic ring containing at least one carbon atom, including monocyclic and bicyclic ring systems, and having at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. Typical heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, and 1H-azepine.

[0037] As used herein, "heterocycle" or "heterocycloalkyl" means a saturated 3-7 member monocyclic or 6-12 member bicyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen and sulfur heteroatoms may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Typical heterocycles include oxiranes, oxetanes, tetrahydrofurans, tetrahydropyrans, 1,4-dioxanes, aziridines, azetidines, pyrrolidines, piperidines, piperazines, pyrrolidinones, hydantoins, valerolactams, thiiranes, thietanes, tetrahydrothiophenes, tetrahydrothiopyrans, morpholines, tetrahydropyridines, and tetrahydropyrimidines. Heterocycles also include bicyclic rings in which a portion of the heterocycle is fused to a benzene or cyclopenta-1,3-diene ring. Heterocycles can be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spirocycles, and bridged bicyclic rings in which one or more carbon atoms of the polycyclic ring described above are replaced by nitrogen, oxygen, or sulfur atoms.Examples of such heteroatoms include fused heterobicyclic rings (bicyclic heterocycles) where the heteroatom is nitrogen, such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, and decahydro-2,6-naphthyridine; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 2, Examples include, but are not limited to, spiro(hetero) rings such as 7-diazaspiro[4.4]nonane, 8-azazspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azazspiro[5.5]undecane, and 3,9-diazaspiro[5.5]undecane; and bridged heterobicyclic rings such as 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, and 2,5-diazabicyclo[2.2.2]octane. In one embodiment of the present invention, the spiroheterocycle is 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, or 1,4-dioxaspiro[4.5]decane.

[0038] "A heterocycle fused to phenyl" refers to a heterocycle attached to two adjacent carbon atoms of a phenyl ring, where the definition of a heterocycle is as described above.

[0039] In this specification, "*" or

[0040] [ka]

[0041] This means that it is connected to other moyati.

[0042] In the present invention, “pharmaceutically acceptable salts” include salts of active compounds prepared with relatively non-toxic acids and bases, depending on specific substitutions found in the compounds referred herein. When the compounds of the present invention have relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base and a pure or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amino or magnesium, or similar salts. When the compounds of the present invention have relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid and a pure or suitable inert solvent. Examples of pharmaceutically acceptable acidic addition salts include not only salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and their analogues, but also hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydrogen iodide, or phosphorous acid and their analogues. The invention also includes salts of amino acids such as arginate and its analogues, and analogues of organic acids such as glucuronic acid or galactunoric acid and its analogues. Some specific compounds of the present invention possess both basic and acidic functionality, which allows them to be converted into basic or acidic addition salts. Other examples of salts are disclosed in literature known in the art to which the present invention belongs.

[0043] As used herein, “effective dose” means an amount of the compound of the present invention sufficient to delay or minimize the progression of cancer with EGFR mutations, or to provide a therapeutic benefit in the treatment or management of cancer with EGFR mutations. “Effective dose” also means an amount sufficient to suppress or reduce the activity of EGFR mutant proteins, either in vitro or in vivo.

[0044] As used herein, the term “treatment” may mean one or more of the following: preventive treatment, palliative treatment, and / or restorative treatment.

[0045] As used herein, the term “compound of the present invention” includes not only the compound of chemical formula 1, but also its clathrates, hydrates, solvates, or polymorphs. Furthermore, unless otherwise specified, the term “compound of the present invention” also includes pharmaceutically acceptable salts of the compound of the present invention. In one embodiment, the compound of the present invention may exist as a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., 85% ee or higher, 90% ee or higher, 95% ee or higher, 97% ee or higher, or 99% ee or higher)). That is, if the compound of chemical formula 1 or a salt thereof according to the present invention is a tautomeric isomer and / or stereoisomer (e.g., a geometrical isomer and a conformational isomer), then each of their separated isomers and mixtures is also included in the category of compounds of the present invention. If the compounds or salts of the present invention have asymmetric carbon in their structure, their optically active compounds and racemic mixtures are also included in the category of compounds of the present invention.

[0046] As used herein, the term “polymorph” means a solid crystalline form or a composite of the compounds of the present invention. Different polymorphs of the same compound exhibit different physical, chemical, and / or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g., thermal or photostability), compressibility and density (important for formulation and manufacturing of products), and solubility (which may affect bioavailability). Differences in stability may result in changes in chemical reactivity (e.g., differential oxidation, such as discoloration occurring more rapidly when composed of one polymorph than when composed of another), or mechanical characteristics (e.g., purified fragments stored as a kinetically preferred polymorph are converted to a thermodynamically more stable polymorph), or both (tablets of one polymorph may be more sensitive to decomposition at high humidity). The different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvent compounds than another, for example, due to its morphology or particle size distribution, or it may be more difficult to filter or wash.

[0047] As used herein, the term "solvent compound" means a compound of the present invention or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent forces. Preferred solvents are volatile and non-toxic and can be administered to humans in very small amounts.

[0048] As used herein, the term "hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bonded by non-covalent forces.

[0049] As used herein, the term "clathrate" refers to a crystalline lattice compound or salt thereof of the present invention that contains spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0050] As used herein, the term "purified" means that, upon separation, the separated product is 90% or more pure, in one embodiment 95% or more pure, in another embodiment 99% or more pure, and in yet another embodiment 99.9% or more pure.

[0051] The term "hydrido" refers to a single -H atom (H) and can be used interchangeably with the symbol "H" or the term "hydrogen".

[0052] When a substituent is described as "arbitrarily substituted" or "selectively substituted," the substituent may (1) remain unsubstituted, or (2) be substituted with one or more of the defined substituents. If the substituted position is unsubstituted, the default substituent is hydrogen.

[0053] As used herein, the singular "one (a, an)" may include plural forms unless otherwise specified.

[0054] The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, generally considered safe for such use, officially approved for such use by a national regulatory body, or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0055] <Inventive compound> One aspect of the present invention provides a compound having the structure of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0056] [ka]

[0057] In chemical formula 1, R1 and R2 are independently hydrogen, a C1-C6 alkyl group, CD3, or a C1-C6 haloalkyl group. R3 to R6 are independently hydrogen, a halogen group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyloxy group, a C3-C6 heterocycloalkyloxy group, or -C(=O)OR7, where R7 is a C1-C5 alkyl group. m and n are independently 0, 1, 2, 3, or 4. A is a divalent 4-7 member heterocycle, a 4-7 member spiroheterocycle, or an 8-10 member bicyclic heterocycle. L is a group that connects A and B by a covalent bond. B is

[0058] [ka]

[0059] And, X is a direct bond, (CH2) 1-6 , O-(CH2) 0-6 , C(O)-(CH2) 0-6 , N(R 13 )-(CH2) 0-6 , C(O)-N(R 13 )-(CH2) 0-6 , N(R 13 )-C(O)-(CH2) 0-6 , N(R 13 ), N(R 13 )-(CHR 14 ), or O-(CHR 14 ) and W is C(R 14 )2 or C(O), R8 is hydrogen, OH, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, or C1-C6 haloalkoxy group. R9 and R 10 Each of these is independently either hydrogen or a C1-C6 alkyl group. R 13 and R 14 Each of these is independently either hydrogen or a C1-C6 alkyl group. o and p are independent of each other, in 1, 2, or 3. be .

[0060] In one preferred embodiment, the present invention relates to the chemical formula 1, R1 and R2 are independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. R3 is hydrogen or a C1-C6 alkyl group. R4 is hydrogen, a halogen (preferably Cl), or a C1-C6 alkyl group. R5 is hydrogen or a C1-C6 alkyl group. R6 is hydrogen, halogen, C1-C6 alkyl group, C1-C6 alkoxy group, or C1-C6 haloalkoxy group. m and n are independently 0, 1, or 2. A is

[0061] [ka]

[0062] And, L is a group that connects A and B by a covalent bond. B is

[0063] [ka]

[0064] And, X is a direct bond, (CH2) 1-6 , O-(CH2) 0-6 , C(O)-(CH2) 0-6 , N(R 13 )-(CH2) 0-6 , C(O)-N(R 13 )-(CH2) 0-6 , N(R 13 )-C(O)-(CH2) 0-6 , N(R 13 ), N(R 13 )-(CHR14 ), or O-(CHR 14 ) and W is C(R 14 )2 or C(O), R8 is hydrogen, OH, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, or C1-C6 haloalkoxy group. R9 and R 10 Each of these is independently either hydrogen or a C1-C6 alkyl group. R 13 and R 14 Each of these is independently either hydrogen or a C1-C6 alkyl group. o and p are independent of each other, in 1, 2, or 3. be The present invention provides compounds or pharmaceutically acceptable salts thereof.

[0065] In another embodiment, the present invention relates to the chemical formula 1 in which L is a directly bonded or divalent saturated or unsaturated C1-C50 hydrocarbon chain; where one or more of the methylene units of L are -Cy-, -O-, -N(R 20 )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R 20 )S(O)2-, -S(O)2N(R 20 )-,-N(R 20 )C(O)-, -C(O)N(R 20 )-,-OC(O)N(R 20 )-,-N(R 20 )C(O)-,-(CH 2O -Cy- can be replaced by one or more selected from the group consisting of CH2)-, -(OCH2CH2)-, -(CH2CH2O)-, -(C(O)CH2CH2)-, and -(CH2CH2C(O))-; where -Cy- is independently a divalent ring substituent, which is phenylene, a 4-7 membered spirohydrocarbon ring, an 8-10 membered bicyclic hydrocarbon ring, a 4-7 membered heterocycle, a 4-7 membered spiroheterocycle, an 8-10 membered bicyclic heterocycle, a 5-6 membered heteroalylene, or an 8-10 membered bicyclic heteroalylene, and R 20The present invention provides a compound of chemical formula 1, wherein the compound is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0066] Preferably, in yet another embodiment, the present invention is characterized in that XL in the chemical formula 1 is -K1-K2-K3-K4-K5-, where, K1 is C1-C6 alkyl, NH, O, CC, N-C1-C6 alkyl, NH-C1-C6 alkyl, O-C1-C6 alkyl,

[0067] [ka]

[0068] And, K2 is a direct bond, C(O), or O. K3 is a direct bond, (CH2) n1 , or (CH2) n1 -O, where n1 is an integer from 0 to 10. K4 is a direct bond, (CH2CH2O) n2 ,

[0069] [ka]

[0070] Here, n2 is an integer between 0 and 5, K5 is a direct bond, (CH2) n3 , NH or N-C1~C3 alkyl, where n3 is an integer from 0 to 3, The present invention provides a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein one of A1 and A2 is N and the other is CH, or both A1 and A2 are N.

[0071] More preferably, yet another embodiment of the present invention provides a compound or a pharmaceutically acceptable salt thereof in which XL of chemical formula 1 is the XL moiety used in the examples described below. In the examples, XL may be bonded to the left side with a variety of B (except X) as described herein and to the right side with a variety of "-A-EGFR-bonded moiety" as described herein.

[0072] More preferably, in yet another embodiment, the present invention relates to the chemical formula 1 in which A is

[0073] [ka]

[0074] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0075] Preferably, one embodiment of the present invention provides a compound having the structure of the following chemical formula 1a or a pharmaceutically acceptable salt thereof.

[0076] [ka]

[0077] In chemical formula 1a, R1 and R2 are independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. R3 to R6 are independently hydrogen, a halogen group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyloxy group, a C3-C6 heterocycloalkyloxy group, or -C(=O)OR7, where R7 is a C1-C5 alkyl group. R6' is a halogen group or a C1-C6 alkyl group. m is 0, 1, 2, 3, or 4. A is a divalent 4-7 member heterocycle, a 4-7 member spiroheterocycle, or an 8-10 member bicyclic heterocycle. L is a group that connects A and B by a covalent bond. B is

[0078] [ka]

[0079] And, X is a direct bond, (CH2) 1-6 , O-(CH2) 0-6 , C(O)-(CH2) 0-6 , N(R 13 )-(CH2) 0-6 , C(O)-N(R 13 )-(CH2) 0-6 , N(R 13 )-C(O)-(CH2) 0-6 , N(R 13 ), N(R 13 )-(CHR 14 ), or O-(CHR 14 ) and W is C(R 14 )2 or C(O), R8 is hydrogen, OH, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, or C1-C6 haloalkoxy group. R9 and R 10 Each of these is independently either hydrogen or a C1-C6 alkyl group. R 13 and R 14 Each of these is independently either hydrogen or a C1-C6 alkyl group. o and p are independent of each other, in 1, 2, or 3. be .

[0080] Among the compounds of chemical formula 1, those having a structure like chemical formula 1a exhibit significantly improved bioavailability, as will be described later. As shown in the exemplary experimental results described later, compounds 74, 76, 77, 80, and 81 showed significantly improved AUC compared to their corresponding compounds 45, 71, 51, 65, and 53.

[0081] Preferably, another embodiment of the present invention is that in the chemical formula 1 or chemical formula 1a, X is O-(CH2) 0-6 , N(R 13 )-(CHR 14 ), or O-(CHR 14 ) and R 14 The present invention provides compounds in which the substituent is a C1-C6 alkyl group (preferably methyl) (other substituents are the same as defined in chemical formula 1 or 1a above). As shown in the exemplary experimental results described later, compounds 69, 70, 75, 78 and 82 showed significantly improved AUC compared to their corresponding compounds 53 and 65. Such compounds are those in which K1 of the -K1-K2-K3-K4-K5- is *-O-C1-C6 alkyl-* or *-NH-C1-C6 alkyl-* (K2, K3, K4 and K5 are the same as defined above), where O or NH is linked to the second or third carbon rather than the terminal of the C1-C6 alkyl.

[0082] To achieve the above-mentioned objectives, the inventors synthesized a variety of compounds and conducted various evaluation experiments to ensure a compound that exhibits high inhibitory, degrading, and / or binding activity to mutant EGFR proteins, high selectivity for these proteins, and preferably effectively degrades mutant EGFR proteins, thereby resulting in a compound with good therapeutic or preventive effects for cancers with EGFR mutations and reduced other side effects, as well as its applications. In addition to pharmacological aspects, the inventors also evaluated pharmacokinetic aspects such as bioavailability. Finally, the inventors completed the invention after confirming that the compound of the present invention is suitable for the objectives of the present invention.

[0083] One embodiment of the present invention provides, as non-limiting examples of the compounds of chemical formula 1 according to the present invention, the compounds of the examples described below and pharmaceutically acceptable salts thereof.

[0084] Preferably, another embodiment of the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein the compound of chemical formula 1 is one of the compounds shown in Table 1 below. The compounds shown in Table 1 below are more preferable in various respects, such as efficacy and bioavailability.

[0085] [Table 1] JPEG0007859684000014.jpg254169JPEG0007859684000015.jpg79169

[0086] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier.

[0087] <Pharmaceutical uses and therapeutic methods of compounds according to the present invention> The present invention further provides a method for treating the following diseases or conditions in individuals who have or are prone to having the following diseases or conditions by administering a therapeutically effective amount of one or more of the aforementioned compounds to the individual. In one embodiment, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In yet another embodiment, the treatment is a restorative treatment.

[0088] 1. Illness or condition The EGFR mutant protein inhibitor and / or degradation compounds according to the present invention are useful for a variety of therapeutic or prophylactic applications. Such compounds can be used to suppress or inhibit EGFR mutant protein activity and may further be used for the treatment of cancers with EGFR mutations or to prevent the progression of such diseases. Accordingly, the present invention provides a method for inhibiting, suppressing, and / or degrading intracellular EGFR mutant protein activity. In such a method, the cells come into contact with an effective amount of the compound of the present invention. In one embodiment, the cells are present in an individual (e.g., a lung cancer patient). The method of the present invention involves administering a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present invention to an individual in need of treatment or prevention.

[0089] In one aspect, the present invention provides a method for inhibiting, degrading, or suppressing EGFR mutant protein activity in cancer cells having EGFR mutations. For example, the present invention may be used for the treatment or prevention of lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, psoriasis, fibroadenoma, and the like, which have EGFR mutations.

[0090] The compounds of the present invention can be administered to the individual in the form of the pharmaceutical compositions described herein.

[0091] In another embodiment, the present invention provides a method for treating or preventing cancers having EGFR mutations in an individual, such as lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma. Such a method includes administering a sufficient amount, i.e., a therapeutically effective amount, of the compound of the present invention to an individual in need of treatment in order to inhibit EGFR mutant protein activity.

[0092] In particular, the compounds of the present invention are useful for the degradation of EGFR mutant proteins having one or more mutations among Del19, T790M, C797S, and L858R, and especially for the degradation of Del19 / T790M / C797S and L858R / T790M / C797S EGFR mutant proteins. Cancers with mutant EGFR having such characteristics include lung cancer, particularly non-small cell lung cancer (NSCLC).

[0093] 2. Individuals (subjects) Suitable individuals to be treated by the present invention include mammals. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and intrauterine mammals. Individuals may be of any sex and may be at any stage of development.

[0094] In one embodiment, the preferred individual to be treated by the present invention is a human.

[0095] 3. Administration and Dosing The compounds of the present invention are generally administered in therapeutically effective amounts.

[0096] The compounds of the present invention can be administered by any preferred route, in the form of a pharmaceutical composition appropriate to such route, and in an effective dose for the intended treatment. The effective dose is generally about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day, in single or divided doses. Depending on age, species, and the disease or condition being treated, dose levels below the lower end of this range may be appropriate. In other cases, even higher doses may be used without adverse side effects. Higher doses may be divided into several smaller doses for daily administration.

[0097] <Pharmaceutical composition, dosage form, and route of administration> To treat the diseases or conditions described herein, the compounds described herein or pharmaceutically acceptable salts thereof may be administered as follows:

[0098] Oral administration The compounds of the present invention may be administered orally, and the oral cavity is a concept that includes swallowing. By oral administration, the compounds of the present invention may enter the gastrointestinal tract, or they may be absorbed directly into the bloodstream from the oral cavity, for example, by buccal or sublingual administration.

[0099] Suitable compositions for oral administration may be solid, liquid, gel, or powder, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0100] Compositions for oral administration may be selectively enteric-coated, and the enteric coating may embody delayed or sustained release. That is, compositions for oral administration according to the present invention may be dosage forms having immediate release or modified release patterns.

[0101] Liquid dosage forms may include solutions, syrups, and suspensions, and such liquid compositions may be in the form of being filled in soft or rigid capsules. Such dosage forms may contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The dosage forms may also contain one or more emulsifiers and / or suspending agents.

[0102] In tablet dosage forms, the amount of the active ingredient, the drug, may be approximately 0.05% to 95% by weight of the total weight of the tablet, more generally approximately 2% to 50% by weight of the dosage form. The tablet may also contain approximately 0.5% to 35% by weight of a disintegrant, more generally approximately 2% to 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0103] Suitable lubricants included for manufacturing tablets may be present in an amount of about 0.1% to about 5% by weight, and talc, silicon dioxide, stearic acid, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc. may be used, but are not limited thereto.

[0104] As binders for manufacturing tablets, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used. As suitable diluents for manufacturing tablets, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used, but are not limited thereto.

[0105] Solubilizers that can optionally be included in tablets can be used at about 0.1% to about 3% by weight based on the total weight of the tablets. For example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM )、caprylic / capric acid mono / diglyceride, sorbitan fatty acid ester, Solutol TM ) HS, etc. can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to specific types of such solubilizers Parenteral administration The compounds of the present invention can be administered directly into the bloodstream, muscles, or internal organs. Preferred methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial injections. Preferred apparatus for parenteral administration includes syringes (including needles and needleless syringes) and injection methods.

[0106] Compositions for parenteral administration may be in dosage forms having an immediate or modified release pattern, the modified release pattern may be a delayed-release pattern or a sustained-release pattern.

[0107] Most parenteral dosage forms are liquid compositions, and such liquid compositions are aqueous solutions containing the pharmacoactive ingredient, salt, buffer, isotonic agent, etc., according to the present invention.

[0108] Furthermore, parenteral dosage forms may be manufactured in a dry form (e.g., lyophilized) or as a sterile non-aqueous solution. These dosage forms may be used with a suitable vehicle, such as sterile water. Solubility enhancers may also be used in the manufacture of parenteral solutions.

[0109] Topical administration The compounds of the present invention can be administered topically via the skin or transdermally. Dosage forms for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration dosage forms may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.

[0110] Compositions for topical administration may be in dosage forms having an immediate or modified release pattern, the modified release pattern may be a delayed-release pattern or a sustained-release pattern. [Effects of the Invention]

[0111] The present invention provides compounds capable of inhibiting or degrading EGFR mutant protein activity and exhibiting diverse pharmacological activities, pharmaceutical compositions containing these as active ingredients, their pharmaceutical uses (particularly for the treatment or prevention of cancer with EGFR mutations, especially lung cancer), and therapeutic methods comprising administering these to individuals in need of treatment or prevention. The compounds according to the present invention or pharmaceutically acceptable salts thereof exhibit high selectivity for mutant EGFR and are excellent in various aspects, including safety, and can exert excellent pharmaceutical effects in inhibiting or degrading EGFR mutant activity. 。 [Modes for carrying out the invention]

[0112] The present invention will be described in detail below, with reference to examples, to aid in understanding the present invention. However, the examples of the present invention can be modified into a variety of other forms, and the scope of the present invention should not be construed as being limited to the examples below. The examples of the present invention are provided to give a more complete explanation of the present invention to a person with average knowledge of the art to which the present invention belongs.

[0113] <Production of the compound of the present invention> The synthesis process of some of the compounds of the present invention is described below. Other compounds not described below can be produced by similar methods by substituting the starting materials, intermediates, and / or reactants.

[0114] Example 1: Synthesis of 5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide (Compound 1)

[0115] [ka]

[0116] Step 1: Synthesis of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide (1-1) To a solution of 5-bromopentanoic acid (398 mg, 2.20 mmol) in dichloromethane (5 mL), oxalyl chloride (964 mL, 11.00 mmol) was added, and one drop of N,N-dimethylformamide was added dropwise. The mixture was concentrated for 1 hour, and tetrahydrofuran (10 mL) and 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (200 mg, 0.73 mmol) were added, and the mixture was stirred overnight at 75°C. The solution was diluted with ethyl acetate and brine, extracted, and dried over anhydrous magnesium sulfate. After filtration and concentration, the compound was purified by silica gel column chromatography to obtain the title compound (244.1 mg, 77%).

[0117] Step 2: Synthesis of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1-2) A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5.0 g, 29.22 mmol), Boc-piperazine (6.5 g, 35.06 mmol), and potassium carbonate (6.0 g, 43.24 mmol) in N,N-dimethylformamide (43 mL) was stirred at room temperature. After stirring overnight, potassium carbonate (3.0 g) was added and the mixture was stirred for 2 days. Water was added to the reaction mixture and stirred, filtered, washed with water, and vacuum dried to obtain the title compound (9.5 g, 96%).

[0118] Step 3: Synthesis of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (1-3) A mixture of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (500 mg, 1.48 mmol) and tetrahydrofuran / ethanol (5 / 5 mL) was purged with argon gas, and 10% Pd / C (50 mg) was added. The mixture was purged with hydrogen gas and stirred for 4 hours, then filtered and concentrated to obtain the title compound (450 mg, 99%).

[0119] Step 4: Synthesis of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (1-4) A mixture of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (450 mg, 1.46 mmol), N-(2-((2,5-dichloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (508 mg, 1.46 mmol), BINAP (255 mg, 0.41 mmol), and potassium carbonate (464 mg, 3.37 mmol) in 1,4-dioxane (5 mL) was purged with argon gas, and Pd(OAc)2 (50 mg, 0.20 mmol) was added. After stirring under reflux overnight and cooling to room temperature, the mixture was filtered through Celite. The solution was diluted with ethyl acetate and brine for extraction and dried over anhydrous magnesium sulfate. After filtration and concentration, the compound was purified by silica gel column chromatography to obtain the title compound (700 mg, 77%).

[0120] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1-5) 20% trifluoroacetic acid / dichloromethane (46 mL) was added to a reactor containing tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (2.9 g, 4.68 mmol) and stirred for 3 hours. The mixture was then neutralized with aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the title compound (2.4 g, 98%).

[0121] Step 6: Synthesis of Compound 1 5-Bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide (67 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), to which diisopropylethylamine (67 mL, 0.39 mmol) was added and stirred at 90°C. After 16 hours, the mixture was concentrated and purified by column chromatography to obtain the title compound (95 mg, 66%).

[0122] Example 2: Synthesis of 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide (Compound 2)

[0123] [ka]

[0124] Step 1: Synthesis of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one (2-1) A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (500 mg, 2.92 mmol), piperidone hydrochloride (470 mg, 3.47 mmol), and potassium carbonate (799 mg, 5.78 mmol) dimethyl sulfoxide (6 mL) was stirred overnight at 80°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (370 mg, 50%).

[0125] Step 2: Synthesis of tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (2-2) A mixture of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one (460 mg, 1.84 mmol) and N-Boc-piperazine (1.0 g, 5.51 mmol) in dichloromethane (18 mL) was mixed with acetic acid (0.3 mL, 5.51 mmol) and stirred for 1.5 hours. NaBH(OAc)3 (580 mg, 2.76 mmol) was added and stirred for 5 hours. After adjusting the pH to ~8 with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (650 mg, 84%).

[0126] Step 3: Synthesis of tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (2-3) A mixture of tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (650 mg, 1.55 mmol) in tetrahydrofuran / ethanol (7 / 7 mL) was purged with argon gas, and 10% Pd / C (65 mg) was added. After purging with hydrogen gas and stirring for 4 hours, the mixture was filtered through Celite and concentrated to obtain the title compound (650 mg, 100%).

[0127] Step 4: Synthesis of tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (2-4) A mixture of tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (640 mg, 1.64 mmol), N-(2-((2,5-dichloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (570 mg, 1.64 mmol), BINAP (285 mg, 0.46 mmol), and potassium carbonate (521 mg, 3.77 mmol) in 1,4-dioxane (6.5 mL) was purged with argon gas, and Pd(OAc)2 (52 mg, 0.23 mmol) was added. After stirring under reflux overnight and cooling to room temperature, the mixture was diluted with ethyl acetate and brine and extracted. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated, and then purified by silica gel column to obtain the title compound (610 mg, 53%).

[0128] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (2-5) 610 g, 0.87 mmol) of tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)piperazine-1-carboxylate was added to a reactor containing 20% ​​trifluoroacetic acid / dichloromethane (9 mL) and stirred for 3 hours. The mixture was then neutralized with aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the title compound (430 mg, 82%).

[0129] Step 6: Synthesis of Compound 2 5-Bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide (51 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), to which diisopropylethylamine (51 mL, 0.29 mmol) was added and stirred at 90°C. After 16 hours, the mixture was concentrated and purified by column chromatography to obtain the title compound (95 mg, 66%).

[0130] Example 3: Synthesis of N-(2-((5-chloro-2-((4-((4-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)butyl)(methyl)amino)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 3)

[0131] [ka]

[0132] Step 1: Synthesis of 4-(4-bromobutoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (3-1) 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol) was dissolved in tetrahydrofuran (9 mL), and 4-bromobutan-1-ol (0.289 mL, 2.74 mmol) and triphenylphosphine (717 mg, 2.74 mmol) were added. Diisopropyl azodicarboxylic acid (0.538 mL, 2.74 mmol) was slowly added and the mixture was stirred overnight. The reaction mixture was concentrated, diluted with isopropanol, and stirred for 2 hours. The precipitated solid was filtered, washed with isopropanol, and dried to obtain the title compound (510 mg, 69%).

[0133] Step 2: Synthesis of tert-butyl(1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)(methyl)carbamate (3-2) Instead of 4-fluoro-2-methoxy-1-nitrobenzene and Boc-piperazine, 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 11.69 mmol) and tert-butylmethyl(piperidine-4-yl)carbamate (2.76 g, 12.86 mmol) were used, and the title compound (3.90 g, 91%) was obtained using the same method as in the Step 2 synthesis method of Example 1.

[0134] Step 3: Synthesis of tert-butyl(1-(4-amino-3-methoxyphenyl)piperidine-4-yl)(methyl)carbamate (3-3) Instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate, tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)(methyl)carbamate (2.0 g, 7.99 mmol) was used, and the title compound (1.65 g, 94% yield) was obtained using the same method as in the step 3 synthesis method of Example 1.

[0135] Step 4: Synthesis of tert-butyl(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)(methyl)carbamate (3-4) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate and N-(2-((2,5-dichloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, tert-butyl (1-(4-amino-3-methoxyphenyl)piperidine-4-yl)(methyl)carbamate (1.5 g, 4.47 mmol) and N-(2-((2,5-dichloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1.63 g, 4.47 mmol) were used, and the title compound (1.52 g, yield 53%) was obtained using the same method as in the step 4 synthesis method of Example 1.

[0136] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (3-5) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl (1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)(methyl)carbamate (0.5 g, 0.774 mmol) was used, and the title compound (410 mg, yield 97%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0137] Step 6: Synthesis of Compound 3 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 4-(4-bromobutoxy)-2-(2,6-dioxopiperidine-3-yl) Soindoline-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) were used to obtain the title compound (21 mg, yield 16%) using the same method as in the step 6 synthesis method of Example 1.

[0138] Example 4: Synthesis of 11-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)undecanamide (compound 4)

[0139] [ka]

[0140] Step 1: Synthesis of 11-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)undecanamide (4-1) Instead of 5-bromopentanoic acid, 11-bromoundecanoic acid (583 mg, 2.20 mmol) was used, and the title compound (236 mg, 62% yield) was obtained using the same method as in Step 1 of Example 1.

[0141] Step 2: Synthesis of Compound 4 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 11-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3- Using dioxoisoindolin-4-yl)undecanamide (80 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol), the title compound (94 mg, yield 64%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0142] Example 5: Synthesis of 11-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)undecaneamide (Compound 5)

[0143] [ka]

[0144] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 11-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Using indolin-4-yl)undecanamide (60 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol), the title compound (65 mg, yield 54%) was obtained using the same method as in the step 6 synthesis method of Example 1. Ta.

[0145] fruit Example 8: Synthesis of 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (compound 8)

[0146] [ka]

[0147] Step 1: Synthesis of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (8-1) Instead of 5-bromopentanoic acid and 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (200 mg, 0.73 mmol), 2-(2-(2-chloroethoxy)ethoxy)acetic acid (535 mg, 2.93 mmol) and 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (268 mg, 0.98 mmol) were used, and the title compound (404 mg, yield 94%) was obtained using the same method as in the Step 1 synthesis method of Example 1.

[0148] Step 2: Synthesis of N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)-2-(2-(2-iodoethoxy)ethoxy)acetamide (8-2) A mixture of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (400 mg, 0.91 mmol) and sodium iodide (1.3 g, 9.14 mmol) in acetone (6 mL) was stirred overnight under reflux. The reaction mixture was concentrated and diluted with water and dichloromethane for extraction. The organic layer was dried over anhydrous magnesium sulfate and filtered through silica gel. After concentration, the mixture was recrystallized with dichloromethane / methyl tert-butyl ether / heptane to obtain the title compound (456 mg, 95%).

[0149] Step 3: Synthesis of Compound 8 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4- Using yl)-2-(2-(2-iodoethoxy)ethoxy)acetamide (71 mg, 0.14 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.14 mmol), the title compound (96 mg, yield 77%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0150] Example 9: Synthesis of 2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (Compound 9)

[0151] [ka]

[0152] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)-2- (2-(2-iodoethoxy)ethoxy)acetamide (61 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used to obtain the title compound (59 mg, yield 51%) using the same method as in the synthesis method of Step 6 of Example 1. Ta.

[0153] fruit Example 12: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)ethoxy)ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)N-methylmethanesulfonamide (compound 12)

[0154] [ka]

[0155] Step 1: Synthesis of 4-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (12-1) Instead of 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindoline-1,3-dione and 4-bromobutan-1-ol, 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindoline-1,3-dione (200 mg, 0.73 mmol) and 2-(2-chloroethoxy)ethane-1-ol (136 mg, 1.10 mmol) were used, and the title compound (257 mg, yield 80%) was obtained using the same method as in the Step 1 synthesis method of Example 3.

[0156] Step 2: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-(2-(2-iodoethoxy)ethoxy)isoindoline-1,3-dione (12-2) Instead of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide, 4-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (250 mg, 0.57 mmol) was used, and the title compound (215 mg, yield 71%) was obtained using the same method as in the step 2 synthesis method of Example 8.

[0157] Step 3: Synthesis of Compound 12 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2,6-dioxopiperidine-3-yl)-4-(2-(2-iodoetho Using xy)ethoxy)isoindoline-1,3-dione (80 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol), the title compound (65 mg, 50% yield) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0158] Example 13: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)ethoxy)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)N-methylmethanesulfonamide (Compound 13)

[0159] [ka]

[0160] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2,6-dioxopiperidine-3-yl)-4-(2-(2-iodoethoxy)ethoxy Using isoindoline-1,3-dione (61 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol), the title compound (79 mg, yield 72%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0161] Example 14: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)butyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 14)

[0162] [ka]

[0163] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 4-(4-bromobutoxy)-2-(2,6-dioxopiperidine-3 Using -yl)isoindoline-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76 mg, 0.15 mmol), the title compound (25 mg, yield 20%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0164] Example 15: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)butyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 15)

[0165] [ka]

[0166] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 4-(4-bromobutoxy)-2-(2,6-dioxopiperidine-3-yl)iso Using ndolin-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (88 mg, 0.15 mmol), the title compound (23 mg, yield 17%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0167] Example 16: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)piperidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 16)

[0168] [ka]

[0169] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-((2-(2-hydroxyethoxy)ethyl)amino)isoindoline-1,3-dione (16-1) 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) was dissolved in dimethylformamide (1.5 mL), to which 2-(2-aminoethoxy)ethane-1-ol (209 mg, 1.99 mmol) and N,N-diisopropylethylamine (64 μL, 0.368 mmol) were added and stirred overnight at 90°C. The mixture was diluted with ethyl acetate and water for extraction, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the compound was purified by column chromatography to obtain the title compound (251 mg, 39%).

[0170] Step 2: Synthesis of 2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethyl 4-methylbenzene sulfonate (16-2) 2-(2,6-dioxopiperidine-3-yl)-4-((2-(2-hydroxyethoxy)ethyl)amino)isoindoline-1,3-dione (150 mg, 0.42 mmol) and 4-toluenesulfonyl chloride (95 mg, 0.50 mmol) were dissolved in dichloromethane (4 mL), and triethylamine (0.17 mL, 1.25 mmol) was slowly added at 0°C. After stirring at room temperature for 24 hours, the mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (155 mg, 73% yield).

[0171] Step 3: Synthesis of Compound 16 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)aminopyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl) Using n-4-yl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (70 mg, 0.14 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.14 mmol), the title compound (29 mg, yield 25%) was obtained using the same method as in step 6 of Example 1. Ta.

[0172] fruit Example 21: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (compound 21)

[0173] [ka]

[0174] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Using endorin-4-yl)acetamide (46 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol), the title compound (66 mg, yield 63%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0175] Example 22: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)acetamide (Compound 22)

[0176] [ka]

[0177] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindo Using phosphorus-4-yl)acetamide (44 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol), the title compound (72 mg, yield 69%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0178] Example 23: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acetamide (Compound 23)

[0179] [ka]

[0180] Step 1: Synthesis of tert-butyl 4-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (23-1) Instead of Boc-piperazine, tert-butyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate (1.0 g, 3.54 mmol) was used, and the title compound (647 mg, 42% yield) was obtained using the same method as in Step 2 of Example 1.

[0181] Step 2: Synthesis of tert-butyl 4-((1-(4-amino-2-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (23-2) Instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate, tert-butyl 4-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (640 mg, 1.47 mmol) was used, and the title compound (572 mg, 96% yield) was obtained using the same method as in the step 3 synthesis method of Example 1.

[0182] Step 3: Synthesis of tert-butyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (23-3) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 4-((1-(4-amino-2-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (570 mg, 1.41 mmol) was used, and the title compound (625 mg, yield 63%) was obtained using the same method as in the step 4 synthesis method of Example 1.

[0183] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (23-4) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (620 mg, 0.17 mmol) was used, and the title compound (535 mg, yield 100%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0184] Step 5: Synthesis of Compound 23 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin Using dorin-4-yl)acetamide (45 mg, 0.11 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol), the title compound (70 mg, yield 67%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0185] Example 24: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)acetamide (Compound 24)

[0186] [Chemistry]

[0187] Instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentaamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (43 mg, 0.11 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol) were used, and the title compound (78 mg, yield 75%) was obtained using the same method as the synthesis method in Step 6 of Example 1.

[0188] Example 25: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 25)

[0189] [Chemistry]

[0190] Step 1: Synthesis of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (25-1) Instead of Boc-piperazine, benzyl 4-(piperazine-1-ylmethyl)piperidine-1-carboxylate (1.0 g, 3.16 mmol) was used, and the title compound (903 mg, yield 61%) was obtained using the same method as in the Step 2 synthesis method of Example 1.

[0191] Step 2: Synthesis of benzyl 4-((4-(4-amino-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (25-2) A solution of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (900 mg, 1.92 mmol) in 1,4-dioxane (15 mL) was added to a solution of NH4Cl (513 mg, 9.60 mmol) in H2O (5 mL) and purged with argon. Zinc (628 mg, 9.60 mmol) was added and the mixture was stirred at 70°C. After 19 hours, the mixture was filtered through Celite and concentrated. The residue was diluted with aqueous sodium chloride solution, made basic with saturated sodium hydrocarbon solution, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the title compound (831 mg, 99% yield).

[0192] Step 3: Synthesis of benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (25-3) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate, benzyl 4-((4-(4-amino-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (830 mg, 1.89 mmol) was used, and the title compound (1.0 g, yield 71%) was obtained using the same method as in the step 4 synthesis method of Example 1.

[0193] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (25-4) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (800 mg, 1.06 mmol) was used, and the title compound (617 mg, yield 94%) was obtained using the same method as in the step 3 synthesis method of Example 1.

[0194] Step 5: Synthesis of Compound 25 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin Using dorin-4-yl)acetamide (45 mg, 0.11 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol), the title compound (33 mg, yield 31%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0195] Example 26: Synthesis of 2-(4-((4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)acetamide (compound 26)

[0196] [ka]

[0197] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl) Using n-4-yl)acetamide (43 mg, 0.11 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol), the title compound (78 mg, yield 75%) was obtained using the same method as in the synthesis method of step 6 of Example 1. Ta.

[0198] fruit Example 30: Synthesis of 3-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propanamide (compound 30)

[0199] [ka]

[0200] Step 1: Synthesis of tert-butyl 9-(3-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-1) Instead of Boc-piperazine, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (6.0 g, 35.06 mmol) was used, and the title compound (13.2 g, yield 93%) was obtained in the same manner as in the step 2 synthesis method of Example 1.

[0201] Step 2: Synthesis of tert-butyl 9-(4-amino-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-2) Instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate, tert-butyl 9-(3-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.5 g, 3.70 mmol) was used, and the title compound (1.4 g, yield 99%) was obtained in the same manner as in the step 3 synthesis method of Example 1.

[0202] Step 3: Synthesis of tert-butyl 9-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-3) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 9-(4-amino-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.4 g, 3.60 mmol) was used, and the title compound (1.4 g, yield 54%) was obtained in the same manner as in the step 4 synthesis method of Example 1.

[0203] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (30-4) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 9-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.4 g, 1.98 mmol) was used, and the title compound (1.2 g, 99% yield) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0204] Step 5: Synthesis of Compound 30 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 3-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Using undolin-4-yl)propanamide (49 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (70 mg, 0.12 mmol), the title compound (61 mg, yield 56%) was obtained using the same method as in the step 6 synthesis method of Example 1. Ta.

[0205] fruitExample 32: Synthesis of 3-(6-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propanamide (compound 32)

[0206] [ka]

[0207] Step 1: Synthesis of tert-butyl 6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (32-1) Instead of Boc-piperazine, tert-butyl 2,6-diazaspiro[3.3]undecane-2-carboxylate (7.4 g, 21.0 mmol) was used, and the title compound (4.8 g, 79% yield) was obtained using the same method as in the Step 2 synthesis method of Example 1.

[0208] Step 2: Synthesis of tert-butyl 6-(4-amino-3-methoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (32-2) Instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate, tert-butyl 6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.29 mmol) was used, and the title compound (950 mg, 70% yield) was obtained using the same method as in the step 3 synthesis method of Example 1.

[0209] Step 3: Synthesis of tert-butyl6-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3.3]undecane-2-carboxylate (32-3) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 6-(4-amino-3-methoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.9 g, 2.81 mmol) was used, and the title compound (0.7 g, 34% yield) was obtained using the same method as in the step 4 synthesis method of Example 1.

[0210] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3,3]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (32-4) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 6-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3.3]undecane-2-carboxylate (0.7 g, 1.98 mmol) was used, and the title compound (580 mg, yield 99%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0211] Step 5: Synthesis of Compound 32 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 3-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Using endorin-4-yl)propanamide (54 mg, 0.13 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (70 mg, 0.13 mmol), the title compound (48 mg, yield 41%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0212] Example 33: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)oxy)ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 33)

[0213] [ka]

[0214] Step 1: Synthesis of tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate (33-1) To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.77 mmol) in DMF (11 mL), sodium hydroxide (346 mg, 8.66 mmol) was added and the mixture was stirred for 30 minutes. ((2-bromoethoxy)methyl)benzene (1.1 mL, 6.93 mmol) was slowly added at 0°C. After stirring overnight at 80°C, the mixture was extracted with ethyl acetate and water. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated, and purified by column chromatography to obtain the title compound (0.95 g, yield 54%).

[0215] Step 2: Synthesis of 3-(2-(benzyloxy)ethoxy)azetidine. (33-2)tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate (0.9 g, 2.93 mmol) was stirred in a 20% trifluoroacetic acid dichloromethane solution (20 mL) at room temperature for 5 hours. The reaction mixture was concentrated and extracted with 1N sodium hydroxide aqueous solution and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (550 mg, yield 92%).

[0216] Step 3: Synthesis of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (33-3) 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindorin-1,3-dione (0.6 g, 2.17 mmol) and 3-(2-(benzyloxy)ethoxy)azetidine (0.5 g, 2.39 mmol) were dissolved in N,N-dimethylformamide (10 mL), to which diisopropylethylamine (757 mL, 4.34 mmol) was added and stirred overnight at 80°C. The mixture was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the title compound (650 mg, yield 65%).

[0217] Step 4: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(2-hydroxyethoxy)azetidine-1-yl)isoindoline-1,3-dione (33-4) A solution of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (500 mg, 1.08 mmol) in tetrahydrofuran / methanol (1 / 1, 20 mL) was purged with argon, and 10% Pd / C (0.2 g) was added. The reaction mixture was purged with hydrogen and stirred overnight. The mixture was diluted with dichloromethane, filtered through Celite, concentrated, and the residue was purified by column chromatography to obtain the title compound (130 mg, yield 32%).

[0218] Step 5: Synthesis of 2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)oxy)ethylmethanesulfonate (33-5) 2-(2,6-dioxopiperidine-3-yl)-5-(3-(2-hydroxyethoxy)azetidine-1-yl)isoindoline-1,3-dione (130 mg, 0.35 mmol) was dissolved in dichloromethane (7 mL), to which triethylamine (146 mL, 1.05 mmol) was added. Methanesulfonyl chloride (54 mL, 0.70 mmol) was slowly added at 0°C. The reaction mixture was extracted with water and dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (90 mg, yield 57%).

[0219] Step 6: Synthesis of Compound 33 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Using zethidine-3-yl)oxy)ethylmethanesulfonate (70 mg, 0.16 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (81 mg, 0.16 mmol), the title compound (40 mg, yield 31%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0220] Example 34: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)oxy)ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 34)

[0221] [ka]

[0222] Step 1: Synthesis of tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-1-carboxylate (34-1) Instead of tert-butyl 3-hydroxyazetidine-1-carboxylate, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol) was used, and the title compound (0.7 g, 42% yield) was obtained using the same method as in the Step 1 synthesis method of Example 33.

[0223] Step 2: Synthesis of 4-(2-(benzyloxy)ethoxy)piperidine (34-2) Instead of tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate, tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-1-carboxylate (0.7 g, 2.09 mmol) was used, and the title compound (480 mg, yield 98%) was obtained using the same method as in the Step 2 synthesis method of Example 33.

[0224] Step 3: Synthesis of 5-(4-(2-(benzyloxy)ethoxy)piperidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (34-3) Instead of 3-(2-(benzyloxy)ethoxy)azetidine, 4-(2-(benzyloxy)ethoxy)piperidine (468 mg, 1.99 mmol) was used, and the title compound (400 mg, 45% yield) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0225] Step 4: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-(4-(2-hydroxyethoxy)piperidine-1-yl)isoindoline-1,3-dione (34-4) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione, 5-(4-(2-(benzyloxy)ethoxy)piperidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (0.4 g, 0.81 mmol) was used, and the title compound (130 mg, yield 40%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0226] Step 5: Synthesis of 2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)oxy)ethylmethanesulfonate (34-5) Instead of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(2-hydroxyethoxy)azetidine-1-yl)isoindoline-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-5-(4-(2-hydroxyethoxy)piperidine-1-yl)isoindoline-1,3-dione (125 mg, 0.31 mmol) was used, and the title compound (135 mg, 90% yield) was obtained using the same method as in the synthesis method of Step 5 of Example 33.

[0227] Step 5: Synthesis of Compound 34 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Using piperidine-4-yl)oxy)ethylmethanesulfonate (70 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (76 mg, 0.15 mmol), the title compound (70 mg, yield 53%) was obtained using the same method as in the step 6 synthesis method of Example 1. Ta.

[0228] fruit Example 39: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)oxy)azetidine-1-yl)ethyl)piperazine-1-yl)-3-fluorophenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (compound 39)

[0229] [ka]

[0230] Step 1: Synthesis of tert-butyl 3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoindoline-4-yl)oxy)azetidine-1-carboxylate (39-1) A mixture of 3-(4-hydroxy-1-oxoindolin-2-yl)piperidine-2,6-dione (297 mg, 1.14 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (646 mg, 2.28 mmol), and potassium carbonate (315 mg, 2.28 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70°C. After stirring overnight, tert-butyl 3-iodoazetidine-1-carboxylate (200 mg) was added and the mixture was stirred for 4 hours. A saturated aqueous solution of NH4Cl was added to the reaction mixture and stirred. The mixture was filtered, washed with water and ethyl acetate, and vacuum dried to obtain the title compound (150 mg, 36%).

[0231] Step 2: Synthesis of 3-(4-(azetidine-3-yloxy)-1-oxoindoline-2-yl)piperidine-2,6-dione hydrochloride (39-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)oxy)azetidine-1-carboxylate (150 mg, 0.36 mmol) was used, and the title compound was obtained using the same method as in the synthesis method of Step 5 of Example 1, and used in the following reaction.

[0232] Step 3: Synthesis of 3-(4-((1-(2-chloroethyl)azetidine-3-yl)oxy)-1-oxoindolin-2-yl)piperidine-2,6-dione (39-3)3-(4-(azetidine-3-yloxy)-1-oxoindolin-2-yl)piperidine-2,6-dione hydrochloride (127 mg, 0.36 mmol) and 1-bromo-2-chloroethane (33 μL, 0.40 mmol) in N,N-dimethylformamide (3.5 mL) were mixed with diisopropylethylamine (219 μL, 0.29 mmol) and stirred at 90°C. After 4.5 hours, the mixture was concentrated and purified by column chromatography to obtain the title compound (70 mg, 51%).

[0233] Step 4: Synthesis of Compound 39 A mixture of 3-(4-((1-(2-chloroethyl)azetidine-3-yl)oxy)-1-oxoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.185 mmol), N-(2-((5-chloro-2-((3-fluoro-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (93 mg, 0.185 mmol), sodium iodide (14 mg, 0.093 mmol), sodium hydroxide (31 mg, 0.371 mmol), and tetrabutylammonium bromide (TBAB, 30 mg, 0.093 mmol) in N,N-dimethylformamide (1 mL) was stirred overnight at 80°C. The mixture was cooled to room temperature, water was added, and the solid was obtained by filtration. The resulting solid was then purified by column chromatography to obtain the title compound (35 mg, 23%).

[0234] Example 40: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)oxy)ethyl)piperazine-1-yl)-3-fluorophenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 40)

[0235] [ka]

[0236] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline Using -5-yl)azetidine-3-yl)oxy)ethylmethanesulfonate (70 mg, 0.16 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (78 mg, 0.16 mmol), the title compound (57 mg, yield 43%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0237] Example 41: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)methyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 41)

[0238] [ka]

[0239] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-methylisoindoline-1,3-dione (41-1) A mixture of 5-methylisofuran-1,3-dione (5.0 g, 30.84 mmol), 3-aminopiperidine-2,6-dione (6.1 g, 37.01 mmol), and sodium acetate (2.5 g, 30.84 mmol) in acetic acid (50 mL) was stirred at 80°C. After 6 hours, the mixture was cooled to room temperature, water was added, and the mixture was stirred. The precipitated solid was filtered, washed with methyl tert-butyl ether, and dried to obtain the title compound (6.1 g, 72%).

[0240] Step 2: Synthesis of 5-(bromomethyl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (41-2) A chloroform solution (10 mL) containing 2-(2,6-dioxopiperidine-3-yl)-5-methylisoindoline-1,3-dione (200 mg, 0.74 mmol) and NBS (144 mg, 0.81 mmol) was mixed with AIBN (24 mg, 0.15 mmol) and stirred under reflux. After stirring overnight, water was added for extraction, the mixture was dried over anhydrous magnesium sulfate, filtered, and the resulting substance (140 mg, mixture) was used in the next reaction.

[0241] Step 3: Synthesis of Compound 41 5-(bromomethyl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (44 mg, 0.125 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (1 mL), to which DIPEA (50 μL, 0.285 mmol) was added and stirred overnight at 50°C. After cooling to room temperature, water was added and the mixture was filtered to obtain a solid, which was then purified by column chromatography to obtain the title compound (48 mg, 48%).

[0242] Example 42: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)methyl)piperazine-1-yl)piperidine-1-yl)-3-fluorophenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 42)

[0243] [ka]

[0244] Instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.119 mmol) was used, and the title compound (56 mg, yield 55%) was obtained using the same method as in the step 3 synthesis method of Example 41.

[0245] Example 43: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 43)

[0246] [ka]

[0247] Instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (50 mg, 0.151 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used, and the title compound (30 mg, yield 28%) was obtained using the same method as in the Step 1 synthesis method of Example 6.

[0248] Example 44: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(((2S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-2-yl)methyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 44)

[0249] [ka]

[0250] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-((S)-2-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione (44-1) Instead of 3-(2-(benzyloxy)ethoxy)azetidine, (S)-pyrrolidine-2-ylmethanol (44 mg, 0.43 mmol) was used, and the title compound (120 mg, 93% yield) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0251] Step 2: Synthesis of ((2S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoindoline-5-yl)pyrrolidine-2-yl)methylmethanesulfonate (44-2) Instead of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(2-hydroxyethoxy)azetidine-1-yl)isoindoline-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-5-((S)-2-(hydroxymethyl)pyrrolidine-1-yl)isoindoline-1,3-dione (1.0 g, 2.53 mmol) was used, and the title compound (416 mg, yield 38%) was obtained using the same method as in the synthesis method of Step 5 of Example 33.

[0252] Step 3: Synthesis of Compound 44 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use ((2S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoindorin-5-yl) Using pyrrolidine-2-yl)methylmethanesulfonate (50 mg, 0.115 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (69 mg, 0.115 mmol), the title compound (18 mg, yield 17%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0253] Example 45: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 45)

[0254] [ka]

[0255] Step 1: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(4-(2-(1,3-dioxoindolin-2-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (45-1) A mixture of 2-(2-bromoethyl)isoindoline-1,3-dione (205 mg, 0.81 mmol), N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (500 mg, 0.81 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile (8 mL) was stirred overnight at 70°C. The reaction mixture was concentrated and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to obtain the title compound (350 mg, yield 57%).

[0256] Step 2: Synthesis of N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (45-2) N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoindolin-2-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (350 mg, 0.45 mmol) was mixed with ethanol (4.5 mL) and hydrazine hydrate (57 mg, 1.13 mmol) was added and stirred at 80°C for 4 hours. The reaction mixture was concentrated and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound, which was used in the next reaction.

[0257] Step 3: Synthesis of Compound 45 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (30 mg, 0.109 mmol) and N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.109 mmol) were used, and the title compound (35 mg, yield 36%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0258] Example 46: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)ethyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 46)

[0259] [ka]

[0260] Step 1: Synthesis of 4-(2-chloroethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (46-1) Instead of 4-bromobutan-1-ol, 2-chloroethane-1-ol (110 μL, 1.64 mmol) was used, and the title compound (323 mg, 94% yield) was obtained using the same method as in Step 1 of Example 3.

[0261] Step 2: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-4-(2-iodoethoxy)isoindoline-1,3-dione (46-2) Instead of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide, 4-(2-chloroethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (320 mg, 1.01 mmol) was used, and the title compound (341 mg, yield 78%) was obtained using the same method as in the step 2 synthesis method of Example 8.

[0262] Step 3: Synthesis of Compound 46 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2,6-dioxopiperidine-3-yl)-4-(2-iodoethoxy)isoindorin Phosphorus-1,3-dione (54 mg, 0.128 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used to obtain the title compound (36 mg, yield 35%) using the same method as in the step 6 synthesis method of Example 1.

[0263] Example 47: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-5-yl)acetamide (Compound 47)

[0264] [ka]

[0265] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl) Using n-5-yl)acetamide (44 mg, 0.116 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol), the title compound (63 mg, yield 61%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0266] Example 48: Synthesis of 2-(4-((4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-2-fluorophenyl)piperazine-1-yl)methyl)piperidine-1-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)acetamide (compound 48)

[0267] [ka]

[0268] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindoline- Using 4-yl)acetamide (44 mg, 0.116 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol), the title compound (63 mg, yield 60%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0269] Example 49: Synthesis of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)piperidine-4-carboxamide (compound 49)

[0270] [ka]

[0271] Step 1: Synthesis of benzyl 4-((4-(tert-butoxycarbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (49-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, benzyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.04 mmol) and tert-butylpiperidine-4-carboxylate (1.1 g, 6.07 mmol) were used, and the title compound (700 mg, yield 43%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0272] Step 2: Synthesis of tert-butyl 1-(piperidine-4-ylmethyl)piperidine-4-carboxylate (49-2) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl 4-((4-(tert-butoxycarbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (700 mg, 1.68 mmol) was used, and the title compound (470 mg, yield 99%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0273] Step 3: Synthesis of tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (49-3) Instead of Boc-piperazine, tert-butyl 1-(piperidine-4-ylmethyl)piperidine-4-carboxylate (1.3 g, 4.60 mmol) was used, and the title compound (240 mg, yield 12%) was obtained using the same method as in the Step 2 synthesis method of Example 1.

[0274] Step 4: Synthesis of tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (49-4) Instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate, tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (240 mg, 0.55 mmol) was used, and the title compound (223 mg, 99% yield) was obtained using the same method as in the step 3 synthesis method of Example 1.

[0275] Step 5: Synthesis of tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (49-5) Instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (223 mg, 0.55 mmol) was used, and the title compound (95 mg, yield 24%) was obtained using the same method as in the step 4 synthesis method of Example 1.

[0276] Step 6: Synthesis of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride (49-6) Instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)propanoate, tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate (100 mg, 0.14 mmol) was used, and the title compound was obtained using the same method as in the Step 2 synthesis method of Example 20, and used in the following reaction.

[0277] Step 7: Synthesis of Compound 49 A mixture of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride (97 mg, 0.14 mmol), 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione (36 mg, 0.86 mmol), and HATU (107 mg, 0.28 mmol) in N,N-dimethylformamide (1 mL) was mixed with diisopropylethylamine (98 μL, 0.56 mmol) and stirred for 2 days. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column to obtain the title compound (21 mg, 17%).

[0278] Example 50: Synthesis of 2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-yl)-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindorin-4-yl)acetamide (compound 50)

[0279] [ka]

[0280] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoindoline Using -4-yl)acetamide (60 mg, 0.158 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (93 mg, 0.158 mmol), the title compound (90 mg, yield 64%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0281] Example 51: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 51)

[0282] [ka]

[0283] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-(4-(2-hydroxyethyl)piperidine-1-yl)isoindoline-1,3-dione (51-1) Instead of 3-(2-(benzyloxy)ethoxy)azetidine, 2-(piperidine-4-yl)ethane-1-ol (412 mg, 3.19 mmol) was used, and the title compound (0.99 g, yield 89%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0284] Step 2: Synthesis of 2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)ethylmethanesulfonate (51-2) Instead of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(2-hydroxyethoxy)azetidine-1-yl)isoindoline-1,3-dione, 2-(2,6-dioxopiperidine-3-yl)-5-(4-(2-hydroxyethyl)piperidine-1-yl)isoindoline-1,3-dione (0.99 g, 2.57 mmol) was used, and the title compound (510 mg, yield 43%) was obtained using the same method as in the Step 2 synthesis method of Example 33.

[0285] Step 3: Synthesis of Compound 51 Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Using piperidine-4-yl)ethylmethanesulfonate (50 mg, 0.108 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (65 mg, 0.108 mmol), the title compound (30 mg, yield 29%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0286] Example 52: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 52)

[0287] [ka]

[0288] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2,6-dioxopiperidine-3-yl)-4-(2-iodoethoxy)isoin Using dorin-1,3-dione (50 mg, 0.116 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol), the title compound (54 mg, yield 52%) was obtained using the same method as in the step 6 synthesis method of Example 1.

[0289] Example 53: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 53)

[0290] [ka]

[0291] Instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (42 mg, 0.125 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.114 mmol) were used, and the title compound (42 mg, yield 41%) was obtained using the same method as in Step 1 of Example 6.

[0292] Example 54: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 54)

[0293] [ka]

[0294] Step 1: Synthesis of benzyl(E)-3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindorin-4-yl)acrylate (54-1) A mixture of tri-tert-butylphosphonium tetrafluoroborate (TTBP·HBF4, 110 mg, 0.38 mmol), Pd2(dba)3 (163 mg, 0.18 mmol), and N-cyclohexyl-N-cyclohexaneamine (0.27 mL, 1.28 mmol) in 1,4-dioxane (6 mL) was purged with argon gas and stirred for 30 minutes. (4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.3 g, 0.89 mmol) and benzyl acrylate (0.3 mL, 1.98 mmol) were added and the mixture was stirred at 55°C for 12 hours. The reaction mixture was filtered through Celite, concentrated, and purified by column chromatography to obtain the title compound (368 mg, 99% yield).

[0295] Step 2: Synthesis of 3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propanoic acid (54-2) Benzyl(E)-3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acrylate (137 mg, 0.33 mmol) was dissolved in tetrahydrofuran (5 mL) and 10% Pd / C (27 mg) was added, then the mixture was purged with hydrogen gas. After stirring overnight, the solution was filtered through Celite and concentrated to obtain the title compound (105 mg, 96% yield).

[0296] Step 3: Synthesis of Compound 54 Instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, 3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)propanoic acid (50 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (92 mg, 0.15 mmol) were used, and the title compound (105 mg, yield 75%) was obtained using the same method as in Step 1 of Example 6. Ta.

[0297] fruit Example 57: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)ethyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (compound 57)

[0298] [ka]

[0299] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(2,6-dioxopiperidine-3-yl)-4-(2-iodoethoxy)isoindorin Phosphorus-1,3-dione (34 mg, 0.079 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (50 mg, 0.079 mmol) were used to obtain the title compound (30 mg, 40% yield) using the same method as in the step 6 synthesis method of Example 1.

[0300] Example 58: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 58)

[0301] [ka]

[0302] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((2-((4-(4-(2-aminoethyl)piperazin-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.109 mmol) was used, and the title compound (20 mg, yield 20%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0303] Example 59: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 59)

[0304] [ka]

[0305] Step 1: Synthesis of benzyl 4-((4-((4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (59-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, benzyl 4-formylpiperidine-1-carboxylate (121 mg, 0.49 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (250 mg, 0.41 mmol) were used, and the title compound (340 mg, yield 97%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0306] Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-((1-(piperidine-4-ylmethyl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (59-2) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl 4-((4-((4-((4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (340 mg, 0.40 mmol) was used, and the title compound (247 mg, yield 79%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0307] Step 3: Synthesis of Compound 59 Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-4-(4-((1-(piperidine-4-ylmethyl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.14 mmol) was used, and the title compound (73 mg, yield 53%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0308] Example 60: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)methyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (compound 60)

[0309] [ka]

[0310] Step 1: Synthesis of tert-butyl 3-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)methyl)azetidine-1-carboxylate (60-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, tert-butyl3-formylazetidine-1-carboxylate (54 mg, 0.293 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.244 mmol) were used, and the title compound (220 mg, yield >100%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0311] Step 2: Synthesis of N-(2-((2-((4-(4-(4-((azetidine-3-ylmethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (60-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 3-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)methyl)azetidine-1-carboxylate (220 mg, 0.244 mmol) was used, and the title compound (250 mg, yield >100%) was obtained using the same method as in the step 5 synthesis method of Example 1.

[0312] Step 3: Synthesis of Compound 60 Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((2-((4-(4-(4-(azetidine-3-ylmethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.189 mmol) was used, and the title compound (28 mg, yield 16%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0313] Example 61: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)methyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 61)

[0314] [ka]

[0315] Step 1: Synthesis of tert-butyl 3-((4-((4-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)methyl)azetidine-1-carboxylate (61-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, tert-butyl3-formylazetidine-1-carboxylate (54 mg, 0.293 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.244 mmol) were used, and the title compound (220 mg, yield >100%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0316] Step 2: Synthesis of N-(2-((2-((4-(4-((1-(azetidine-3-ylmethyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (61-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 3-((4-((4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)methyl)azetidine-1-carboxylate (220 mg, 0.244 mmol) was used, and the title compound (260 mg, yield >100%) was obtained using the same method as in the step 5 synthesis method of Example 1.

[0317] Step 3: Synthesis of Compound 61 Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((2-((4-(4-((1-(azetidine-3-ylmethyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.189 mmol) was used, and the title compound (30 mg, yield 17%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0318] Example 62: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)methyl)piperidine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 62)

[0319] [ka]

[0320] Step 1: Synthesis of tert-butyl 4-((4-(((((benzyloxy)carbonyl)amino)methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (62-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, tert-butyl-4-formylpiperidine-1-carboxylate (945 mg, 4.43 mmol) and benzyl(piperidine-4-ylmethyl)carbamate (1.0 g, 4.03 mmol) were used, and the title compound (1.5 g, 80% yield) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0321] Step 2: Synthesis of benzyl((1-(piperidine-4-ylmethyl)piperidine-4-yl)methyl)carbamate (62-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 4-((4-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate (1.5 g, 3.37 mmol) was used, and the title compound (900 mg, yield 81%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0322] Step 3: Synthesis of benzyl((1-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (62-3) Instead of Boc-piperazine, benzyl((1-(piperidine-4-ylmethyl)piperidine-4-yl)methyl)carbamate (400 mg, 1.16 mmol) was used, and the title compound (540 mg, 94% yield) was obtained using the same method as in the Step 2 synthesis method of Example 1.

[0323] Step 4: Synthesis of benzyl((1-((1-(4-amino-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (62-4) Instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl ((1-((1-(3-methoxy-4-nitrophenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (540 mg, 1.09 mmol) was used, and the title compound (480 mg, yield 95%) was obtained using the same method as in the Step 2 synthesis method of Example 25.

[0324] Step 5: Synthesis of benzyl((1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (62-5) Instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (420 mg, 0.95 mmol), benzyl ((1-((1-(4-amino-3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (480 mg, 1.03 mmol) was used, and the title compound (480 mg, yield 60%) was obtained using the same method as in the step 3 synthesis method of Example 35.

[0325] Step 6: Synthesis of N-(2-((2-((4-(4-((4-(((aminomethyl)piperidine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (62-6) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl((1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-yl)methyl)carbamate (480 mg, 0.62 mmol) was used, and the title compound (395 mg, yield 99%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0326] Step 7: Synthesis of Compound 62 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (129 mg, 0.47 mmol) and N-(2-((2-((4-(4-((4-(((aminomethyl)piperidine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (200 mg, 0.31 mmol) were used, and the title compound (48 mg, yield 17%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0327] Example 63: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)amino)methyl)piperidine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 63)

[0328] [ka]

[0329] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((2-((4-(4-((4-((aminomethyl)piperidine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.16 mmol) was used, and the title compound (65 mg, yield 47%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0330] Example 64: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)propanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 64)

[0331] [ka]

[0332] Step 1: Synthesis of benzyl(E)-3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl)acrylate (64-1) Instead of (4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione), (5-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (100 mg, 0.30 mmol) was used, and the title compound (120 mg, yield 96%) was obtained using the same method as the Step 1 synthesis method of Example 54.

[0333] Step 2: Synthesis of 3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)propanoic acid (64-2) Instead of benzyl(E)-3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)acrylate, benzyl(E)-3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)acrylate (120 mg, 0.29 mmol) was used, and the title compound (60 mg, yield 63%) was obtained using the same method as in the Step 2 synthesis method of Example 54.

[0334] Step 3: Synthesis of Compound 64 Instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, 3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)propanoic acid (40 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74 mg, 0.12 mmol) were used, and the title compound (75 mg, yield 67%) was obtained using the same method as in the Step 1 synthesis method of Example 6.

[0335] Example 65: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)glycyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 65)

[0336] [ka]

[0337] Step 1: Synthesis of tert-butyl(2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-2-oxoethyl)carbamate (65-1) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (351 mg, 0.57 mmol) and (tert-butoxycarbonyl)glycine (100 mg, 0.57 mmol) were used, and the title compound (350 mg, 79%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0338] Step 2: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (65-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl (2-(4-((4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-2-oxoethyl)carbamate (150 mg, 0.19 mmol) was used, and the title compound (120 mg, yield 92%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0339] Step 3: Synthesis of Compound 65 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (45 mg, 0.16 mmol) and N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) were used, and the title compound (80 mg, yield 53%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0340] Example 66: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)glycyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (compound 66)

[0341] [ka]

[0342] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) was used, and the title compound (28 mg, yield 19%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0343] Example 67: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 67)

[0344] [ka]

[0345] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (111 mg, 0.18 mmol) was used, and the title compound (90 mg, yield 57%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0346] Example 68: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 68)

[0347] [ka]

[0348] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (111 mg, 0.18 mmol) was used, and the title compound (110 mg, yield 70%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0349] Example 69: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 69)

[0350] [ka]

[0351] Step 1: Synthesis of (S)-N-(2-((5-chloro-2-((4-(4-((1-(2-hydroxypropanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (69-1) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (137 mg, 0.22 mmol) and (S)-hydroxypropanoic acid (20 mg, 0.22 mmol) were used, and the title compound (80 mg, 53%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0352] Step 2: Synthesis of Compound 69 Instead of 4-bromobutan-1-ol, (S)-N-(2-((5-chloro-2-((4-(4-((1-(2-hydroxypropanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.12 mmol) was used, and the title compound (60 mg, yield 55%) was obtained using the same method as in the Step 1 synthesis method of Example 3.

[0353] Example 70: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)-L-alanyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 70)

[0354] [ka]

[0355] Step 1: Synthesis of tert-butyl(S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-1-oxopropan-2-yl))carbamate (70-1) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (130 mg, 0.21 mmol) and (tert-butoxycarbonyl)-L-alanine (40 mg, 0.21 mmol) were used, and the title compound (130 mg, 79%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0356] Step 2: Synthesis of N-(2-((2-((4-(4-((1-(L-alanyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70-2) Instead of tert-butyl4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl(S)-(1-(4-((4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-1-oxopropan-2-yl))carbamate (128 mg, 0.16 mmol) was used, and the title compound (105 mg, yield 94%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0357] Step 3: Synthesis of Compound 70 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (30 mg, 0.11 mmol) and N-(2-((2-((4-(4-((1-(L-alanylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75 mg, 0.11 mmol) were used, and the title compound (60 mg, yield 60%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0358] Example 71: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 71)

[0359] [ka]

[0360] Step 1: Synthesis of tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (71-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, tert-butyl3-formylazetidine-1-carboxylate (65 mg, 0.31 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (130 mg, 0.22 mmol) were used, and the title compound (103 mg, yield 60%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0361] Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidine-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (100 mg, 0.125 mmol) was used, and the title compound (90 mg, yield >100%) was obtained using the same method as in the step 5 synthesis method of Example 1.

[0362] Step 3: Synthesis of Compound 71 Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (88 mg, 0.126 mmol) was used, and the title compound (64 mg, yield 53%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0363] Example 72: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)prop-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethasulfonamide (Compound 72)

[0364] [ka]

[0365] Step 1: Synthesis of 2-(2,6-dioxopiperidine-3-yl)-5-(3-hydroxyprop-1-in-1-yl)isoindoline-1,3-dione (72-1) 5-Bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (3.0 g, 8.90 mmol), prop-2-in-1-ol (0.78 mL, 12.82 mmol), and CuI (576 mg, 3.03 mmol) were mixed in N,N-dimethylformamide (45 mL) and N,N-diisopropyldiamine (3.1 mL, 17.80 mmol) was added, and the mixture was purged with argon gas. Pd(PPh3)2Cl2 (1.0 g, 1.42 mmol) was added and the mixture was stirred overnight at 75°C. The mixture was extracted with dichloromethane and water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was recrystallized in toluene to obtain the title compound (1.0 g, yield 36%).

[0366] Step 2: Synthesis of 5-(3-chloroprop-1-in-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (72-2) 2-(2,6-dioxopiperidine-3-yl)-5-(3-hydroxyprop-1-in-1-yl)isoindorin-1,3-dione (170 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which N,N-diisopropyldiamine (0.13 mL, 1.62 mmol) was added. Methanesulfonyl chloride (0.05 mL, 0.65 mmol) was slowly added at 0°C. The reaction mixture was stirred overnight and then extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (150 mg, yield 84%).

[0367] Step 3: Synthesis of Compound 72 Instead of 5-(bromomethyl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 5-(3-chloroprop-1-in-1-yl)-2-(2,6-dioxopiperidine-3- Using yl)isoindoline-1,3-dione (77 mg, 0.23 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (140 mg, 0.23 mmol), the title compound (180 mg, yield 87%) was obtained using the same method as in the step 3 synthesis method of Example 41.

[0368] Example 73: Synthesis of N-(2-((5-chloro-2-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)prop-2-in-1-yl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 73)

[0369] [ka]

[0370] Instead of 5-(bromomethyl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 5-(3-chloroprop-1-in-1-yl)-2-(2,6-dioxopiperidine-1-yl) Using lysine-3-yl)isoindoline-1,3-dione (50 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78 mg, 0.15 mmol), the title compound (68 mg, yield 56%) was obtained using the same method as in the step 3 synthesis method of Example 41.

[0371] Example 74: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 74)

[0372] [ka]

[0373] Step 1: Synthesis of benzyl 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (74-1) Instead of Boc-piperazine, benzyl 4-(piperidine-4-yl)piperazine-1-carboxylate (619 mg, 2.04 mmol) was used, and the title compound (430 mg, 45% yield) was obtained using the same method as in Step 2 of Example 1.

[0374] Step 2: Synthesis of benzyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidine-4-yl)piperazine-1-carboxylate (74-2) Instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)piperazine-1-carboxylate (988 mg, 1.09 mmol) was used, and the title compound (873 mg, yield 94%) was obtained using the same method as in the Step 2 synthesis method of Example 25.

[0375] Step 3: Synthesis of benzyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidine-4-yl)piperazine-1-carboxylate (74-3) Instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidine-4-yl)piperazine-1-carboxylate (873 mg, 1.99 mmol) was used, and the title compound (1.1 g, yield 74%) was obtained using the same method as in the step 3 synthesis method of Example 35.

[0376] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-4) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidine-4-yl)piperazine-1-carboxylate (1.1 g, 1.67 mmol) was used, and the title compound (648 mg, yield 72%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0377] Step 5: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoindolin-2-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-5) Instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (300 mg, 0.49 mmol) was used, and the title compound (80 mg, yield 22%) was obtained using the same method as in the Step 1 synthesis method of Example 45.

[0378] Step 6: Synthesis of N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-6) Instead of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoindolin-2-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxyphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoindolin-2-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.10 mmol) was used, and the title compound (49 mg, yield 74%) was obtained using the same method as in the Step 2 synthesis method of Example 45.

[0379] Step 7: Synthesis of Compound 74 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (22 mg, 0.079 mmol) and N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (47 mg, 0.072 mmol) were used, and the title compound (21 mg, yield 32%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0380] Example 75: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)-L-alanyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 75)

[0381] [ka]

[0382] Step 1: Synthesis of benzyl 4-((4-(5-methoxy-2-methyl-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (75-1) A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (6.5 g, 35.11 mmol), benzyl 4-(piperazine-1-ylmethyl)piperidine-1-carboxylate (14.4 g, 36.86 mmol), and potassium carbonate (17.0 g, 122.87 mmol) dimethyl sulfoxide (87 mL) was stirred at 110°C. After stirring overnight, water was added to the reaction mixture and stirred, filtered, and washed with water. The residue was dissolved in ethyl acetate and washed sequentially with water and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (14.0 g, 72%).

[0383] Step 2: Synthesis of benzyl 4-((4-(4-amino-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (75-2) Instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-((4-(5-methoxy-2-methyl-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (794 mg, 1.60 mmol) was used, and the title compound (718 mg, 99% yield) was obtained using the same method as in the Step 2 synthesis method of Example 25.

[0384] Step 3: Synthesis of benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (75-3) Instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-((4-(4-amino-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (718 mg, 1.58 mmol) was used, and the title compound (1.0 g, yield 83%) was obtained using the same method as in the step 3 synthesis method of Example 35.

[0385] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-4) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate (1.0 g, 1.31 mmol) was used, and the title compound (800 mg, yield >100%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0386] Step 5: Synthesis of tert-butyl(S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-1-oxopropan-2-yl))carbamate (75-5) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) and (tert-butoxycarbonyl)-L-alanine (54 mg, 0.29 mmol) were used, and the title compound (175 mg, 92%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0387] Step 6: Synthesis of N-(2-((2-((4-(4-((1-(L-alanyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-6) Instead of tert-butyl4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl(S)-(1-(4-((4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-1-oxopropan-2-yl))carbamate (172 mg, 0.22 mmol) was used, and the title compound (148 mg, yield 98%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0388] Step 7: Synthesis of Compound 75 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (57 mg, 0.21 mmol) and N-(2-((2-((4-(4-((1-(L-alanylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (145 mg, 0.21 mmol) were used, and the title compound (80 mg, yield 40%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0389] Example 76: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 76)

[0390] [ka]

[0391] Step 1: Synthesis of tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxy-5-methylphenyl)piperidine-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (76-1) Instead of 1-(3-methoxy-4-nitrophenyl)piperidine-4-one and N-Boc-piperazine, tert-butyl4-formylpiperidine-1-carboxylate (78 mg, 0.37 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) were used, and the title compound (108 mg, yield 54%) was obtained using the same method as in the Step 2 synthesis method of Example 2.

[0392] Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxy-5-methylphenyl)piperidine-4-yl)piperazine-1-yl)methyl)piperidine-1-carboxylate (106 mg, 0.13 mmol) was used, and the title compound (91 mg, yield 99%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0393] Step 3: Synthesis of Compound 76 Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (90 mg, 0.126 mmol) was used, and the title compound (80 mg, yield 65%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0394] Example 77: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)ethyl)piperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 77)

[0395] [ka]

[0396] Instead of 5-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide, use 2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Lysine-4-yl)ethylmethanesulfonate (70 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-piperazine-1-yl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethylsulfonamide (93 mg, 0.15 mmol) were used to obtain the title compound (65 mg, yield 44%) using the same method as in the step 6 synthesis method of Example 1.

[0397] Example 78: Synthesis of N-(2-((5-chloro-2-((4-((4-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)-L-alanyl)piperazine-1-yl)methyl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 78)

[0398] [ka]

[0399] Step 1: Synthesis of benzyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (78-1) Instead of benzyl 4-(piperazine-1-ylmethyl)piperidine-1-carboxylate, benzyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate (2.3 g, 5.79 mmol) was used, and the title compound (2.6 g, 97% yield) was obtained using the same method as in the Step 3 synthesis method of Example 33.

[0400] Step 2: Synthesis of benzyl 4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (78-2) Instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (2.6 g, 5.39 mmol) was used, and the title compound (2.38 g, 98% yield) was obtained using the same method as in the Step 2 synthesis method of Example 25.

[0401] Step 3: Synthesis of benzyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (78-3) Instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazine-1-yl)methyl)piperidine-1-carboxylate, benzyl 4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (3.2 g, 7.00 mmol) was used, and the title compound (4.4 g, yield 83%) was obtained using the same method as in the step 3 synthesis method of Example 35.

[0402] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78-4) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (3.7 g, 4.85 mmol) was used, and the title compound (3.5 g, yield >100%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0403] Step 5: Synthesis of tert-butyl(S)-(1-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxopropan-2-yl)carbamate (78-5) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazine-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) and (tert-butoxycarbonyl)-L-alanine (45 mg, 0.24 mmol) were used, and the title compound (183 mg, 95%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0404] Step 6: Synthesis of N-(2-((2-((4-(4-((4-(L-alanylpiperazine-1-yl)methyl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78-6) Instead of tert-butyl4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl(S)-(1-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxopropan-2-yl)carbamate (173 mg, 0.22 mmol) was used, and the title compound (110 mg, yield 71%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0405] Step 7: Synthesis of Compound 78 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (66 mg, 0.24 mmol) and N-(2-((2-((4-((4-((4-((L-alanylpiperazine-1-yl)methyl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) were used, and the title compound (67 mg, yield 44%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0406] Example 79: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 79)

[0407] [ka]

[0408] Instead of 3-(2-(benzyloxy)ethoxy)azetidine, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-ylmethyl)piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.11 mmol) was used, and the title compound (51 mg, yield 52%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0409] Example 80: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)glycyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 80)

[0410] [ka]

[0411] Step 1: Synthesis of tert-butyl(2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-2-oxoethyl)carbamate (80-1) Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindolin-2-yl)piperidine-2,6-dione, N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (151 mg, 0.24 mmol) and (tert-butoxycarbonyl)glycine (42 mg, 0.24 mmol) were used, and the title compound (135 mg, 72%) was obtained using the same method as in the step 7 synthesis method of Example 49.

[0412] Step 2: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80-2) Instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, tert-butyl (2-(4-((4-((5-chloro-4-((2-(N-methylmethanesulfonamide)phenyl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-methylphenyl)piperazine-1-yl)methyl)piperidine-1-yl)-2-oxoethyl)carbamate (130 mg, 0.17 mmol) was used, and the title compound (105 mg, yield 93%) was obtained using the same method as in the synthesis method of Step 5 of Example 1.

[0413] Step 3: Synthesis of Compound 80 Instead of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindoline-1,3-dione (40 mg, 0.15 mmol) and N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (99 mg, 0.15 mmol) were used, and the title compound (65 mg, yield 48%) was obtained using the same method as in the step 3 synthesis method of Example 33.

[0414] Example 81: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 81)

[0415] [ka]

[0416] Instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (53 mg, 0.16 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidine-4-ylmethyl)piperazine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.16 mmol) were used, and the title compound (105 mg, yield 70%) was obtained using the same method as in the Step 1 synthesis method of Example 6.

[0417] Example 82: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2S)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 82)

[0418] [ka]

[0419] Step 1: Synthesis of benzyl(2S)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoate (82-1) Instead of 4-bromobutan-1-ol, benzyl(S)-2-hydroxypropanoate (520 mg, 2.89 mmol) was used, and the title compound (270 mg, 32% yield) was obtained using the same method as in Step 1 of Example 3.

[0420] Step 2: Synthesis of (2S)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoic acid (82-2) Instead of 5-(3-(2-(benzyloxy)ethoxy)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, benzyl(2S)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoate (165 mg, 0.38 mmol) was used, and the title compound (133 mg, yield >100%) was obtained using the same method as in the step 4 synthesis method of Example 33.

[0421] Step 3: Synthesis of Compound 82 Instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamide)phenyl)amino)pyrimidine-2-yl)amino)3-methoxyphenyl)piperidine-4-yl)methyl)piperidine-4-carboxylate hydrochloride and 3-(4-amino-1-oxoindorin-2-yl)piperidine-2,6-dione, use N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidine-4-ylmethyl Using (109 mg, 0.17 mmol) piperazine-1-yl phenyl)aminopyrimidine-4-yl)aminophenyl)-N-methylmethanesulfonamide (2S)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propanoic acid (60 mg, 0.17 mmol), the title compound (70 mg, 42%) was obtained using the same method as in the synthesis method of Step 7 of Example 49.

[0422] The NMR and MS data obtained during the synthesis process of the compounds in the above examples are summarized in Table 2 below.

[0423] [Table 2] JPEG0007859684000081.jpg245169JPEG0007859684000082.jpg250169JPEG0007859684000083.jpg255166JPEG0007859684000084.j pg195169JPEG0007859684000085.jpg245169JPEG0007859684000086.jpg255166JPEG0007859684000087.jpg240169JPEG0007859684 000088.jpg241169JPEG0007859684000089.jpg230169JPEG0007859684000090.jpg195169JPEG0007859684000091.jpg230169JPEG00 07859684000092.jpg155169JPEG0007859684000093.jpg255163JPEG0007859684000094.jpg255166JPEG0007859684000095.jpg91169

[0424] <Evaluation of the compound of the present invention> Experimental Example 1: Testing of EGFR protein resolution in Ba / F3 cells expressing normal EGFR or C797S mutant EGFR. Normal EGFR, mutant EGFR del19+T790M+C797S , or mutant EGFR L858R+T790M+C797S In Ba / F3 cells expressing the compound of the present invention, we confirmed its ability to degrade mutant EGFR proteins. Western blotting was performed using an EGFR antibody.

[0425] Specifically, EGFR-expressing Ba / F3 cells were cultured in RPMI 1640 (Gibco, NY, USA) containing 10% fetal bovine serum (FBS, Gibco, NY, USA). The compounds of the present invention were used against normal EGFR and mutant EGFR. del19+T790M+C797S or mutant EGFR L858R+T790M+C797SCells expressing EGFR were treated with concentrations of 0.1 μM and 1 μM for 24 hours, respectively. Afterward, they were washed twice with phosphate-buffered saline (PBS), and SDS-PAGE was performed using 30 μg of cell lysate. The proteins separated from the gel were transferred to a nitrocellulose membrane, and EGFR protein expression levels were confirmed using an EGFR antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA). EGFR bands separated by Western blotting were quantitatively analyzed using a Fluo-S MultiImager (Bio-Rad, Hercules, CA, USA).

[0426] The results of the experiment are shown in Table 3 below.

[0427] [Table 3]

[0428] Experimental Example 2: Pharmacokinetic Evaluation Pharmacokinetic studies of the compound of the present invention were conducted as follows: After a single oral administration of the compound of the present invention to ICR mice, the time-dependent concentration of the compound was tracked and analyzed.

[0429] The compound of the present invention was suspended in 10% DMSO / 90% (aqueous solution of 30% HPbCD) and orally administered to mice at a dose of 5 mg / kg. After blood was collected at determined times, plasma was separated. The analysis of the drug was performed using HPLC (XBridge C18 column, water, mobile phase 0.1% formic acid: acetonitrile (30:70, % / %)) and MS / MS (ESI positive, MRM). Mouse plasma and each commercial standard solution were mixed at a ratio of 9:1 and prepared at concentrations of 5, 50, 100, 500, 1,000 and 5,000 ng / mL for calibration. In addition, the QC samples were prepared by mixing mouse plasma and the QC standard solution at a ratio of 9:1 and preparing them at concentrations of 100, 750 and 2,500 ng / mL. 一百μL of the plasma sample was transferred to a centrifuge tube, 10 μL of the internal standard solution and 300 μL of methanol were added, and then mixed for about 30 seconds for pretreatment. The tube was centrifuged at 3,000 × g (4 °C) for about 5 minutes, the upper layer liquid was collected and transferred to an LC vial, and then injected into the instrument. Thereafter, the concentration of the compound in mouse plasma was quantified by applying a previously validated analytical method. Pharmacokinetic parameters were calculated using the WinNonlin 5.2 (Pharsight, USA) program. Non-compartmental modeling (best fit) was used to calculate AUC 0-t 、AUC 0-∞ 、Cmax, Tmax, and t 1 / 2 were calculated. The results of the pharmacokinetic parameters were expressed as mean and standard deviation (SD), and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

[0430] The test results are shown in Table 4 below

[0431]

Table 4

[0432] All references to the present invention are included herein by reference as their contents are described herein. When introducing elements of the present invention or its preferred forms, “a, an,” “the,” and “said” are intended to mean that there are one or more elements. The terms “comprising, including” and “having” are intended to be comprehensive and mean that there may be additional elements other than those listed. The present invention has been described above in particular aspects or forms, but should not be construed as being limited to the details of these aspects or forms.

Claims

1. The compounds listed in the table below or their pharmaceutically acceptable salts. Table 1

2. A composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition for the treatment or prevention of cancer having an EGFR mutation, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

4. A pharmaceutical composition for the treatment or prevention of cancer having an EGFR mutation according to claim 3, wherein the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, psoriasis, or fibroadenoma.

5. A pharmaceutical composition for the treatment or prevention of cancer having an EGFR mutation according to claim 3, wherein the cancer is lung cancer.

6. The pharmaceutical composition for the treatment or prevention of cancer having an EGFR mutation according to claim 5, wherein the lung cancer is non-small cell lung cancer.

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