Compounds for inhibiting EGFR mutant cancers and their pharmaceutical uses

Abstract

The present disclosure provides compounds of specific chemical structures or pharmaceutically acceptable salts thereof, which have the activity of inhibiting and / or degrading mutant EGFR proteins. The present disclosure also provides compositions comprising such compounds or pharmaceutically acceptable salts thereof. The present disclosure provides the use of the compounds, salts thereof and compositions comprising the compounds, salts thereof according to the present disclosure for the treatment or prevention of cancers with EGFR mutations, especially lung cancer, as medicaments. The present disclosure also provides a method for the treatment or prevention of EGFR mutant cancers, especially lung cancer, which method comprises administering to a subject in need of treatment an effective amount of a compound, a salt thereof according to the present invention or a composition comprising the compound, a salt thereof according to the present invention.

Description

Technical Field

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

[0002] The present disclosure relates to a group of compounds for inhibiting, i.e., treating or preventing, cancer exhibiting an EGFR mutation. The present disclosure also relates to a pharmaceutical composition comprising such a compound. The present disclosure also relates to a useful method of using such a compound for treating or preventing cancer exhibiting an EGFR mutation, particularly cancer exhibiting an EGFR mutation of any one or more of del19, T790M, C797S, and L858R. In other words, the present disclosure relates to the medical use of the compound according to the present invention for treating or preventing the cancer. Background Art

[0003] Epidermal growth factor receptor (EGFR) is a protein composed of a receptor part and a tyrosine kinase part, and is used to transmit signals from outside the cell through the cell membrane to inside the cell. EGFR plays an important role in normal cell regulation through intracellular signal transduction. However, it is known that activating EGFR mutations or overexpression of EGFR characterized by ligand-independent tyrosine kinase activity induce the growth, differentiation, angiogenesis, metastasis, resistance expression, etc. of cancer cells by abnormally activating the cell signal transduction system. It has been reported that EGFR is abnormally overexpressed or frequently mutated in most solid cancer cells, which is associated with poor prognosis. For example, lung cancer, liver cancer, esophageal cancer, gastric cancer, colon 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, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma are known to be related to EGFR mutations (Cancer Communications. 2020; 40: 43-59).

[0004] Among them, it is known that 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 important causes of non-small cell lung cancer. Therefore, based on the prediction that if the cancer cell signal transduction through the epidermal growth factor receptor is blocked, the anti-cancer effect will be excellent, research on developing anti-cancer drugs targeting the epidermal growth factor receptor is being actively conducted.

[0005] The first drug developed as an EGFR tyrosine kinase inhibitor in small molecules is Gefitinib, which is a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among EGFR subtypes. Another drug with such characteristics is Erlotinib, and this EGFR-targeted therapy is mainly used for patients with EGFR-activating mutations with non-small cell lung cancer (NSCLC) as the main indication.

[0006] However, it has been reported that NSCLC patients with EGFR-activating mutations treated with Gefitinib or Erlotinib develop drug resistance after about 8 to 16 months, and about 60% of them show resistance due to the EGFR T790M mutation. (Helena A. Yu et al., Clin Cancer Res. 19(8), 2240, 2013).

[0007] Irreversible inhibitors have been proposed to overcome resistance to existing EGFR inhibitors such as Gefitinib or Erlotinib. However, since EGFR irreversible inhibitors also have high activity against EGFR WT (wild type) that also exists in normal cells, serious side effects will occur when the dose for overcoming resistance caused by the EGFR T790M mutation is administered. This shows the limitations of clinical applications.

[0008] As an alternative to this protocol, many drugs including the EGFR mutant-selective inhibitors osimertinib, olmutinib, naquotinib, and Avitinib are in the clinical development stage. However, according to the clinical results of osimertinib for non-small cell lung cancer patients with EGFR-resistant mutations, after about 10 months, other resistance mechanisms are activated, resulting in drug resistance, and the C797S mutation appears at a high rate of 20% or higher. The C797S mutation is a point mutation in which cysteine 773 (Cys773), which forms a covalent bond with the EGFR irreversible inhibitor, is changed to serine. As a result, it is impossible to form a covalent bond with the EGFR irreversible inhibitor, leading to a decrease in reactivity to the drug.

[0009] As described above, the development of EGFR-targeted therapy shows limitations, and the drug efficacy cannot be maintained within a certain period due to the expression of primary and secondary resistance. In particular, except for the reports of early preclinical studies, there is no research on the EGFR C797S mutation even for substances undergoing clinical research, so there is an urgent need for effective treatment for this. SUMMARY OF THE INVENTION

[0010] TECHNICAL PROBLEM

[0011] Accordingly, the problem to be solved by the present disclosure is to provide a compound having the activity of repressing, inhibiting, and / or degrading cancer expressing an EGFR mutation, a pharmaceutical composition comprising the compound as an active ingredient, and its medical use for treating or preventing cancer showing an EGFR mutation.

[0012] Another problem to be solved by the present disclosure is to provide a method for treating or alleviating cancer expressing an EGFR mutation, which comprises administering a compound according to the present invention to a patient in need of treatment, improvement, or prevention of cancer expressing an EGFR mutation, wherein the compound inhibits cancer cells expressing an EGFR mutation.

[0013] Technical solution Summary of the Invention

[0015] To solve the above problems, an embodiment of the present invention provides a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula 1]

[0017]

[0018] In Chemical Formula 1,

[0019] R1 and R2 are each independently hydrogen, C1-C6 alkyl, CD3, or C1-C6 haloalkyl,

[0020] R3 to R6 are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 heterocycloalkoxy, or -C(=O)OR7, wherein R7 is C1-C5 alkyl,

[0021] m and n are each independently 0, 1, 2, 3, or 4,

[0022] A is a divalent 4- to 7-membered heterocycle, 4- to 7-membered spiro heterocycle, or 8- to 10-membered bicyclic heterocycle,

[0023] L is a group connecting A and B by a covalent bond,

[0024] B is

[0025]

[0026]

[0027] X is a direct bond, (CH2) 1-6 、O-(CH2) 0-6 、C(O)-(CH2) 0-6 、N(R13 )-(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 ),

[0028] W is C(R 14 )2 or C(O),

[0029] R8 is hydrogen, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy,

[0030] R9 and R 10 are each independently hydrogen or C1-C6 alkyl,

[0031] R 13 and R 14 are each independently hydrogen or C1-C6 alkyl,

[0032] o and p are each independently 1, 2 or 3,

[0033] Y is C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 aryl, C3-C10 heteroaryl or (where when Y is , X is connected to form ),

[0034] Z is O or S,

[0035] R 11 is hydrogen, C1-C6 alkyl or (CH2) 1-6 -C(O) (where when R 11 is (CH2) 1-6 -C(O), X can be connected to form (CH2) 1-6 -C(O)-X),

[0036] R 12 is hydrogen, C1-C6 alkyl or C1-C6 cycloalkyl,

[0037] R 15 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 cycloalkyl,

[0038] R 16 is hydrogen, C1-C4 alkyl, N-(R 17 )R 18, a C3-C10 aryl or C3-C10 heteroaryl, wherein R 17 and R 18 are each independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl or -C(O).

[0039] The compounds of the present disclosure are excellent in degrading EGFR mutant proteins in cancers having EGFR mutations. Therefore, a preventive or therapeutic effect on cancers showing EGFR mutations can be expected.

[0040] In particular, the compounds of the present disclosure have the advantage of differentially degrading mutant EGFR proteins including C797S, etc., rather than the EGFR proteins of cells having normal EGFR.

[0041] The compounds according to the present disclosure can be particularly used to degrade EGFR mutant proteins showing any one or more of Del19, T790M, C797S and L858R mutations, and can be particularly used to degrade Del19 / T790M / C797S and L858R / T790M / C797S mutant proteins. The mutant EGFR (including C797S) is a resistance mutation that appears after treatment with the third-generation therapeutic agent Tagrisso (osimertinib ). The compounds of the present disclosure have the advantage of being usable for inhibiting, degrading, etc., lung cancers having an EGFR C797S mutation, particularly non-small cell lung cancer (NSCLC) cells.

[0042] In the compounds of the present disclosure, the right part in the chemical structure is used to bind and / or inhibit mutant EGFR proteins, etc., and the left part serves as an E3 ligase binder to induce the ubiquitin-proteasome system (UPS). It is expected that this will further promote the degradation and / or inhibition of this protein, but the present invention is not limited to these mechanisms predicted by theory.

[0043] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or additive.

[0044] In another embodiment, the present disclosure provides a method for treating cancer exhibiting an EGFR mutation, which comprises administering to a subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Cancers exhibiting an EGFR mutation are, for example, lung cancer, liver cancer, esophageal cancer, gastric cancer, colon 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, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma, etc. Preferably, the cancer exhibiting an EGFR mutation is lung cancer. More preferably, the cancer exhibiting an EGFR mutation is non-small cell lung cancer.

[0045] In other words, the present disclosure provides a medical use, characterized by using the compound of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment, the medical use of the present invention is for treating or preventing the diseases or disorders described herein.

[0046] The compounds, pharmaceutical compositions containing such compounds, and their medical uses are described more fully in the detailed description of the invention below. Detailed Description of the Invention

[0048] The following description is merely illustrative and is not intended to limit the invention, its application, or uses.

[0049] Definitions

[0050] The following terms used herein are defined as follows.

[0051] The terms "substituent", "radical", "group", "moiety", and "fragment" used herein are used interchangeably.

[0052] Unless the context clearly indicates otherwise, as used herein, the term "alkyl" means a saturated straight-chain or branched-chain acyclic hydrocarbon having 1 to 10 carbon atoms. "Lower alkyl" means an alkyl group having 1 to 4 carbon atoms. Representative saturated straight-chain alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl, while saturated branched-chain alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 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, 3,3-diethylhexyl, and the like.

[0053] As used herein, the term "C 1-6 ", "C1-6" or "C1-C6" means having 1 to 6 carbon atoms. For example, C 1-6 alkyl means an alkyl group having any integer number of carbon atoms from 1 to 6.

[0054] As used herein, the terms "halogen " and "halo " mean fluorine, chlorine, bromine or iodine. In a preferred embodiment of the present invention, the halogen is chlorine or fluorine.

[0055] As used herein, the terms "haloalkyl", "haloalkoxy", "haloalkenyl", or "haloalkynyl" mean an alkyl, alkoxy, alkenyl, or alkynyl group in which one or more hydrogen atoms are replaced by halogen atoms. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CCl3, -CHCl2, -CH2Cl, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CCl3, -CH2-CHCl2, -CH2-CH2Cl, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, etc.,

[0056] wherein the alkyl and halogen are as described above. In one embodiment of the present invention, the haloalkyl is -CF3.

[0057] As used herein, the term "alkoxy" means -O-(alkyl), which includes -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, etc., wherein the alkyl is as defined above. As used herein, the term "lower alkoxy" means -O-(lower alkyl), wherein the lower alkyl is as defined above.

[0058] The terms "aryloxy", "cycloalkoxy", or "heterocycloalkoxy" are RO-, where R is an aryl, cycloalkyl, or heterocycloalkyl as defined herein, respectively. "Arylthio" is RS-, where R is an aryl as defined above.

[0059] As used herein, the term "aryl" means a carbocyclic aromatic group containing 3 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthryl, fluorenyl, indenyl, and azulenyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0060] The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Some examples of monocyclic include, but are not limited to, (C3-C7) cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Some examples of polycyclic include, but are not limited to, fused bicyclic (bicyclic hydrocarbon rings), such as octahydropentalene and decalin; 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, such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.2.2]octane. The cycloalkyl can be unsubstituted or optionally substituted. In one embodiment of the present invention, the cycloalkyl is monocyclic. In one embodiment of the present invention, the cycloalkyl is cyclopropyl. In one embodiment of the present invention, the "spiro hydrocarbon 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.

[0061] The term "heteroaryl" as used herein means an aromatic heterocycle having 3 to 10 members and having at least one heteroatom selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom, including both monocyclic and bicyclic systems. Representative heteroaryls are furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, azole, iso azole, thiazole, isothiazole, diazole, benzofuran, benzothiophene, quinoline, indole, benzo azole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, etc.

[0062] The term "heterocycle" or "heterocycloalkyl" means a 3- to 7-membered monocyclic or 6- to 12-membered bicyclic, saturated heterocycle containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatoms can be optionally quaternized. Representative heterocycles include ethylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-di Alkanes, aziridines, azetidines, pyrrolidines, piperidines, piperazines, pyrrolidinones, hydantoins, valerolactams, thiiranes, thietanes, tetrahydrothiophenes, tetrahydrothiopyrans, morpholines, tetrahydropyridines, and tetrahydropyrimidines. The heterocycles include bicyclics, where a portion of the heterocycle is fused to a benzene or cyclopent - 1,3 - diene ring. The heterocycle can be attached through any heteroatom or carbon atom. Additionally, the heterocycles include fused bicyclics, spirocycles, and bridged bicyclics, where one or more carbon atoms of the above polycycles are replaced by nitrogen, oxygen, or sulfur atoms. For example, when the heteroatom is nitrogen, these include but are not limited to fused heterobicyclics (bicyclic heterocycles), such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4 - c]pyrrole, decahydroisoquinoline, and decahydro - 2,6 - naphthyridine; spiro(hetero)cycles, such as 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, 2,7 - diazaspiro[4.4]nonane, 8 - azaspiro[4.5]decane, 2,8 - diazaspiro[4.5]decane, 3 - azaspiro[5.5]undecane, and 3,9 - diazaspiro[5.5]undecane; and bridged heterobicyclics, 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.

[0063] "Heterocycle fused to a phenyl group" means a heterocycle attached to two adjacent carbon atoms of a benzene ring, where the heterocycle is defined as above.

[0064] In this specification, "*" or means attached to another moiety.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from the active compounds according to the present disclosure with relatively non-toxic acids or bases (depending on the specific substituents of those compounds). When the compound has a relatively acidic group, the base addition salt can be obtained by contacting the neutral compound with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, organic amino, magnesium salts, etc. When the compound has a relatively basic group, the acid addition salt can be obtained by contacting the neutral compound with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from non-toxic organic acids and non-toxic inorganic acids. The non-toxic organic acids include, but are not limited to, 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc., and the non-toxic inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfide, hydroiodic acid, phosphorous acid, etc. Pharmaceutically acceptable salts also include salts of amino acids, such as arginine salts or analogs thereof, and also include analogs of organic acids such as glucuronic acid or galacturonic acid. Some specific compounds of the present disclosure have both basic and acidic functional groups for the conversion of compounds having basic or acidic moieties (addition) salts. Other examples of salts are known from the literature known in the art of the present invention.

[0066] As used herein, "effective amount" refers to an amount of a compound of the present invention sufficient to slow or minimize the progression of cancer having an EGFR mutation or to provide a therapeutic benefit in the treatment or management of cancer having an EGFR mutation. "Effective amount" also refers to an amount sufficient to inhibit or reduce the EGFR mutant protein in vitro or in vivo.

[0067] As used herein, the term "treatment" can be any one or more of prophylactic treatment, palliative treatment, and / or restorative treatment.

[0068] The phrase "compounds of the invention" as used herein includes any compound of Formula 1 and its clathrates, hydrates, solvates or polymorphs. Further, even if the term "compounds of the invention" does not mention its pharmaceutically acceptable salts, the term includes its salts. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, e.g., those substantially free (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee or greater than 99% ee) of other stereoisomers. In other words, if a compound or its salt of Formula 1 according to the present disclosure is a tautomer and / or a stereoisomer (e.g., geometric isomers and conformational isomers), then such individual isomers and mixtures thereof are also included within the scope of the present disclosure. If the compounds or their salts of the present disclosure have asymmetric carbons in their structures, their active optical isomers and their racemic mixtures are also included within the scope of the present disclosure.

[0069] The term "polymorph" as used herein means a solid crystalline form of a compound or its complex of the present disclosure. Different polymorphs of the same compound may exhibit different physical, chemical and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (which are important in formulation and product manufacture), and dissolution rate (which can affect bioavailability). Differences in stability can be caused by changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors faster when containing one polymorph than when containing another) or mechanical properties (e.g., a tablet crumbles during storage because the kinetically favored polymorph converts to the thermodynamically more stable polymorph) or both (e.g., a tablet of one polymorph is more prone to cracking at high humidity). The different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than another or may be more difficult to filter or wash free of impurities (due to, e.g., the shape or size distribution of its particles).

[0070] The term "solvate" as used herein means a compound or its salt according to the present disclosure that further contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and acceptable for administration to humans in trace amounts.

[0071] The term "hydrate" as used herein means a compound or its salt according to the present disclosure that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0072] As used herein, the term "inclusion compound" means a compound or a salt thereof in lattice form that contains a space (e.g., a channel) in which a guest molecule (e.g., a solvent or water) is entrapped.

[0073] As used herein, the term "purified" means that when separated, the purity of the separated product is greater than 90%, in one embodiment greater than 95%, in another embodiment greater than 99%, and in another embodiment greater than 99.9%.

[0074] The term "hydrogen" refers to a single H atom (H) and may be used interchangeably with the symbol "H" or the term "hydrogen".

[0075] If a substituent is described as "optionally substituted", the substituent may be (1) unsubstituted or (2) substituted with one or more defined substituents. If the position that can be substituted is unsubstituted, the default substituent is hydrogen.

[0076] Unless the context clearly dictates otherwise, the singular forms used herein include the plural forms.

[0077] The term "pharmaceutically acceptable" means suitable for use in pharmaceutical formulations and is generally considered safe for such use. The term also means that it has been officially approved by a national regulatory agency for such use or has been included in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0078] Compounds of the Invention

[0079] One embodiment of the present invention provides a compound having the structure of Formula 1 or a pharmaceutically acceptable salt thereof.

[0080] [Formula 1]

[0081]

[0082] In Formula 1,

[0083] R1 and R2 are each independently hydrogen, C1-C6 alkyl, CD3 or C1-C6 haloalkyl,

[0084] R3 to R6 are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 heterocycloalkoxy or -C(=O)OR7, where R7 is C1-C5 alkyl,

[0085] m and n are each independently 0, 1, 2, 3 or 4,

[0086] A is a divalent 4- to 7-membered heterocycle, 4- to 7-membered spiroheterocycle or 8- to 10-membered bicyclic heterocycle,

[0087] L is a group that covalently links A and B,

[0088] B is

[0089] or

[0090]

[0091] 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 ),

[0092] W is C(R 14 )2 or C(O),

[0093] R8 is hydrogen, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy,

[0094] R9 and R 10 are each independently hydrogen or C1-C6 alkyl,

[0095] R 13 and R 14 are each independently hydrogen or C1-C6 alkyl,

[0096] o and p are each independently 1, 2 or 3,

[0097] Y is C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 aryl, C3-C10 heteroaryl or

[0098]

[0099] (where when Y is ,

[0100] X is linked to form ),

[0101] Z is O or S,

[0102] R 11is hydrogen, a C1-C6 alkyl group, or (CH2) 1-6 -C(O) (wherein when R 11 is (CH2) 1-6 -C(O), X is linked to form (CH2) 1-6 -C(O)-X),

[0103] R 12 is hydrogen, a C1-C6 alkyl group, or a C1-C6 cycloalkyl group,

[0104] R 15 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C1-C6 cycloalkyl group,

[0105] R 16 is hydrogen, a C1-C4 alkyl group, N-(R 17 )R 18 、a C3-C10 aryl group, or a C3-C10 heteroaryl group, wherein R 17 and R 18 are each independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or -C(O).

[0106] In a preferred embodiment, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, wherein

[0107] R1 and R2 are each independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group,

[0108] R3 is hydrogen or a C1-C6 alkyl group,

[0109] R4 is hydrogen, a halogen (preferably C1), or a C1-C6 alkyl group,

[0110] R5 is hydrogen or a C1-C6 alkyl group,

[0111] R6 is hydrogen, a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group,

[0112] m and n are each independently 0, 1, or 2,

[0113] A is

[0114]

[0115] L is a group that covalently links A and B

[0116] B is

[0117]

[0118]

[0119] 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 ),

[0120] W is C(R 14 )2 or C(O),

[0121] R8 is hydrogen, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy,

[0122] R9 and R 10 are each independently hydrogen or C1-C6 alkyl,

[0123] R 13 and R 14 are each independently hydrogen or C1-C6 alkyl,

[0124] o and p are each independently 1, 2 or 3,

[0125] Y is C1-C6 alkyl or C1-C6 haloalkyl or

[0126]

[0127] (wherein when Y is ,

[0128] X is linked to form ),

[0129] Z is O or S,

[0130] R 11 is hydrogen, C1-C6 alkyl or (CH2) 1-6 -C(O),

[0131] R 12 is hydrogen, C1-C6 alkyl or C1-C6 cycloalkyl,

[0132] R 15 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 cycloalkyl,

[0133] R 16 is hydrogen, a C1-C4 alkyl group, N-(R 17 )R 18 , a C3-C10 aryl group or a C3-C10 heteroaryl group, where R 17 and R 18 are each independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or -C(O).

[0134] In another embodiment, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, wherein L is a direct bond or a divalent, saturated or unsaturated C1-C50 hydrocarbon chain; at least one methylene unit of L may be replaced by one or more selected from the following:

[0135] -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)-, -(CH2OCH2)-, -(OCH2CH2)-, -(CH2CH2O)-, -(C(O)CH2CH2)- and -(CH2CH2C(O))-.

[0136] wherein, -Cy- is each independently a divalent ring substituent which is a phenylene group, a 4- to 7-membered spiro hydrocarbon ring, an 8- to 10-membered bicyclic hydrocarbon ring, a 4- to 7-membered heterocyclic ring, a 4- to 7-membered spiro heterocyclic ring, an 8- to 10-membered bicyclic heterocyclic ring, a 5- to 6-membered heteroarylene group or an 8- to 10-membered bicyclic heteroarylene group, where R 20 is hydrogen or a C1-C4 alkyl group.

[0137] Preferably, in another embodiment, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, wherein X-L of Chemical Formula 1 is -K1-K2-K3-K4-K5-,

[0138] K1 is a C1-C6 alkyl group, NH, O, C≡C, N-C1-C6 alkyl group, NH-C1-C6 alkyl group, O-C1-C6 alkyl group,

[0139]

[0140] K2 is a direct bond, C(O) or O,

[0141] K3 is a direct bond, (CH2) n1 or (CH2) n1 -O, where n1 is an integer from 0 to 10,

[0142] K4 is a direct bond, (CH2CH2O) n2 ,

[0143]

[0144]

[0145] where n2 is an integer from 0 to 5,

[0146] K5 is a direct bond, (CH2) n3 , NH or N-C1-C3 alkyl, where n3 is an integer from 0 to 3, and

[0147] One of A1 and A2 is N, and the other is CH, or both A1 and A2 are N.

[0148] More preferably, another embodiment of the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein X-L of Formula 1 is the X-L moiety used in the following examples. The X-L used in the examples can be connected to a plurality of Bs (except X) disclosed herein on the left and to a plurality of "-A-EGFR-binding moieties" disclosed herein on the right.

[0149] More preferably, in another embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula 1, wherein A is

[0150]

[0151] Preferably, one embodiment of the present invention provides a compound or a pharmaceutically acceptable salt thereof represented by the following Formula 1a

[0152] [Formula 1a]

[0153]

[0154] In Formula 1a,

[0155] R1 and R2 are each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl,

[0156] R3 to R6 are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 heterocycloalkoxy or -C(=O)OR7, where R7 is C1-C5 alkyl,

[0157] R6' is halogen or C1-C6 alkyl,

[0158] m is 0, 1, 2, 3, or 4,

[0159] A is a divalent 4- to 7-membered heterocycle, a 4- to 7-membered spiro heterocycle, or an 8- to 10-membered bicyclic heterocycle,

[0160] L is a group that connects A and B through a covalent bond.

[0161] B is

[0162] or

[0163]

[0164] 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 ),

[0165] W is C(R 14 )2 or C(O),

[0166] R8 is hydrogen, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy,

[0167] R9 and R 10 are each independently hydrogen or C1-C6 alkyl,

[0168] R 13 and R 14 are each independently hydrogen or C1-C6 alkyl,

[0169] o and p are each independently 1, 2 or 3,

[0170] Y is C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 aryl, C3-C10 heteroaryl or

[0171]

[0172] (where Y is hour,

[0173] X is ),

[0174] Z is O or S,

[0175] R 11 is hydrogen, a C1-C6 alkyl group or (CH2) 1-6 -C(O),

[0176] R 12 is hydrogen, a C1-C6 alkyl group or a C1-C6 cycloalkyl group,

[0177] R 15 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C1-C6 cycloalkyl group,

[0178] R 16 is hydrogen, a C1-C4 alkyl group, N-(R 17 )R 18 , a C3-C10 aryl group or a C3-C10 heteroaryl group, wherein R 17 and R 18 are each independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or -C(O).

[0179] In the compounds of Formula 1, when they have the same structure as Formula 1a, as described hereinafter, the bioavailability is significantly improved. As shown in the exemplary experimental results described hereinafter, compounds 74, 76, 77, 80 and 81 show significantly improved AUC compared to the corresponding compounds 45, 71, 51, 65 and 53.

[0180] Preferably, one embodiment of the present invention further provides a compound represented by Formula 1 or Formula 1a or a pharmaceutically acceptable salt thereof, wherein X is O-(CH2) 0-6 , N(R 13 )-(CHR 14 ) or O-(CHR 14 ), and R 14 is a C1-C6 alkyl group (preferably methyl) (the remaining substituents are the same as those defined in Formula 1 or 1a). As shown in the exemplary experimental results described hereinafter, compounds 69, 70, 75, 78 and 82 show significantly improved AUC compared to the corresponding compounds 53 and 65. These compounds are those in which K1 of -K1-K2-K3-K4-K5- is *-O-C1-C6 alkyl-* or *-NH-C1-C6 alkyl-* (K2, K3, K4 and K5 are the same as the previous definitions), wherein O or NH is connected to the 2nd or 3rd carbon other than the C1-C6 alkyl terminus.

[0181] After synthesizing various compounds, the present inventors conducted various evaluation experiments to ensure obtaining compounds and their uses that have particularly high inhibitory, degradative, and / or binding activities against mutant EGFR proteins, have high selectivity for them, and preferably effectively degrade mutant EGFR proteins, and thus have good therapeutic or prophylactic effects on cancers showing EGFR mutations and reduced other side effects. In addition to the pharmacological aspects, the present inventors also evaluated the pharmacokinetic aspects, such as bioavailability. Finally, the present invention was completed by confirming that the compounds of the present invention are suitable for the purposes of the present invention.

[0182] One embodiment of the present invention provides the compounds of the following-described examples and their pharmaceutically acceptable salts as some non-limiting examples of the compounds of Formula 1 according to the present invention.

[0183] Preferably, another embodiment of the present invention provides compounds and their pharmaceutically acceptable salts, wherein the compound of Formula 1 is the compound of Table 1 below. The compounds of Table 1 below are more preferred in various aspects such as drug potency and bioavailability.

[0184] [Table 1]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 according to the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0191] Medical Use and Therapeutic Methods of the Compounds According to the Invention

[0192] The present invention also provides a method for treating a disease or disorder in a subject suffering from or susceptible to the disease or disorder by administering to the subject a therapeutically effective amount of one or more of the above-described compounds. In one embodiment, the treatment is prophylactic treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0193] 1. Disease or disorder

[0194] The compounds of the present invention for inhibiting and / or degrading EGFR mutant proteins can be used for a variety of therapeutic or prophylactic uses. These compounds can be used to repress or inhibit the activity of EGFR mutant proteins and can also be used to treat cancers showing EGFR mutations or prevent the progression of these diseases. Accordingly, the present invention provides a method for inhibiting, repressing, and / or degrading the activity of EGFR mutant proteins in cells. In this method, cells are contacted with an effective amount of the compounds of the present invention. In one embodiment, the cells are in a subject (e.g., a lung cancer patient). The method of the present invention includes administering to a subject in need of treatment or prophylaxis a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound of the present invention.

[0195] In one embodiment, the present invention provides a method for inhibiting, degrading, or suppressing the activity of EGFR mutant proteins in cancer cells showing EGFR mutations. For example, the present invention can be used to treat or prevent lung cancer, liver cancer, esophageal cancer, gastric cancer, colon 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, blood cancer, lymphoma, skin cancer, psoriasis, fibroadenoma, etc. having EGFR mutations.

[0196] The compounds of the present invention can be administered to a subject in the form of the pharmaceutical compositions described herein.

[0197] In another embodiment, the present invention provides a method for treating or preventing cancer showing EGFR mutations in a subject, and cancers showing such EGFR mutations include lung cancer, liver cancer, esophageal cancer, gastric cancer, colon 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, blood cancer, lymphoma, skin cancer, psoriasis, fibroadenoma, etc. Such a method includes administering to a subject in need of treatment an amount (i.e., a therapeutically effective amount) of the compound of the present invention sufficient to inhibit the activity of EGFR mutant proteins.

[0198] In particular, the compounds of the present invention can be used to degrade EGFR mutant proteins showing any one or more of the mutations Del19, T790M, C797S, and L858R, and can be particularly used to degrade Del19 / T790M / C797S and L858R / T790M / C797S EGFR mutant proteins. Cancers having these mutant EGFRs can be lung cancer, particularly non-small cell lung cancer (NSCLC).

[0199] 2. Subject

[0200] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and encompass mammals in utero. The subject can be of either sex and can be at any stage of development.

[0201] In one embodiment, a suitable subject to be treated according to the present invention is a human.

[0202] 3. Administration and dosing

[0203] The compounds of the present invention are generally administered in a therapeutically effective amount.

[0204] The compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. In single or divided doses, the effective dose is generally in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day. Depending on the age, species, and disease or disorder being treated, dose levels below the lower limit of this range may be appropriate. In other cases, even larger doses can be used without adverse side effects. Larger doses can also be divided into several smaller doses for administration throughout the day.

[0205] Pharmaceutical Compositions, Dosage Forms and Routes of Administration

[0206] For the treatment of the above diseases or disorders, the compounds described herein or their pharmaceutically acceptable salts can be administered as follows:

[0207] Oral administration

[0208] The compounds of the present invention can be administered orally (including by swallowing) such that the compound enters the gastrointestinal tract or is absorbed directly into the bloodstream from the mouth (e.g., buccally or sublingually).

[0209] Suitable compositions for oral administration include solid, liquid, gel, or powder formulations and have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0210] The compositions for oral administration can optionally be enteric-coated and can exhibit delayed or sustained release through the enteric coating. In other words, the compositions for oral administration according to the present invention can be formulations with an immediate release or modified release pattern.

[0211] Liquid formulations can include solutions, syrups, and suspensions, which can be used in soft or hard capsules. Such formulations can contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations can also contain one or more emulsifiers and / or suspending agents.

[0212] In tablet dosage forms, the amount of drug, active ingredient present can be from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight. Additionally, the tablets can contain a disintegrant, which is present in an amount from about 0.5% to about 35% by weight of the dosage form, more typically about 2% to about 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0213] Suitable lubricants for tablets can be present in an amount from about 0.1% to about 5% by weight and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.

[0214] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starches, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0215] Suitable solubilizers for tablets can be present in an amount from about 0.1% to about 3% by weight and include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM (Nikkol), fatty acid esters, Gelucire TM 、mono / diglycerides of caprylic / capric acid, sorbitan fatty acid esters, and Solutol HS TM .

[0216] Parenteral administration

[0217] The compounds of the present disclosure can be administered directly into the bloodstream, muscle, or viscera. Suitable modes of parenteral administration include intravenous, intramuscular, subcutaneous, intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needles and needleless syringes) and infusion methods.

[0218] Compositions for parenteral administration can be formulated for immediate release or modified release, including delayed release or sustained release.

[0219] Most parenteral formulations are liquid compositions, and the liquid compositions are aqueous solutions containing the active ingredient, salts, buffers, isotonic agents, etc. according to the present invention.

[0220] Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with suitable carriers such as sterile water. Solubilizing enhancers can also be used to prepare parenteral solutions.

[0221] Topical administration

[0222] The compounds of the present invention can be topically administered to the skin or transdermally administered. Formulations for such topical administration may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohols, mineral oils, glycerin, polyethylene glycols, etc. Topical administration can also be carried out by electroporation, iontophoresis, phonophoresis, etc.

[0223] Compositions for topical administration can be formulated for immediate release or modified release, including delayed release or sustained release.

[0224] Beneficial effects

[0225] The present invention relates to compounds capable of exhibiting various pharmacological activities by inhibiting or degrading the activity of EGFR mutant proteins, pharmaceutical compositions containing the compounds as active ingredients and their medical uses (especially for treating or preventing cancers showing EGFR mutations, especially lung cancer), and a treatment method, which includes administering them to a subject in need of treatment or prevention. The compounds or pharmaceutically acceptable salts thereof according to the present invention are excellent in many aspects such as safety due to their high selectivity for mutant EGFR, and can exhibit excellent medical effects in the inhibition or degradation of the activity of EGFR mutants. Description of the drawings

[0226] Figure 1 are the results of Western blot experiments, which show the protein degradation ability against normal EGFR, Del 19 / T790M / C797S mutant EGFR (EGFR de119+T790M+C797S )(DTC) and L858R / T790M / C797S mutant EGFR (EGFR L858R+T790M+C797S )(LTC) according to the concentration of the compound of Example 10.

[0227] Figure 2 are the results of Western blot experiments, which show the protein degradation against Del19 / T790M / C797S mutant EGFR (EGFR de119+T790M+C797S ) and L858R / T790M / C797S mutant EGFR (EGFR L858R+T790M+C797S ) according to the concentration and treatment time of Compound 10. Detailed description of the invention

[0228] In the following, the present invention has been described in considerable detail by way of examples to assist those skilled in the art in understanding the present invention. However, the following examples are provided by way of illustration and are not intended to limit the scope of the present invention. Obviously, various changes can be made without departing from the spirit and scope of the present invention or sacrificing all its substantial advantages.

[0229] Preparation of the Compounds of the Invention

[0230] In the following, the synthesis methods of some compounds of the present invention will be described, and other compounds not mentioned below can be prepared in a similar manner by replacing the starting materials, intermediates and / or reactants.

[0231] Example 1: Synthesis of 5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (Compound 1)

[0232]

[0233]

[0234] Step 1: Synthesis of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pent anamide (1-1)

[0235] To a solution of 5-bromopentanoic acid (398 mg, 2.20 mmol) in dichloromethane (5 mL) was added oxalyl chloride (964 mL, 11.00 mmol), followed by 1 drop of N,N-dimethylformamide. The solution was concentrated for 1 hour. Tetrahydrofuran (10 mL) and 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (200 mg, 0.73 mmol) were added, and the mixture was stirred overnight at 75 °C. The mixture was extracted by dilution with ethyl acetate and brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the product was purified by silica gel column chromatography to obtain the title compound (244.1 mg, 77%).

[0236] Step 2: Synthesis of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1-2)

[0237] 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 stirred for 2 days. Water was added to the reaction mixture, and the mixture was stirred, filtered, washed with water and dried in vacuo to obtain the title compound (9.5 g, 96%).

[0238] Step 3: Synthesis of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (1-3)

[0239] A mixture of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (500 mg, 1.48 mmol) in tetrahydrofuran / ethanol (5 / 5 mL) was purged with argon, and 10% Pd / C (50 mg) was added. After replacement with hydrogen, it was stirred for 4 hours, filtered and concentrated to obtain the title compound (450 mg, 99%).

[0240] Step 4: Synthesis of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (1-4)

[0241] Purge 1,4-dihydroquinone with argon A mixture of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (450 mg, 1.46 mmol), N-(2-((2,5-dichloropyrimidin-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 2-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (5 mL). The mixture was stirred under reflux overnight, cooled to room temperature, and filtered through celite. Extracted by diluting with ethyl acetate and brine, and dried over anhydrous magnesium sulfate. After filtering and concentrating, the title compound (700 mg, 77%) was obtained by purification using a silica gel column.

[0242] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl) amino)phenyl)-N-methylmethanesulfonamide (1-5)

[0243] Tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (2.9 g, 4.68 mmol) was added to a reactor containing 20% ​​trifluoroacetic acid / dichloromethane (46 mL), stirred for 3 hours, and neutralized with aqueous sodium bicarbonate. After extraction with dichloromethane, it was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (2.4 g, 98%).

[0244] Step 6: Synthesis of Compound 1

[0245] To a solution of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (67 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added diisopropylethylamine (67 mL, 0.39 mmol), and the mixture was stirred at 90 °C. After 16 h, it was concentrated and purified by column chromatography to afford the title compound (95 mg, 66%).

[0246] Example 2: Synthesis of 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (Compound 2)

[0247]

[0248] Step 1: Synthesis of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (2-1)

[0249] A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (500 mg, 2.92 mmol), piperidinone hydrochloride (470 mg, 3.47 mmol) and potassium carbonate (799 mg, 5.78 mmol) in dimethyl sulfoxide (6 mL) was stirred at 80 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (370 mg, 50%).

[0250] Step 2: Synthesis of tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2-2)

[0251] To a mixture of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (460 mg, 1.84 mmol) and N-Boc-piperazine (1.0 g, 5.51 mmol) in dichloromethane (18 mL) was added acetic acid (0.3 mL, 5.51 mmol), and the mixture was stirred for 1 h 30 min. After adding NaBH(OAc)3 (580 mg, 2.76 mmol) and stirring for 5 h, the pH was adjusted to about 8 with aqueous sodium bicarbonate, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by column chromatography to afford the title compound (650 mg, 84%).

[0252] Step 3: Synthesis of tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (2-3)

[0253] The mixture of tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (650 mg, 1.55 mmol) in tetrahydrofuran / ethanol (7 / 7 mL) was purged with argon, and 10% Pd / C (65 mg) was added. After replacing with hydrogen and stirring for 4 h, the mixture was filtered through celite and concentrated to afford the title compound (650 mg, 100%).

[0254] Step 4: Synthesis of tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (2-4)

[0255] Purged with argon, 1,4-di A mixture of tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (640 mg, 1.64 mmol), N-(2-((2,5-dichloropyrimidin-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 decane (6.5 mL) was purged with argon, and Pd(OAc)2 (52 mg, 0.23 mmol) was added. After stirring overnight under reflux and cooling to room temperature, the mixture was extracted by diluting with ethyl acetate and brine. After drying over anhydrous magnesium sulfate, filtering and concentrating, the title compound (610 mg, 53%) was obtained by purification on a silica gel column.

[0256] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino yl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (2-5)

[0257] 20% Trifluoroacetic acid / dichloromethane (9 mL) was added to a reactor containing tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (610 g, 0.87 mmol), stirred for 3 h, and then neutralized with aqueous sodium bicarbonate. After extraction with dichloromethane, drying over anhydrous magnesium sulfate, filtering and concentrating, the title compound (430 mg, 82%) was obtained.

[0258] Step 6: Synthesis of Compound 2

[0259] To a solution of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide (51 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) in N,N-dimethylformamide (1.5 mL) was added diisopropylethylamine (51 mL, 0.29 mmol) and the mixture was stirred at 90 °C. After 16 h, the mixture was concentrated and purified by column chromatography to afford the title compound (95 mg, 66%).

[0260] Example 3: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)(methyl)amino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 3)

[0261]

[0262]

[0263] Step 1: Synthesis of 4-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3- 1)

[0264] 2-(2,6-Dioxopiperidin-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 azodicarboxylate (0.538 m, 2.74 mmol) was added slowly and the mixture was stirred overnight. The reaction mixture was concentrated, diluted with isopropanol and stirred for 2 h. The precipitated solid was filtered, washed with isopropanol and dried to afford the title compound (510 mg, 69%).

[0265] Step 2: Synthesis of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (3-2)

[0266] The title compound (3.90 g, 91%) was obtained using a method similar to the synthetic method of Step 2 in Example 1 above, substituting 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 11.69 mmol) and tert-butyl methyl(piperidin-4-yl)carbamate (2.76 g, 12.86 mmol) for 4-fluoro-2-methoxy-1-nitrobenzene and Boc-piperazine, respectively.

[0267] Step 3: Synthesis of tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate (3-3)

[0268] The title compound (1.65 g, 94% yield) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, where tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (2.0 g, 7.99 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0269] Step 4: Synthesis of tert-butyl (1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate (3-4)

[0270] The title compound (1.52 g, 53% yield) was obtained using a method similar to the synthesis method in Step 4 of Example 1 above, where tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate (1.5 g, 4.47 mmol) and N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1.63 g, 4.47 mmol) were used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate and N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0271] Step 5: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino yl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (3-5)

[0272] The title compound (410 mg, 97% yield) was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, where tert-butyl (1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate (0.5 g, 0.774 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0273] Step 6: Synthesis of Compound 3

[0274] The title compound (21 mg, yield 16%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 4-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0275] Example 4: Synthesis of 11-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide (Compound 4)

[0276]

[0277] Step 1: Synthesize 11-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide (4-1) (4-1)

[0278] The title compound (236 mg, yield 62%) was obtained using a method similar to the synthesis method in Step 1 of Example 1 above, wherein 11-bromoundecanoic acid (583 mg, 2.20 mmol) was used instead of 5-bromopentanoic acid.

[0279] Step 2: Synthesize Compound 4

[0280] The title compound (94 mg, yield 64%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 11-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide (80 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0281] Example 5: Synthesis of 11-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide (Compound 5)

[0282]

[0283] The title compound (65 mg, yield 54%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 11-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide (60 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used in place of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0284] Example 6: Synthesis of (2R,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)pentanamido)3,3-dimethylbutanoyl)4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 6)

[0285]

[0286]

[0287] Step 1: Synthesize (2R,4R)-1-((S)-2-(5-bromopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (6-1)

[0288] To a mixture of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (200 mg, 0.43 mmol), 5-bromopentanoic acid (155 mg, 0.86 mmol) and dimethylaminopyridine (11 mg, 0.086 mmol) in dichloromethane (4 mL) was added diisopropylethylamine (149 μL, 0.86 mmol), and the mixture was stirred for 5 minutes, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) was added. After stirring overnight, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain the title compound (203 mg, 80%).

[0289] Step 2: Synthesize Compound 6

[0290] The title compound (46 mg, yield 34%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein (2R,4R)-1-((S)-2-(5-bromopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (80 mg, 0.14 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.14 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0291] Example 7: Synthesis of (2R,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 7)

[0292]

[0293] Step 1: Synthesize tert-butyl 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)-3- methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pentanoate (7-1)

[0294] The title compound (71 mg, yield 56%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein tert-butyl 5-bromovalerate (43 mg, 0.18 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.17 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)valeramide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0295] Step 2: Synthesize 5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)pentanoic acid (7-2)

[0296] The compound obtained in Step 1 was dissolved in 20% trifluoroacetic acid / dichloromethane (1 mL) and stirred overnight. The reaction mixture was concentrated, diluted with 4N 1,4-dioxane (1.5 mL), stirred for 1 hour, and then concentrated and used in the next reaction. The title compound (60 mg, yield 57%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)valeric acid obtained in Step 2 were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromovaleric acid, respectively.

[0297] Step 3: Synthesize Compound 7

[0298] Example 8: Synthesis of 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 8)

[0299]

[0300]

[0301] ​Step 1: Synthesize 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-di oxoisoindolin-4-yl)acetamide (8-1)

[0302] The title compound (404 mg, 94% yield) was obtained using a method similar to the synthesis method of Step 1 in Example 1 above, wherein 2-(2-(2-chloroethoxy)ethoxy)acetic acid (535 mg, 2.93 mmol) and 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (268 mg, 0.98 mmol) were used instead of 5-bromovaleric acid and 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (200 mg, 0.73 mmol), respectively.

[0303] Step 2: Synthesize N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(2- (2-iodoethoxy)ethoxy)acetamide (8-2)

[0304] A mixture of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-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 extracted by dilution with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered through silica gel. After concentration, the title compound (456 mg, 95%) was obtained by recrystallization from dichloromethane / methyl tert-butyl ether / heptane.

[0305] Step 3: Synthesize Compound 8

[0306] The title compound (96 mg, 77% yield) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(2-(2-iodoethoxy)ethoxy)acetamide (71 mg, 0.14 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.14 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0307] Example 9: Synthesis of 2-(2-(2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 9)

[0308]

[0309] The title compound (59 mg, yield 51%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-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)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0310] Example 10: Synthesis of (2R,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 10)

[0311]

[0312] Step 1: Synthesize tert-butyl 2-(2-(2-iodoethoxy)ethoxy)acetate (10-1)

[0313] A mixture of tert-butyl 2-(2-(2-chloroethoxy)ethoxy)acetate (300 mg, 1.26 mmol) and sodium iodide (754 mg, 5.02 mmol) in acetone (8 mL) was stirred under reflux overnight. The reaction mixture was concentrated and extracted by dilution with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the title compound (387 mg, 93%).

[0314] Step 2: Synthesize tert-butyl 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl) (ethoxy) ethoxy)acetate (10-2)

[0315] The title compound (198 mg, yield 91%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein tert-butyl 2-(2-(2-iodoethoxy)ethoxy)acetate (100 mg, 0.30 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (160 mg, 0.30 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0316] Step 3: Synthesize 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino) pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethoxy)ethoxy)acetic acid hydrochloride (10-3)

[0317] The title compound was obtained using a method similar to the synthesis method of Step 2 in Example 7 above, wherein tert-butyl 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethoxy)ethoxy)acetate (195 mg, 0.27 mmol) was used instead of tert-butyl 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pentanoate, and the title compound was then used in the next reaction.

[0318] Step 4: Synthesize Compound 10

[0319] The title compound (99 mg, 41% yield) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (105 mg, 0.23 mmol) and 2-(2-(2-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethoxy)ethoxy)acetic acid hydrochloride were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0320] Example 11: Synthesis of (2R,4R)-1-((S)-2-(2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 11)

[0321]

[0322] Step 1: Synthesize tert-butyl 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)acetate (11-1)

[0323] Diisopropylethylamine (72 μL, 0.43 mmol) was added to a solution of tert-butyl 2-bromoacetate (34 mg, 0.17 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.17 mmol) in dichloromethane (1.5 mL) and stirred for 4 h. Extraction was carried out by dilution with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and used for the next reaction.

[0324] Step 2: Synthesize 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)acetic acid hydrochloride (11-2)

[0325] The title compound was obtained using a method similar to the synthesis method in Step 2 of Example 7 above, where tert-butyl 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-yl)acetate (122 mg, 0.17 mmol) was used instead of tert-butyl 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pentanoate, and the title compound was then used in the next reaction.

[0326] Step 3: Synthesize Compound 11

[0327] The title compound (40 mg, yield 28%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, where (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (62 mg, 0.13 mmol) and 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-yl)acetic acid hydrochloride were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0328] Example 12: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)N-methylmethanesulfonamide (Compound 12)

[0329]

[0330] Step 1: Synthesize 4-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (12-1)

[0331] The title compound (257 mg, yield 80%) was obtained using a method similar to the synthesis method in Step 1 of Example 3 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (200 mg, 0.73 mmol) and 2-(2-chloroethoxy)ethanol (136 mg, 1.10 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione and 4-bromobutan-1-ol, respectively.

[0332] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-iodoethoxy)ethoxy)isoindoline-1, 3-dione (12-2)

[0333] The title compound (215 mg, yield 71%) was obtained using a method similar to the synthesis method in Step 2 of Example 8 above, wherein 4-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (250 mg, 0.57 mmol) was used instead of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide.

[0334] Step 3: Synthesis of Compound 12

[0335] The title compound (65 mg, yield 50%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-iodoethoxy)ethoxy)isoindoline-1,3-dione (80 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0336] Example 13: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)N-methylmethanesulfonamide (Compound 13)

[0337]

[0338] The title compound (79 mg, yield 72%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-iodoethoxy)ethoxy)isoindoline-1,3-dione (61 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0339] Example 14: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 14)

[0340]

[0341] The title compound (25 mg, yield 20%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 4-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0342] Example 15: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 15)

[0343]

[0344] The title compound (23 mg, yield 17%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein 4-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (88 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0345] Example 16: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)piperidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 16)

[0346]

[0347] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-hydroxyethoxy)ethyl)amino)isoind oline-1,3-dione (16-1)

[0348] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) in dimethylformamide (1.5 mL) was added 2-(2-aminoethoxy)ethanol (209 mg, 1.99 mmol) and N,N-diisopropylethylamine (64 μl, 0.368 mmol), and the mixture was stirred overnight at 90 °C. Extraction was carried out by dilution with ethyl acetate and water, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and concentrated, and the title compound (251 mg, 39%) was obtained by column purification.

[0349] Step 2: Synthesis of 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )ethoxy)ethyl 4-toluenesulfonate (16-2)

[0350] 2-(2,6-Dioxopiperidin-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 h, 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, yield 73%).

[0351] Step 3: Synthesis of Compound 16

[0352] The title compound (29 mg, yield 25%) was obtained using a method similar to the synthetic method of step 6 of Example 1 above, wherein 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl 4-toluenesulfonate (70 mg, 0.14 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.14 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0353] Example 17: Synthesis of (2R,4R)-1-((S)-2-(5-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 17)

[0354]

[0355] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (17-1)

[0356] The title compound (2.0 g, yield 98%) was obtained using a method similar to the synthetic method of step 2 of Example 1 above, wherein 1,2-difluoro-4-nitrobenzene (1.0 g, 6.29 mmol) was used instead of 4-fluoro-2-methoxy-1-nitrobenzene.

[0357] Step 2: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (17-2)

[0358] The title compound (430 mg, yield 95%) was obtained using a method similar to the synthesis method in step 3 of Example 1 above, where tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (500 mg, 1.54 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0359] Step 3: Synthesis of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin- 2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (17-3)

[0360] The title compound (540 mg, yield 56%) was obtained using a method similar to the synthesis method in step 4 of Example 1 above, where tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (450 mg, 1.52 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0361] Step 4: Synthesis of N-(2-((5-chloro-2-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino) phenyl)-N-methylmethanesulfonamide (17-4)

[0362] The title compound (70 mg, yield 84%) was obtained using a method similar to the synthesis method in step 5 of Example 1 above, where tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (100 mg, 0.17 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0363] Step 5: Synthesis of Compound 17

[0364] The title compound (41 mg, yield 34%) was obtained using a method similar to the synthesis method in step 2 of Example 1 above, where N-(2-((5-chloro-2-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (59 mg, 0.12 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0365] Synthesis of Example 18: (2R,4R)-1-((S)-2-(5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 18)

[0366]

[0367] Step 1: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (18-1)

[0368] The title compound (600 mg, yield 80%) was obtained by a method similar to the synthesis method of Step 1 in Example 2 above, where 1,2-difluoro-4-nitrobenzene (500 mg, 3.14 mmol) was used instead of 4-fluoro-2-methoxy-1-nitrobenzene.

[0369] Step 2: Synthesis of tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (18-2)

[0370] The title compound (320 mg, yield 62%) was obtained by a method similar to the synthesis method of Step 2 in Example 2 above, where 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (300 mg, 1.26 mmol) was used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one.

[0371] Step 3: Synthesis of tert-butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (18-3)

[0372] The title compound (300 mg, yield 100%) was obtained by a method similar to the synthesis method of Step 3 in Example 2 above, where tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (320 mg, 0.78 mmol) was used instead of tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate.

[0373] Step 4: Synthesis of tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin- 2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (18-4)

[0374] The title compound (280 mg, yield 53%) was obtained by a method similar to the synthesis method of Step 3 in Example 2 above, where tert-butyl 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (290 mg, 0.77 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate.

[0375] Step 5: Synthesis of N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (18-5) Step 6: Synthesis of Compound 18

[0376] The title compound (2.5 g, 96% yield) was obtained using a method similar to the synthesis method of Step 3 in Example 2 above, wherein tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylate (3.1 g, 4.43 mmol) was used instead of tert-butyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate.

[0377] Step 1: Synthesis of tert-butyl 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)acetate (19-1)

[0378] The title compound (42 mg, 32% yield) was obtained using a method similar to the synthesis method of Step 2 in Example 6 above, wherein N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0379] Example 19: Synthesis of (2R,4R)-1-((S)-2-(2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 19)

[0380]

[0381] Step 2: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)acetic acid hydrochloride (19-2) Step 3: Synthesis of Compound 19

[0382] The title compound was obtained using a method similar to the synthesis method of Step 1 of Example 11 above, wherein N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.17 mmol) was used instead of tert-butyl 2-bromoacetate (34 mg, 0.17 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, and the title compound was used in the next reaction.

[0383] Step l: Synthesis of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin- ​

[0384] The title compound was obtained using a method similar to the synthesis method of Step 2 of Example 7 above, wherein tert-butyl 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)acetate (119 mg, 0.17 mmol) was used instead of tert-butyl 5-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pentanoate, and subsequently the title compound was used in the next reaction.

[0385] ​

[0386] The title compound (80 mg, yield 36%) was obtained using a method similar to the synthesis method of Step 1 of Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (62 mg, 0.13 mmol) and 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)acetic acid hydrochloride were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid.

[0387] Example 20: Synthesis of (2R,4R)-1-((S)-2-(3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 20)

[0388]

[0389] ​ tert-Butyl (2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoate (20-1)

[0390] To a solution of tert-butyl 3-bromopropionate (35 mg, 0.17 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.17 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (74 μL, 0.43 mmol) and the mixture was stirred for 4 h. The mixture was extracted by dilution with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and used for the next reaction.

[0391] Step 2: Synthesis of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride (20-2) Step 3: Synthesis of Compound 20

[0392] To the solution of tert-butyl 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate obtained in the step of Example 20-1 at 40 °C was added 4N HCl 1,4-dioxane and dichloromethane (2 mL), and the mixture was stirred for 3 h. The title compound obtained by concentrating and drying the reaction mixture under vacuum was used for the next reaction. The title compound obtained by concentrating and drying the reaction mixture under vacuum was used for the next reaction.

[0393] Step 1: Synthesis of tert-Butyl 4-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0394] The title compound (57 mg, yield 37%) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, where (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (75 mg, 0.16 mmol) and 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0395] Example 21: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 21)

[0396]

[0397] The title compound (66 mg, yield 63%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, where 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (46 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0398] Example 22: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (Compound 22)

[0399]

[0400] The title compound (72 mg, yield 69%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (44 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.12 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0401] Example 23: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 23)

[0402]

[0403] Step 2: Synthesis of tert-Butyl 4-((1-(4-amino-2-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (23-1)

[0404] The title compound (647 mg, yield 42%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, where tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (1.0 g, 3.54 mmol) was used instead of Boc-piperazine.

[0405] Step 3: Synthesis of tert-Butyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (23-3) (23-2)

[0406] The title compound (572 mg, yield 96%) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, where tert-butyl 4-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (640 mg, 1.47 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0407] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (23-4) Step 5: Synthesis of Compound 23

[0408] The title compound (625 mg, yield 63%) was obtained using a method similar to the synthesis method in Step 4 of Example 1 above, where tert-butyl 4-((1-(4-amino-2-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (570 mg, 1.41 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0409] Step 1: Synthesis of Benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate Step 2: Synthesis of Benzyl 4-((4-(4-amino-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0410] The title compound (535 mg, yield 100%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where tert-butyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (620 mg, 0.17 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0411] Step 3: Synthesis of Benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (25-3)

[0412] The title compound (70 mg, yield 67%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (45 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 instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0413] Example 24: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (Compound 24)

[0414]

[0415] The title compound (78 mg, yield 75%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 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 in place of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0416] Example 25: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)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)

[0417]

[0418]

[0419] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (25-4) (25-1)

[0420] The title compound (903 mg, yield 61%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, where benzyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.0 g, 3.16 mmol) was used in place of Boc-piperazine.

[0421] Step 5: Synthesis of Compound 25 (25-2)

[0422] To 1,4-di A solution of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (900 mg, 1.92 mmol) in alkane (15 mL) was added to NHCl (513 mg, 9.60 mmol) in H2O (5 mL), and purged with argon. Zn (628 mg, 9.60 mmol) was added, and the mixture was stirred at 70 °C. After 19 hours, the mixture was filtered through diatomaceous earth and concentrated. The residue was diluted with an aqueous sodium chloride solution, made basic with a saturated aqueous sodium hydrocarbon solution, and 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).

[0423] Step 1: Synthesis of tert-Butyl 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (27-1) Step 2: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (27-2)

[0424] The title compound (1.0 g, 71% yield) was obtained using a method similar to the synthesis method of Step 4 of Example 1 above, where benzyl 4-((4-(4-amino-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (830 mg, 1.89 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0425] Step 3: Synthesis of Compound 27 Step 1: Synthesis of tert-Butyl 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (28-1)

[0426] Using a method similar to the synthesis method of Step 3 of Example 1 above, where benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (800 mg, 1.06 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0427] ​

[0428] The title compound (33 mg, yield 31%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (45 mg, 0.11 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0429] Example 26: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (Compound 26)

[0430]

[0431] The title compound (78 mg, yield 75%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 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-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.11 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0432] Example 27: Synthesis of (2R,4R)-1-((S)-2-(2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 27)

[0433]

[0434] ​ ​

[0435] The title compound (119 mg, yield 100%) was obtained by a method similar to the synthesis method in Step 6 of Example 1 above, wherein tert-butyl 2-bromoacetate (32 mg, 0.16 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 (100 mg, 0.16 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0436] ​ ​

[0437] The title compound was obtained by a method similar to the synthesis method in Step 2 of Example 20 above, wherein tert-butyl 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (119 mg, 0.16 mmol) was used instead of hydrochloride salt of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propionic acid, and the title compound was then used in the next reaction.

[0438] ​

[0439] The title compound (104 mg, yield 59%) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride obtained in Step 2 were used to replace (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0440] Example 28: Synthesis of (2R,4R)-1-((S)-2-(2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 28)

[0441]

[0442] ​ ​

[0443] The title compound (91 mg, yield 94%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein tert-butyl 2-bromoacetate (26 mg, 0.13 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (82 mg, 0.13 mmol) were used to replace 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0444] Step 2: Synthesize 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid hydrochloride (28-2) Step 3: Synthesize Compound 28

[0445] The title compound was obtained using a method similar to the synthesis method of Step 2 in Example 20 above, wherein tert-butyl 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (91 mg, 0.13 mmol) was used instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride, and then the title compound was used in the next reaction.

[0446] Step 1: Synthesize tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate

[0447] The title compound (73 mg, yield 51%) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid hydrochloride obtained in Step 2 were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0448] Example 29: Synthesis of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)piperidine-4-carboxamide (Compound 29)

[0449]

[0450]

[0451] Step 2: Synthesize tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (29-1)

[0452] The title compound (462 mg, yield 64%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, wherein tert-butyl 1-(piperidin-4-ylmethyl)piperidine-4-carboxylate (470 mg, 1.66 mmol) was used instead of Boc-piperazine.

[0453] Step 3: Synthesize tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (29-3) (29-2)

[0454] The title compound (223 mg, yield 99%) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, wherein tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (240 mg, 0.55 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0455] Step 4: Synthesize 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride (29-4) Step 5: Synthesize Compound 29

[0456] The title compound (95 mg, yield 24%) was obtained using a method similar to the synthesis method in Step 4 of Example 1 above, wherein tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (223 mg, 0.55 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0457] Step 1: Synthesize tert-butyl 9-(3-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-1) Step 2: Synthesize tert-butyl 9-(4-amino-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-2)

[0458] The title compound was obtained using a method similar to the synthesis method in Step 2 of Example 20 above, wherein tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (90 mg, 0.13 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, and the title compound was subsequently used in the next reaction.

[0459] Step 3: Synthesize tert-butyl 9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30-3)

[0460] The title compound (27 mg, yield 20%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride obtained in Step 2 were used to replace (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0461] Example 30: Synthesis of 3-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5,5]undecan-3-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanamide (Compound 30)

[0462]

[0463]

[0464] Step 4: Synthesize N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethylsulfonamide (30-4) Step 5: Synthesize Compound 30

[0465] The title compound (13.2 g, yield 93%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, wherein tert-butyl 3,9-diazaspiro[5,5]undecane-3-carboxylate (6.0 g, 35.06 mmol) was used to replace Boc-piperazine.

[0466] Step 1: Synthesize tert-butyl 2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate (31-1) Step 2: Synthesize 2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetic acid hydrochloride (31-2)

[0467] The title compound (1.4 g, yield 99%) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, wherein tert-butyl 9-(3-methoxy-4-nitrophenyl)-3,9-diazaspiro[5,5]undecane-3-carboxylate (1.5 g, 3.70 mmol) was used to replace tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0468] Step 3: Synthesize Compound 31 Step 1: Synthesize tert-butyl 6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0469] The title compound (1.4 g, yield 54%) was obtained using a method similar to the synthesis method in step 4 of Example 1 above, where tert-butyl 9-(4-amino-3-methoxyphenyl)-3,9-diazaspiro[5,5]undecane-3-carboxylate (1.4 g, 3.60 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0470] Step 2: Synthesize tert-butyl 6-(4-amino-3-methoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate ​

[0471] The title compound (1.2 g, yield 99%) was obtained using a method similar to the synthesis method in step 5 of Example 1 above, where tert-butyl 9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5,5]undecane-3-carboxylate (1.4 g, 1.98 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0472] ​

[0473] The title compound (61 mg, yield 56%) was obtained using a method similar to the synthesis method in step 6 of Example 1 above, where 3-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanamide (49 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5,5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethylsulfonamide (70 mg, 0.12 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0474] Example 31: Synthesis of (2R,4R)-1-((S)-2-(2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5,5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 31)

[0475]

[0476] ​ ​

[0477] The title compound (119 mg, yield 100%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein tert-butyl 2-bromoacetate (26 mg, 0.13 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.17 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0478] ​ ​

[0479] The title compound was obtained using a method similar to the synthesis method of Step 2 in Example 20 above, wherein tert-butyl 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (119 mg, 0.17 mmol) was used instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride, and the title compound was then used in the next reaction.

[0480] ​

[0481] The title compound (85 mg, yield 34%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5,5]undecan-3-yl)acetic acid hydrochloride obtained in Step 2 were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid, respectively.

[0482] Example 32: Synthesis of 3-(6-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3,3]heptan-2-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanamide (Compound 32)

[0483]

[0484] ​ (32-1)

[0485] The title compound (4.8 g, yield 79%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, wherein tert-butyl 2,6-diazaspiro[3,3]heptane-2-carboxylate (7.4 g, 21.0 mmol) was used instead of Boc-piperazine.

[0486] ​ (32-2)

[0487] The title compound (950 mg, yield 70%) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, wherein tert-butyl 6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (1.5 g, 4.29 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0488] Step 3: Synthesize tert-butyl 6-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2- yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3.3]undecane-2-carboxylate (32-3)

[0489] The title compound (0.7 g, yield 34%) was obtained using a method similar to the synthesis method in step 4 of Example 1 above, wherein tert-butyl 6-(4-amino-3-methoxyphenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (0.9 g, 2.81 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0490] Step 4: Synthesize N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (32-4)

[0491] The title compound (580 mg, yield 99%) was obtained using a method similar to the synthesis method in step 5 of Example 1 above, wherein tert-butyl 6-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-2,6-diazaspiro[3,3]undecane-2-carboxylate (0.7 g, 1.98 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0492] Step 5: Synthesize Compound 32

[0493] The title compound (48 mg, yield 41%) was obtained using a method similar to the synthesis method in step 6 of Example 1 above, wherein 3-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-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)pyrimidin-4-yl)amino)phenyl)-N-methylmethylsulfonamide (70 mg, 0.13 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0494] Example 33: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 33)

[0495]

[0496] Step 1: Synthesize tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate (33-1)

[0497] Sodium hydroxide (346 mg, 8.66 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.77 mmol) in DMF (11 mL), and the mixture was stirred for 30 minutes. ((2-Bromoethoxy)methyl)benzene (1.1 mL, 6.93 mmol) was added dropwise at 0 °C. After stirring overnight at 80 °C, the mixture was extracted with ethyl acetate and water. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The title compound (0.95 g, 54% yield) was obtained by filtration, concentration, and purification by column chromatography.

[0498] Step 2: Synthesize 3-(2-(benzyloxy)ethoxy)azetidine (33-2)

[0499] A solution of tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate (0.9 g, 2.93 mmol) in 20% trichloroacetic acid in dichloromethane (20 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated and extracted with 1 N aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound (550 mg, 92% yield).

[0500] Step 3: Synthesize 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione (33-3)

[0501] Diisopropylethylamine (757 μL, 4.34 mmol) was added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.6 g, 2.17 mmol) and 3-(2-(benzyloxy)ethoxy)azetidine (0.5 g, 2.39 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred overnight at 80 °C. After extraction with ethyl acetate and water, 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 give the title compound (650 mg, 65% yield).

[0502] Step 4: Synthesize 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethoxy)azetidin-1-yl) isoindoline-1,3-dione (33-4)

[0503] The solution of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-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 replaced with hydrogen and stirred overnight. It was diluted with dichloromethane, filtered through diatomaceous earth, and concentrated. The residue was purified by column chromatography to obtain the title compound (130 mg, yield 32%).

[0504] Step 5: Synthesize ethyl 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin- 3-yl)oxy)methanesulfonate (33-5)

[0505] Triethylamine (146 mL, 1.05 mmol) was added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethoxy)azetidin-1-yl)isoindoline-1,3-dione (130 mg, 0.35 mmol) in dichloromethane (7 mL), and then 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%).

[0506] Step 6: Synthesize Compound 33

[0507] The title compound (40 mg, yield 31%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where ethyl 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)methanesulfonate (70 mg, 0.16 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (81 mg, 0.16 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0508] Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 34)

[0509]

[0510] Step 1: Synthesize tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-1-carboxylate (34-1)

[0511] The title compound (0.7 g, yield 42%) was obtained by a method similar to the synthesis method in Step 6 of Example 1 above, where tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol) was used instead of tert-butyl 3-hydroxyazetidine-1-carboxylate.

[0512] Step 2: Synthesize 4-(2-(benzyloxy)ethoxy)piperidine (34-2)

[0513] The title compound (480 mg, yield 98%) was obtained by a method similar to the synthesis method in Step 2 of Example 33 above, where tert-butyl 4-(2-(benzyloxy)ethoxy)piperidine-1-carboxylate (0.7 g, 2.09 mmol) was used instead of tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-1-carboxylate.

[0514] Step 3: Synthesize 5-(4-(2-(benzyloxy)ethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione (34-3)

[0515] The title compound (400 mg, yield 45%) was obtained by a method similar to the synthesis method in Step 3 of Example 33 above, where 4-(2-(benzyloxy)ethoxy)piperidine (468 mg, 1.99 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0516] Step 4: Synthesize 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethoxy)piperidin-1-yl)isoindol ine-1,3-dione (34-4)

[0517] The title compound (130 mg, yield 40%) was obtained by a method similar to the synthesis method in Step 4 of Example 33 above, where 5-(4-(2-(benzyloxy)ethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.4 g, 0.81 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0518] Step 5: Synthesize ethyl 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin- 4-yl)oxy)methanesulfonate (34-5)

[0519] The title compound (135 mg, 90% yield) was obtained using a method similar to the synthesis method of Step 5 in Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethoxy)piperidin-1-yl)isoindoline-1,3-dione (125 mg, 0.31 mmol) was used instead of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethoxy)azetidin-1-yl)isoindoline-1,3-dione.

[0520] Step 5: Synthesize Compound 34

[0521] The title compound (70 mg, 53% yield) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein ethyl 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)methanesulfonate (70 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0522] Example 35: Synthesis of (2S,4R)-1-((S)-2-(2-(4-((4-(3-chloro-4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 35)

[0523]

[0524] Step 1: Synthesize benzyl 4-((4-(3-chloro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (35-1)

[0525] The title compound (428 mg, 72% yield) was obtained using a method similar to the synthesis method of Step 2 in Example 1 above, wherein 2-chloro-4-fluoro-1-nitrobenzene (221 mg, 1.26 mmol) was used instead of 4-fluoro-2-methoxy-1-nitrobenzene.

[0526] Step 2: Synthesize benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (35-2)

[0527] The title compound (420 mg, 99% yield) was obtained using a method similar to the synthesis method of Step 2 of Example 25 above, wherein 4-((4-(3-chloro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (408 mg, 0.91 mmol) was used instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0528] Step 3: Synthesize benzyl 4-((4-(3-chloro-4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino) pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (35-3)

[0529] Methanesulfonic acid (0.12 mL, 1.90 mmol) was added to a solution of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (420 mg, 0.95 mmol) and N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (396 mg, 1.14 mmol) in isopropanol (9.5 mL), and the mixture was stirred overnight under reflux. The mixture was extracted by diluting with dichloromethane and aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the title compound (316 mg, 44%) was obtained by purification using a silica gel column.

[0530] Step 4: Synthesize N-(2-((5-chloro-2-((2-chloro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino 2-(4-((1-(3-chloro-4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid tert-butyl ester (35-4)

[0531] At room temperature, a saturated aqueous solution of benzyl 4-((4-(3-chloro-4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (50 mg, 0.066 mmol) in hydrochloric acid (1 mL) was stirred overnight. The mixture was extracted by diluting with dichloromethane and aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The title compound (21 mg, 52%) was obtained by filtration and concentration.

[0532] Step 5: Synthesis of 2-(4-((1-(3-chloro-4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid tert-butyl ester (35-5) Step 6: Synthesis of 2-(4-((1-(3-chloro-4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (35-6)

[0533] The title compound (50 mg, yield 99%) was obtained using a method similar to the synthesis method of Step 1 in Example 11 above, where N-(2-((5-chloro-2-((2-chloro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.114 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0534] Step 7: Synthesis of Compound 35 Step 1: Synthesis of benzyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (36-1)

[0535] The title compound was obtained using a method similar to the synthesis method of Step 2 in Example 20 above, where tert-butyl 2-(4-((1-(3-chloro-4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (50 mg, 0.068 mmol) was used instead of tert-butyl 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propionate, and the title compound was then used in the next reaction.

[0536] Step 2: Synthesis of benzyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (36-2)

[0537] The title compound (51 mg, yield 69%) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, where hydrochloride of 2-(4-((1-(3-chloro-4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid (46 mg, 0.068 mmol) was used instead of 5-bromovaleric acid.

[0538] Example 36: Synthesis of (2S,4R)-1-((S)-2-(2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 36)

[0539]

[0540] Step 3: Synthesis of benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (36-3)

[0541] The title compound (765 mg, yield 67%) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, where 1,2-difluoro-4-nitrobenzene (400 mg, 2.51 mmol) and benzyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (798 mg, 2.51 mmol) were used to replace 4-fluoro-2-methoxy-1-nitrobenzene and Boc-piperazine, respectively.

[0542] Step 4: Synthesis of N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (36-4)

[0543] The title compound (700 mg, yield 99%) was obtained using a method similar to the synthesis method in Step 2 of Example 25 above, where benzyl 4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (750 mg, 1.64 mmol) was used to replace benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0544] Step 5: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid tert-butyl ester (36-5) Methane Step 6: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (36-6) (4-((5-chloro-4-((2-((N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid tert-butyl ester

[0545] The title compound (1.1 g, yield 91%) was obtained using a method similar to the synthesis method in Step 3 of Example 35 above, where benzyl 4-((4-(4-amino-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (700 mg, 1.64 mmol) was used to replace benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0546] Step 7: Synthesis of Compound 36 Step 1: Synthesis of tert-butyl 3-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate (37-1)

[0547] The title compound (900 mg, yield 99%) was obtained using a method similar to the synthesis method in Step 4 of Example 33 above, where benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (1.1 g, 1.49 mmol) was used to replace 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0548] Step 2: Synthesis of N-(2-((2-((4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (37-2) Step 3: Synthesis of 2-(3-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid tert-butyl ester

[0549] The title compound (75 mg, yield 63%) was synthesized using a method similar to the synthesis method in Step 1 of Example 11 above, where N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.166 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0550] ​ ​

[0551] The title compound (65 mg, 98%) was obtained using a method similar to the synthesis method in Step 2 of Example 20 above, where tert-butyl 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (70 mg, 0.098 mmol) was used instead of 3 -(4-(1- ​ ​ 。

[0552] ​

[0553] The title compound (32 mg, yield 31%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, where 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate hydrochloride (45 mg, 0.096 mmol) was used instead of 5-bromovaleric acid.

[0554] Example 37: Synthesis of (2S,4R)-1-((S)-2-(2-(3-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)azetidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 37)

[0555]

[0556]

[0557] ​​

[0558] The title compound (230 mg, 87% yield) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, where tert-butyl 3-formylazetidine-1-carboxylate (107 mg, 0.58 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (200 mg, 0.39 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0559] ​ ​

[0560] The title compound was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, where tert-butyl 3-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate (225 mg, 0.33 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0561] ​ tert-Butyl (azetidin-1-yl)((piperidin-4-yl)methyl)acetate (37-3)

[0562] The title compound (40 mg, 42% yield) was obtained using a method similar to the synthesis method in Step 1 of Example 11 above, where N-(2-((2-((4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.166 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0563] Step 4: Synthesis of 2-(3-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidin-1-yl)acetic acid hydrochloride (37-4) Step 5: Synthesis of Compound 37

[0564] The title compound was obtained using a method similar to the synthesis method of Step 2 in Example 20 above, wherein tert-butyl 2-(3-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidin-1-yl)acetate (80 mg, 0.117 mmol) was used instead of tert-butyl 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propionate.

[0565] Step 1: Synthesis of benzyl 4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)piperidine-1-carboxylate

[0566] The title compound (45 mg, yield 48%) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, wherein 2-(3-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-1-yl)acetic acid hydrochloride (85 mg, 0.118 mmol) was used instead of 5-bromopentanoic acid.

[0567] Example 38: Synthesis of (2S,4R)-1-((S)-2-(1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 38)

[0568]

[0569] Step 2: Synthesis of tert-butyl 1-(piperidin-4-ylmethyl)azetidine-3-carboxylate (38-2) (38-1)

[0570] The title compound (640 mg, yield 56%) was obtained using a method similar to the synthesis method of Step 2 in Example 2 above, wherein benzyl 4-formylpiperidine-1-carboxylate (732 mg, 2.96 mmol) and tert-butyl azetidine-3-carboxylate (857 mg, 4.44 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0571] Step 3: Synthesis of tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (38-3)

[0572] The title compound (400 mg, 95% yield) was obtained using a method similar to the synthesis method of Step 4 in Example 33 above, where 4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (1.3 g, 3.40 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0573] Step 4: Synthesis of tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (38-4) Step 5: Synthesis of tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (38-5)

[0574] The title compound (510 mg, 80% yield) was obtained using a method similar to the synthesis method of Step 2 in Example 1 above, where tert-butyl 1-(piperidin-4-ylmethyl)azetidine-3-carboxylate (400 mg, 1.57 mmol) was used instead of Boc-piperazine.

[0575] Step 6: Synthesis of 1-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylic acid hydrochloride (38-6) Step 7: Synthesis of Compound 38

[0576] The title compound (470 mg, 99% yield) was obtained using a method similar to the synthesis method of Step 3 in Example 1 above, where benzyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (510 mg, 1.26 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0577] Step 1: Synthesis of tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)azetidine-1-carboxylate (39-1) Step 2: Synthesis of 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (39-2)

[0578] The title compound (506 mg, 59% yield) was obtained using a method similar to the synthesis method of Step 4 in Example 1 above, where tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (470 mg, 2.25 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0579] Step 3: Synthesis of 3-(4-((1-(2-chloroethyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39-3) Step 4: Synthesis of Compound 39

[0580] The title compound was obtained using a method similar to the synthesis method in Step 2 of Example 20 above, wherein tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylate (100 mg, 0.146 mmol) was used instead of tert-butyl 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propionate.

[0581] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione (41-1)

[0582] The title compound (87 mg, yield 60%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein hydrochloride of 1-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)azetidine-3-carboxylic acid (87 mg, 0.14 mmol) was used instead of 5-bromovaleric acid.

[0583] Example 39: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)azetidin-1-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 39)

[0584]

[0585] Step 2: Synthesis of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (41-2) Step 3: Synthesis of Compound 41

[0586] A mixture of 3-(4-hydroxy-1-oxoisoindolin-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 further added and stirred for 4 hours. Saturated aqueous NH4Cl solution was added to the reaction mixture, stirred, filtered, washed with water and ethyl acetate, and dried in vacuo to obtain the title compound (150 mg, 36%).

[0587] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (44-1) Step 2: Synthesis of methyl ((2S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-2-yl)methanesulfonate (44-2)

[0588] The title compound was obtained using a method similar to the synthesis method of Step 5 of Example 1 above, wherein tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)azetidine-1-carboxylate (150 mg, 0.36 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate, and the title compound was then used in the next reaction.

[0589] Step 3: Synthesis of Compound 44 ​

[0590] Diisopropylethylamine (219 μL, 0.29 mmol) was added to a solution of 3-(4-(azetidin-3-yloxy)-1-oxoisoindolin-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), and the mixture was stirred at 90 °C. After 4.5 h, the mixture was concentrated and purified by column chromatography to obtain the title compound (70 mg, 51%).

[0591] ​

[0592] A mixture of 3-(4-((1-(2-chloroethyl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.185 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (93 mg, 0.185 mmol) in N,N-dimethylformamide (1 mL) was stirred at 80 °C overnight. The mixture was cooled to room temperature, water was added, and the solid was obtained by filtration and then purified by column chromatography to obtain the title compound (35 mg, 23%).

[0593] Example 40: Synthesis of N-(2-((5-chloro-2-((4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)ethyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 40)

[0594]

[0595] The title compound (57 mg, 43% yield) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein ethyl 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)methanesulfonate (70 mg, 0.16 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78 mg, 0.16 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0596] Example 41: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 41)

[0597]

[0598] ​

[0599] A mixture of 5-methylisobenzofuran-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%).

[0600] ​

[0601] AIBN (24 mg, 0.15 mmol) was added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione (200 mg, 0.74 mmol) and NBS (144 mg, 0.81 mmol) in chloroform (10 mL), and the mixture was stirred under reflux. After stirring overnight, the mixture was extracted with water, dried over anhydrous magnesium sulfate, filtered, and the resulting material (140 mg, mixture) was used for the next reaction.

[0602] ​

[0603] To a solution of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (44 mg, 0.125 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.114 mmol) in N,N-dimethylformamide (1 mL) was added DIPEA (50 μL, 0.285 mmol) and the mixture was stirred overnight at 50 °C. After cooling to room temperature, water was added and the solid was filtered off. The solid was purified by column chromatography to afford the title compound (48 mg, 48%).

[0604] Example 42: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 42)

[0605]

[0606] The title compound (56 mg, 55% yield) was obtained using a method similar to the synthetic method of Step 3 of Example 41 above, wherein N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.119 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0607] Example 43: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 43)

[0608]

[0609] The title compound (30 mg, yield 28%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (50 mg, 0.151 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid.

[0610] Example 44: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(((2S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 44)

[0611]

[0612] ​ ​

[0613] The title compound (120 mg, yield 93%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein (S)-pyrrolidin-2-ylmethanol (44 mg, 0.43 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0614] ​ ​

[0615] The title compound (416 mg, yield 38%) was obtained using a method similar to the synthesis method in Step 5 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (1.0 g, 2.53 mmol) was used instead of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethoxy)azetidin-1-yl)isoindoline-1,3-dione.

[0616] ​

[0617] The title compound (18 mg, yield 17%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein methyl ((2S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-2-yl)methanesulfonate (50 mg, 0.115 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (69 mg, 0.115 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0618] Example 45: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 45)

[0619]

[0620] Step 1: Synthesize N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piper azin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (45-1)

[0621] 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)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (500 mg, 0.81 mmol) and potassium carbonate (280 mg, 2.03) 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, and the residue was purified by column chromatography to obtain the title compound (350 mg, yield 57%).

[0622] Step 2: Synthesize N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methox ylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (45-2)

[0623] To a suspension of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (350 mg, 0.45 mmol) in ethanol (4.5 mL) was added hydrazine hydrate (57 mg, 1.13 mmol), and the mixture was 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 quantitatively, which was used in the next reaction.

[0624] Step 3: Synthesize Compound 45

[0625] The title compound (35 mg, yield 36%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (30 mg, 0.109 mmol) and N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.109 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine.

[0626] Example 46: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 46)

[0627]

[0628]

[0629] Step 1: Synthesize 4-(2-chloroethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (46- 1)

[0630] The title compound (323 mg, yield 94%) was obtained using a method similar to the synthesis method in Step 1 of Example 3 above, wherein 2-chloroethan-1-ol (110 μL, 1.64 mmol) was used instead of 4-bromobutan-1-ol.

[0631] Step 2: Synthesize 2-(2,6-dioxopiperidin-3-yl)-4-(2-iodoethoxy)isoindoline-1,3-dione (46- 2)

[0632] The title compound (341 mg, yield 78%) was obtained using a method similar to the synthesis method in Step 2 of Example 8 above, where 4-(2-chloroethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (320 mg, 1.01 mmol) was used instead of 2-(2-(2-chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide.

[0633] Step 3: Synthesize Compound 46

[0634] The title compound (36 mg, yield 35%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, where 2-(2,6-dioxopiperidin-3-yl)-4-(2-iodoethoxy)isoindoline-1,3-dione (54 mg, 0.128 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0635] Example 47: Synthesis of 2-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 47)

[0636]

[0637] The title compound (63 mg, yield 61%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (44 mg, 0.116 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0638] Example 48: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (Compound 48)

[0639]

[0640] The title compound (63 mg, yield 60%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (44 mg, 0.116 mmol) and N-(2-((5-chloro-2-((3-fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0641] Example 49: Synthesis of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 49)

[0642]

[0643] Step 1: Synthesize benzyl 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (49-1)

[0644] The title compound (700 mg, 43% yield) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, where benzyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.04 mmol) and tert-butyl piperidine-4-carboxylate (1.1 g, 6.07 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0645] Step 2: Synthesize tert-butyl 1-(piperidin-4-ylmethyl)piperidine-4-carboxylate (49-2)

[0646] The title compound (470 mg, 99% yield) was obtained using a method similar to the synthesis method in Step 4 of Example 33 above, where benzyl 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (700 mg, 1.68 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0647] Step 3: Synthesize tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (49-3)

[0648] The title compound (240 mg, 12% yield) was obtained using a method similar to the synthesis method in Step 2 of Example 1 above, where tert-butyl 1-(piperidin-4-ylmethyl)piperidine-4-carboxylate (1.3 g, 4.60 mmol) was used instead of Boc-piperazine.

[0649] Step 4: Synthesize tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (49-4)

[0650] The title compound (223 mg, 99% yield) was obtained using a method similar to the synthesis method in Step 3 of Example 1 above, where tert-butyl 1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (240 mg, 0.55 mmol) was used instead of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate.

[0651] Step 5: Synthesize tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (49-5)

[0652] The title compound (95 mg, yield 24%) was obtained using a method similar to the synthesis method in Step 4 of Example 1 above, where tert-butyl 1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (223 mg, 0.55 mmol) was used instead of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate.

[0653] Step 6: Synthesize hydrochloride of tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (49-6)

[0654] The title compound was obtained using a method similar to the synthesis method in Step 2 of Example 20 above, where tert-butyl 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (100 mg, 0.14 mmol) was used instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride, and the title compound was then used in the next reaction.

[0655] Step 7: Synthesize Compound 49

[0656] To a mixture of hydrochloride of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid (97 mg, 0.14 mmol), 3-(4-amino-1-oxoisoindolin-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 added diisopropylethylamine (98 μL, 0.56 mmol), and the mixture was stirred for two days. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then purified by silica gel column to obtain the title compound (21 mg, 17%).

[0657] Example 50: Synthesis of 2-(9-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (Compound 50)

[0658]

[0659] The title compound (90 mg, yield 64%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (60 mg, 0.158 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (93 mg, 0.158 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0660] Example 51: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 51)

[0661]

[0662] Step 1: Synthesize 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline- 1,3-dione (51-1)

[0663] The title compound (0.99 g, yield 89%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein 2-(piperidin-4-yl)ethan-1-ol (412 mg, 3.19 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0664] Step 2: Synthesize ethyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin- 4-yl)methanesulfonate (51-2)

[0665] The title compound (510 mg, yield 43%) was obtained using a method similar to the synthesis method in Step 2 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (0.99 g, 2.57 mmol) was used instead of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethoxy)azetidin-1-yl)isoindoline-1,3-dione.

[0666] Step 3: Synthesize Compound 51

[0667] The title compound (30 mg, yield 29%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein ethyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methanesulfonate (50 mg, 0.108 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (65 mg, 0.108 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0668] Example 52: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 52)

[0669]

[0670] The title compound (54 mg, yield 52%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-(2-iodoethoxy)isoindoline-1,3-dione (50 mg, 0.116 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.116 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0671] Example 53: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 53)

[0672]

[0673] The title compound (42 mg, yield 41%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (42 mg, 0.125 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70 mg, 0.114 mmol) were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid.

[0674] Example 54: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 54)

[0675]

[0676] Step 1: Synthesize benzyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acrylate (54-1) Step 2: Synthesize 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanoic acid (54-

[0677] Purged with argon in 1,4-di A mixture of tri-tert-butylphosphine tetrafluoroborate (TTBP.HBF4, 110 mg, 0.38 mmol), Pd2(dba)3 (163 mg, 0.18 mmol) and N-cyclohexyl-N-cyclohexylamine (0.27 mL, 1.28 mmol) in 2-(4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.3 g, 0.89 mmol) and benzyl acrylate (0.3 mL, 1.98 mmol) was added and 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, yield 99%).

[0678] Step 3: Synthesize Compound 54 2)

[0679] To a solution of (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)benzyl acrylate (137 mg, 0.33 mmol) in tetrahydrofuran (5 mL) was added 10% Pd / C (27 mg) and replaced with hydrogen. After stirring overnight, the mixture was filtered through celite and concentrated to obtain the title compound (105 mg, 96% yield).

[0680] Step 1: Synthesize ((S)-1-cyclopropyl-2-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benz

[0681] The title compound (105 mg, 75% yield) was obtained using a procedure similar to the synthesis method of step 1 of Example 6 above, wherein 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propanoic acid (50 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (92 mg, 0.15 mmol) were used to replace (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromovaleric acid, respectively.

[0682] Example 55: Synthesis of (2R,4R)-1-((S)-2-(2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-2-cyclopropylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 55)

[0683]

[0684] ​ tert-Butyl ((S)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (55-1)

[0685] The title compound (330 mg, 57%) was obtained using a method similar to the synthesis method of step 7 of Example 49 above, wherein (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (243 mg, 1.13 mmol) and (2R,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (400 mg, 1.13 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, respectively.

[0686] Step 2: Synthesis of (2R,4R)-1-((S)-2-amino-2-cyclopropylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide hydrochloride (55-2) Step 3: Synthesis of Compound 55

[0687] The title compound was obtained using a method similar to the synthesis method of step 2 of Example 20 above, wherein ((S)-1-cyclopropyl-2-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)carbamic acid tert-butyl ester (324 mg, 0.63 mmol) was used instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride, and the title compound was then used in the next reaction.

[0688] Step 1: Synthesis of ((S)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (56-1)

[0689] The title compound (73 mg, 51%) was obtained using a method similar to the synthesis method of Step 7 in Example 49 above, wherein (2R,4R)-1-((S)-2-amino-2-cyclopropylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximide hydrochloride (60 mg, 0.134 mmol) and 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (100 mg, 0.134 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0690] Example 56: Synthesis of (2R,4R)-1-((2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetyl)-L-valyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 56)

[0691]

[0692] Step 2: Synthesis of (2R,4R)-1-(L-valyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (56-2) Step 3: Synthesis of Compound 56

[0693] The title compound (232 mg, 79%) was obtained using a method similar to the synthesis method of Step 7 in Example 49 above, wherein (tert-butoxycarbonyl)-L-valine (122 mg, 0.565 mmol) and (2R,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (200 mg, 0.565 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0694] Step 1: Synthesis of 4-((4-((4-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (59- Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (59-2)

[0695] The title compound was obtained using a method similar to the synthesis method in Step 2 of Example 20 above, wherein tert-butyl ((S)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (460 mg, 0.89 mmol) was used instead of 3-(4-(1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propanoic acid hydrochloride, and subsequently the title compound was used in the next reaction.

[0696] Step 3: Synthesis of Compound 59

[0697] The title compound (63 mg, 44%) was obtained using a method similar to the synthesis method in Step 7 of Example 49 above, wherein (2R,4R)-1-(L-valyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (61 mg, 0.134 mmol) and 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (100 mg, 0.134 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0698] Example 57: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 57)

[0699]

[0700] The title compound (30 mg, yield 40%) was obtained using a method similar to the synthesis method of Step 6 in Example 1 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-(2-iodoethoxy)isoindoline-1,3-dione (34 mg, 0.079 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (50 mg, 0.079 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0701] Example 58: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 58)

[0702]

[0703] The title compound (20 mg, yield 20%) was obtained using a method similar to the synthesis method of Step 3 in Example 33 above, wherein N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.109 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0704] Example 59: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 59)

[0705]

[0706] Step 1: Synthesis of tert-Butyl 3-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azetidine-1-carboxylate Step 2: Synthesis of N-(2-((2-((4-(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (60-2) 1)

[0707] The title compound (340 mg, yield 97%) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, wherein benzyl 4-formylpiperidine-1-carboxylate (121 mg, 0.49 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (250 mg, 0.41 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0708] Step 3: Synthesis of Compound 60 Step 1: Synthesis of tert-Butyl 3-((4-((4-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (61-1)

[0709] The title compound (247 mg, yield 79%) was obtained using a method similar to the synthesis method in Step 4 of Example 33 above, wherein benzyl 4-((4-((4-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (340 mg, 0.40 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0710] Step 2: Synthesis of N-(2-((2-((4-(4-((1-(azetidin-3-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (61-2)

[0711] The title compound (73 mg, yield 53%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein N-(2-((5-chloro-2-((2-methoxy-4-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.14 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0712] Example 60: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 60)

[0713]

[0714] Step 3: Synthesis of Compound 61 Step 1: Synthesis of 4-((4-((((benzyloxy) (60-1)

[0715] The title compound (220 mg, yield > 100%) was obtained using a method similar to the synthesis method of Step 2 in Example 2 above, wherein tert-butyl 3-formylazetidine-1-carboxylate (54 mg, 0.293 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.244 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0716] )amino)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (62-1)

[0717] The title compound (250 mg, yield > 100%) was obtained using a method similar to the synthesis method of Step 5 in Example 1 above, wherein tert-butyl 3-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azetidine-1-carboxylate (220 mg, 0.244 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0718] ​

[0719] The title compound (28 mg, yield 16%) was obtained using a method similar to the synthesis method of Step 3 in Example 33 above, wherein N-(2-((2-((4-(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.189 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0720] Example 61: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 61)

[0721]

[0722] ​ ​ ​

[0723] The title compound (220 mg, yield > 100%) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, wherein tert-butyl 3-formylazetidine-1-carboxylate (54 mg, 0.293 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.244 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine.

[0724] ​ ​

[0725] The title compound (260 mg, yield > 100%) was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, wherein tert-butyl 3-((4-((4-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (220 mg, 0.244 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0726] ​

[0727] The title compound (30 mg, yield 17%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein N-(2-((2-((4-(4-((1-(azetidin-3-ylmethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.189 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0728] Example 62: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 62)

[0729]

[0730]

[0731] ​ Carbonyl ​ ​

[0732] The title compound (1.5 g, 80% yield) was obtained using a method similar to the synthesis method of step 2 in Example 2 above, wherein tert-butyl 4-formylpiperidine-1-carboxylate (945 mg, 4.43 mmol) and benzyl ((piperidin-4-ylmethyl)amino)carbamate (1.0 g, 4.03 mmol) were used to replace 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0733] Step 2: Synthesis of benzyl ((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)carbamate (62-2)

[0734] The title compound (900 mg, 81% yield) was obtained using a method similar to the synthesis method of step 5 in Example 1 above, wherein tert-butyl 4-((4-((((benzyloxy)carbonyl)amino)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.5 g, 3.37 mmol) was used to replace tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0735] Step 3: Synthesis of ((1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl) benzyl carbamate (62-3)

[0736] The title compound (540 mg, 94% yield) was obtained using a method similar to the synthesis method of step 2 in Example 1 above, wherein benzyl ((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)carbamate (400 mg, 1.16 mmol) was used to replace Boc-piperazine.

[0737] Step 4: Synthesis of ((1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl) benzyl carbamate (62-4)

[0738] The title compound (480 mg, 95% yield) was obtained using a method similar to the synthesis method of step 2 in Example 25 above, wherein benzyl ((1-((1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)carbamate (540 mg, 1.09 mmol) was used to replace benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0739] Step 5: Synthesis of ((1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)benzyl carbamate (62-5) Step 6: Synthesis of N-(2-((2-((4-(4-((4-(aminomethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-

[0740] The title compound (480 mg, yield 60%) was obtained using a method similar to the synthesis method in Step 3 of Example 35 above, wherein ((1-((1-(4-amino-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)carbamic acid benzyl ester (480 mg, 1.03 mmol) was used instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (420 mg, 0.95 mmol).

[0741] methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (62-6) Step 7: Synthesis of Compound 62

[0742] The title compound (395 mg, yield 99%) was obtained using a method similar to the synthesis method in Step 4 of Example 33 above, wherein ((1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)carbamic acid benzyl ester (480 mg, 0.62 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0743] Step 1: Synthesis of benzyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acrylate (64-1)

[0744] The title compound (48 mg, yield 17%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (129 mg, 0.47 mmol) and N-(2-((2-((4-(4-((4-(aminomethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (200 mg, 0.31 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine respectively.

[0745] Example 63: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 63)

[0746]

[0747] The title compound (65 mg, yield 47%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein N-(2-((2-((4-(4-((4-(aminomethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.16 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0748] Example 64: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propanoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 64)

[0749]

[0750] Step 2: Synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propanoic acid (64- Step 3: Synthesis of Compound 64

[0751] The title compound (120 mg, yield 96%) was obtained using a method similar to the synthesis method in Step 1 of Example 54 above, wherein (5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100 mg, 0.30 mmol) was used instead of (4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0752] Step 1: Synthesis of tert-butyl (2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)carbamate (65-1) 2)

[0753] The title compound (60 mg, yield 63%) was obtained using a method similar to the synthesis method in Step 2 of Example 54 above, wherein benzyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acrylate (120 mg, 0.29 mmol) was used instead of benzyl (E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acrylate.

[0754] Step 2: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidin-4-yl)methyl)piperazin-1-yl)-

[0755] The title compound (75 mg, 67% yield) was obtained using a method similar to the synthesis method of Step 1 in Example 6 above, wherein 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propanoic acid (40 mg, 0.12 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74 mg, 0.12 mmol) were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid.

[0756] Example 65: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 65)

[0757]

[0758] 2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (65-2) Step 3: Synthesis of Compound 65 Step 1: Synthesis of (S)-N-(2-((5-chloro-2-((4-(4-((1-(2-hydroxypropanoyl)piperidin-4-yl)methyl)

[0759] The title compound (350 mg, 79% yield) was obtained using a method similar to the synthesis method of Step 7 in Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (351 mg, 0.57 mmol) and (tert-butoxycarbonyl)glycine (100 mg, 0.57 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0760] piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (69-1) Step 2: Synthesis of Compound 69

[0761] The title compound (120 mg, yield 92%) was obtained using a method similar to the synthesis method in step 5 of Example 1 above, wherein tert-butyl (2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)carbamate (150 mg, 0.19 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0762] Step 1: Synthesis of (S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxopropan-2-yl))aminotert-

[0763] The title compound (80 mg, yield 53%) was obtained using a method similar to the synthesis method in step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (45 mg, 0.16 mmol) and N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, respectively.

[0764] Example 66: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 66)

[0765]

[0766] The title compound (28 mg, yield 19%) was obtained using a method similar to the synthesis method in step 3 of Example 33 above, wherein N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0767] Example 67: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 67)

[0768]

[0769] The title compound (90 mg, yield 57%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, where N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (111 mg, 0.18 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0770] Example 68: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 68)

[0771]

[0772] The title compound (110 mg, yield 70%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, where N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (111 mg, 0.18 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0773] Example 69: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propanoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 69)

[0774]

[0775] butyl carbamate (70-1) Step 2: Synthesis of N-(2-((2-((4-(4-((1-(L-alanyl)piperidin-4-yl)methyl)piperazin-1-yl)-

[0776] The title compound (80 mg, 53%) was obtained using a method similar to the synthesis method of Step 7 in Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (137 mg, 0.22 mmol) and (S)-hydroxypropanoic acid (20 mg, 0.22 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0777] ​

[0778] The title compound (60 mg, 55% yield) was obtained using a method similar to the synthesis method of Step 1 in Example 3 above, wherein (S)-N-(2-((5-chloro-2-((4-(4-((1-(2-hydroxypropanoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.12 mmol) was used instead of 4-bromobutan-1-ol.

[0779] Example 70: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-L-alanyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 70)

[0780]

[0781] ​ ​ ​

[0782] The title compound (130 mg, 79%) was obtained using a method similar to the synthesis method of Step 7 of Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (130 mg, 0.21 mmol) and (tert-butoxycarbonyl)-L-alanine (40 mg, 0.21 mmol) were used to replace 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, respectively.

[0783] ​ ((2-Methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (70-2)

[0784] The title compound (105 mg, yield 94%) was obtained using a method similar to the synthesis method of Step 5 of Example 1 above, wherein (S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxopropan-2-yl))carbamic acid tert-butyl ester (128 mg, 0.16 mmol) was used to replace tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0785] (Step 3: Synthesis of Compound 70

[0786] The title compound (60 mg, yield 60%) was obtained using a method similar to the synthesis method of Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (30 mg, 0.11 mmol) and N-(2-((2-((4-(4-((1-(L-alanyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75 mg, 0.11 mmol) were used to replace 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, respectively.

[0787] Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 71) in Example 71

[0788]

[0789] (Step 1: Synthesis of 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (71-1) (Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71-2)

[0790] The title compound (103 mg, yield 60%) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, where tert-butyl 3-formylazetidine-1-carboxylate (65 mg, 0.31 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (130 mg, 0.22 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0791] (Step 3: Synthesis of Compound 71 (Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxyprop-1-yn-1-yl)isoindoline-1,3-dione (72-1)

[0792] The title compound (90 mg, yield >100%) was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, where tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (100 mg, 0.125 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0793] (Step 2: Synthesis of 5-(3-chloroprop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (72-2)

[0794] The title compound (64 mg, yield 53%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, where N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (88 mg, 0.126 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0795] Example 72: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 72)

[0796]

[0797] (Step 3: Synthesis of Compound 72 (Step 1: Synthesis of Benzyl 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate

[0798] To a mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.0 g, 8.90 mmol), prop-2-yn-1-ol (0.78 mL, 12.82 mmol), and CuI (576 mg, 3.03 mmol) in N,N-dimethylformamide (45 mL) was added N,N-diisopropylethylamine (3.1 mL, 17.80 mmol), and the mixture was purged with argon. Pd(PPh3)2Cl2 (1.0 g, 1.42 mmol) was added thereto, and the mixture was stirred overnight at 75 °C. After extraction with dichloromethane and water, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was recrystallized from toluene to obtain the title compound (1.0 g, yield 36%).

[0799] (Step 2: Synthesis of Benzyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylate (Step 3: Synthesis of Benzyl 4-(1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylate (74-3)

[0800] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxyprop-2-yn-1-yl)isoindoline-1,3-dione (170 mg, 0.54 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.13 mL, 1.62 mmol), and then methanesulfonyl chloride (0.05 mL, 0.65 mmol) was slowly added at 0 °C. After the reaction mixture was stirred overnight, it was 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%).

[0801] (Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-4)

[0802] The title compound (180 mg, yield 87%) was obtained using a method similar to the synthesis method in Step 3 of Example 41 above, wherein 5-(3-chloroprop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (77 mg, 0.23 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (140 mg, 0.23 mmol) were used instead of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0803] Example 73: Synthesis of N-(2-((5-chloro-2-((4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 73)

[0804]

[0805] The title compound (68 mg, yield 56%) was obtained using a method similar to the synthesis method in Step 3 of Example 41 above, wherein 5-(3-chloroprop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78 mg, 0.15 mmol) were used instead of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, respectively.

[0806] Example 74: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 74)

[0807]

[0808]

[0809] (Step 5: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-5) (74-1)

[0810] The title compound (430 mg, yield 45%) was obtained by a method similar to the synthesis method in step 2 of Example 1 above, wherein 4-(piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (619 mg, 2.04 mmol) was used instead of Boc-piperazine.

[0811] (Step 6: Synthesis of N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxymethyl-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (74-6) (74-2)

[0812] The title compound (873 mg, yield 94%) was obtained by a method similar to the synthesis method in step 2 of Example 25 above, wherein 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (988 mg, 1.09 mmol) was used instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0813] (Step 7: Synthesis of Compound 74 (Step 1: Synthesis of Benzyl 4-((4-(5-methoxy-2-methyl-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (75-1)

[0814] The title compound (1.1 g, yield 74%) was obtained by a method similar to the synthesis method in step 3 of Example 35 above, wherein 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (873 mg, 1.99 mmol) was used instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0815] (Step 2: Synthesis of Benzyl 4-((4-(4-amino-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (75-2) (74 - 4)

[0816] The title compound (648 mg, yield 72%) was obtained by a method similar to the synthesis method in step 4 of Example 33 above, wherein 4-(1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylic acid benzyl ester (1.1 g, 1.67 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0817] (Step 3: Synthesis of Benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (75-3) (Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-4) (Step 5: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-5)

[0818] The title compound (80 mg, yield 22%) was obtained using a method similar to the synthesis method of Step 1 of Example 45 above, wherein N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (300 mg, 0.49 mmol) was used instead of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0819] (Step 6: Synthesis of N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxymethyl-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-6) (Step 7: Synthesis of Compound 75

[0820] The title compound (49 mg, yield 74%) was obtained using a method similar to the synthesis method of Step 2 of Example 45 above, wherein N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80 mg, 0.10 mmol) was used instead of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0821] (Step 1: Synthesis of 4-((4-(5-methoxy-2-methyl-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (76-1)

[0822] The title compound (21 mg, yield 32%) was obtained using a method similar to the synthesis method of Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (22 mg, 0.079 mmol) and N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (47 mg, 0.072 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, respectively.

[0823] Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-L-alanyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 75)

[0824]

[0825] (Step 2: Synthesis of 4-((4-(4-amino-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (76-2) (Step 3: Synthesis of 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (76-3)

[0826] A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (6.5 g, 35.11 mmol), benzyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (14.4 g, 36.86 mmol) and potassium carbonate (17.0 g, 122.87 mmol) in dimethyl sulfoxide (87 mL) was stirred at 110 °C. After stirring overnight, water was added to the reaction mixture, which was then stirred, filtered and washed with water. The residue was washed successively with ethyl acetate, then water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (14.0 g, 72%).

[0827] (Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76-4) - (Step 5: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76-5) (Step 6: Synthesis of N-(2-((2-((4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxymethyl-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76-6)

[0828] The title compound (718 mg, yield 99%) was obtained by a method similar to the synthesis method of Step 2 in Example 25 above, wherein benzyl 4-((4-(5-methoxy-2-methyl-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (794 mg, 1.60 mmol) was used instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0829] (Step 7: Synthesis of Compound 76 Benzyl (2-((5-chloro-2-((2-methoxy-5-methylphenyl)amino)-5-methoxypyrimidin-4-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (75-3)

[0830] The title compound (1.0 g, yield 83%) was obtained by a method similar to the synthesis method of Step 3 in Example 33 above, wherein benzyl 4-((4-(4-amino-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (718 mg, 1.58 mmol) was used instead of benzyl 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0831] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-4)

[0832] The title compound (800 mg, yield > 100%) was obtained using a method similar to the synthesis method of Step 4 of Example 33 above, wherein 4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (1.0 g, 1.31 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0833] Step 5: Synthesis of (S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino yl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxopropan-2- yl))tert-butyl carbamate (75-5)

[0834] The title compound (175 mg, 92%) was obtained using a method similar to the synthesis method of Step 7 of Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) and (tert-butoxycarbonyl)-L-alanine (54 mg, 0.29 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, respectively.

[0835] Step 6: Synthesis of N-(2-((2-((4-(4-((1-(L-alanyl)piperidin-4-yl)methyl)piperazin-1- yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (75-6)

[0836] The title compound (148 mg, yield 98%) was obtained using a method similar to the synthesis method of Step 5 of Example 1 above, wherein tert-butyl ((S)-(1-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxopropan-2-yl))carbamate (172 mg, 0.22 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0837] Step 7: Synthesis of Compound 75

[0838] The title compound (80 mg, yield 40%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (57 mg, 0.21 mmol) and N-(2-((2-((4-(4-((1-(L-alanyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (145 mg, 0.21 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine, respectively.

[0839] Example 76: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 76)

[0840]

[0841] Step 1: Synthesis of tert-Butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-3-methoxy-5-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (76-1)

[0842] The title compound (108 mg, yield 54%) was obtained using a method similar to the synthesis method in Step 2 of Example 2 above, wherein tert-butyl 4-formylpiperidine-1-carboxylate (78 mg, 0.37 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) were used instead of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one and N-Boc-piperazine, respectively.

[0843] Step 2: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(piperidin-4-ylmethyl)piper azin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (76-2)

[0844] The title compound (91 mg, 99% yield) was obtained using a method similar to the synthesis method in step 5 of Example 1 above, wherein tert-butyl 4-((4-(1-(4-((5-chloro-4-((2-N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxy-5-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (106 mg, 0.13 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0845] Step 3: Synthesis of Compound 76

[0846] The title compound (80 mg, 65% yield) was obtained using a method similar to the synthesis method in step 3 of Example 33 above, wherein N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (90 mg, 0.126 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0847] Example 77: Synthesis of N-(2-((5-chloro-2-((4-(4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 77)

[0848]

[0849] The title compound (65 mg, yield 44%) was obtained using a method similar to the synthesis method in Step 6 of Example 1 above, wherein ethyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methanesulfonate (70 mg, 0.15 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (93 mg, 0.15 mmol) were used instead of 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pentanamide and N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

[0850] Example 78: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-L-alanyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 78)

[0851]

[0852] Step 1: Synthesis of Benzyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (78-1) Step 2: Synthesis of Benzyl 4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (78-2)

[0853] The title compound (2.6 g, yield 97%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (2.3 g, 5.79 mmol) was used instead of benzyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate.

[0854] Step 3: Synthesis of Benzyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (78-3)

[0855] The title compound (2.38 g, yield 98%) was obtained using a method similar to the synthesis method in Step 2 of Example 25 above, wherein benzyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (2.6 g, 5.39 mmol) was used instead of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate.

[0856] Step 4: Synthesis of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-ylmethyl)piperidin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78-4)

[0857] The title compound (4.4 g, 83% yield) was obtained using a method similar to the synthesis method of Step 3 of Example 35 above, wherein 4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid benzyl ester (3.2 g, 7.00 mmol) was used instead of 4-((4-(4-amino-3-chlorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester.

[0858] Step 5: Synthesis of (S)-(1-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin- 2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxopropan-2-

[0859] The title compound (3.5 g, yield > 100%) was obtained using a method similar to the synthesis method of Step 4 of Example 33 above, wherein 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid benzyl ester (3.7 g, 4.85 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0860] yl)tert-butyl carbamate (78-5) ​ ​

[0861] The title compound (183 mg, 95%) was obtained using a method similar to the synthesis method of Step 7 of Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.24 mmol) and (tert-butoxycarbonyl)-L-alanine (45 mg, 0.24 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0862] Step 6: Synthesis of N-(2-((2-((4-(4-((4-(L-alanyl)piperazin-1-yl)methyl)piperidin-1-yl)- 2-methoxy-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (78-6)

[0863] The title compound (110 mg, yield 71%) was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, where tert-butyl (S)-(1-(4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (173 mg, 0.22 mmol) was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0864] Step 7: Synthesis of Compound 78

[0865] The title compound (67 mg, yield 44%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, where 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (66 mg, 0.24 mmol) and N-(2-((2-((4-(4-((4-(L-alanyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (110 mg, 0.16 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine.

[0866] Example 79: Synthesis of N-(2-((5-chloro-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 79)

[0867]

[0868] The title compound (51 mg, yield 52%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, where N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (71 mg, 0.11 mmol) was used instead of 3-(2-(benzyloxy)ethoxy)azetidine.

[0869] Example 80: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 80)

[0870]

[0871] Step 1: Synthesis of (2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino tert-butyl carbonate (80-1)

[0872] The title compound (135 mg, 72%) was obtained using a method similar to the synthesis method in Step 7 of Example 49 above, where N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (151 mg, 0.24 mmol) and (tert-butoxycarbonyl)glycine (42 mg, 0.24 mmol) were used instead of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid hydrochloride and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione respectively.

[0873] Step 2: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidin-4-yl)methyl)piperazin-1-yl)- 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (80-2)

[0874] The title compound (105 mg, yield 93%) was obtained using a method similar to the synthesis method in Step 5 of Example 1 above, where (2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethanesulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)carbamic acid tert-butyl ester was used instead of tert-butyl 4-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0875] Step 3: Synthesis of Compound 80

[0876] The title compound (65 mg, yield 48%) was obtained using a method similar to the synthesis method in Step 3 of Example 33 above, wherein 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (40 mg, 0.15 mmol) and N-(2-((5-chloro-2-((4-(4-((1-glycylpiperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (99 mg, 0.15 mmol) were used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 3-(2-(benzyloxy)ethoxy)azetidine.

[0877] Example 81: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 81)

[0878]

[0879] The title compound (105 mg, yield 70%) was obtained using a method similar to the synthesis method in Step 1 of Example 6 above, wherein 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (53 mg, 0.16 mmol) and N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.16 mmol) were used instead of (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride and 5-bromopentanoic acid.

[0880] Example 82: Synthesis of N-(2-((5-chloro-2-((4-(4-((1-((2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propanoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (Compound 82)

[0881]

[0882] Step 1: Synthesis of benzyl (2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy yl)propionate (82-1)

[0883] The title compound (270 mg, yield 32%) was obtained using a method similar to the synthesis method in Step 1 of Example 3 above, wherein (S)-benzyl 2-hydroxypropanoate (520 mg, 2.89 mmol) was used instead of 4-bromobutan-1-ol.

[0884] Step 2: Synthesis of (2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy yl)propanoic acid (82-2)

[0885] The title compound (133 mg, yield > 100%) was obtained using a method similar to the synthesis method in Step 4 of Example 33 above, wherein benzyl (2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propanoate (165 mg, 0.38 mmol) was used instead of 5-(3-(2-(benzyloxy)ethoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0886] Step 3: Synthesis of Compound 82

[0887] The title compound (70 mg, yield 42%) was obtained using a method similar to the synthesis method in Step 7 of Example 49 above, wherein N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (109 mg, 0.17 mmol) and (2S)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propanoic acid (60 mg, 0.17 mmol) were used instead of hydrochloride of 1-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfinylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid and 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione. The NMR and mass spectrometry results of the compounds obtained in the examples are summarized in Table 2 below.

[0888] [Table 2]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910] Evaluation of the compounds of the present invention

[0911] Experimental Example 1: EGFR Protein Degradation Test in Ba / F3 Cells Expressing Normal EGFR or C797S Mutant EGFR

[0912] The ability of the compounds of the present invention to degrade mutant EGFR protein was confirmed in Ba / F3 cells expressing normal EGFR, mutant EGFR del19+T790M+C797S or mutant EGFR L858R+T790M+C797S Western blot assays were performed using an EGFR antibody.

[0913] Specifically, Ba / F3 cells expressing EGFR were cultured in RPMI 1640 (Gibco, NY, USA) containing 10% fetal bovine serum (FBS, Gibco, NY, USA). Cells expressing normal EGFR, mutant EGFR del19+T790M+C797S or mutant EGFR L858R+T790M+C797S were treated with the compounds of the present invention at concentrations of 0.1 μM and 1 μM for 24 hours, respectively. After that, they were washed twice with phosphate buffered saline (PBS), and SDS-PAGE was performed with 30 μg of cell lysates. After transferring the separated proteins on the gel to a nitrocellulose membrane, the expression level of EGFR protein was confirmed using an EGFR antibody (Santa Cruz biotechnology, Santacruz, CA, USA). The EGFR bands separated by Western blotting were quantitatively analyzed using a Fluo-S MultiImager (Bio-Rad, Hercules, CA, USA).

[0914] The experimental results are shown in Table 3 below.

[0915] [Table 3]

[0916]

[0917]

[0918] DTC: EGFR de119+T790M+C797S

[0919] LTC: EGFR L858R+T790M+C797S

[0920] ++: Protein degradation > 80%

[0921] +: Protein degradation 20% to 80%

[0922] -: Protein degradation < 20%

[0923] Experimental Example 2: Pharmacokinetic evaluation

[0924] The pharmacokinetic test of the compounds of the present invention was carried out as follows. After a single oral administration of the compounds of the present invention to ICR mice, the concentration of the compounds over time was traced and analyzed.

[0925] 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. Blood was collected at fixed times and plasma was separated. Drug analysis was performed using HPLC (XBridge C18 column, Waters, mobile phase 0.1% formic acid: acetonitrile (30:70, % / %)) and MS / MS (ESI positive, MRM). Mouse plasma and each commercially available standard solution were mixed at a ratio of 9:1 and prepared and calibrated at concentrations of 5, 50, 100, 500, 100, and 5,000 ng / mL. In addition, QC samples were prepared by mixing mouse plasma and QC standard solution at a ratio of 9:1 and prepared at concentrations of 100, 750, and 2,500 ng / mL. 100 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 x g (4 °C) for about 5 minutes, and the supernatant was taken and transferred to an LC vial and injected into the instrument. Then, the compound concentration in mouse plasma was quantified by applying a previously validated assay. For pharmacokinetic parameters, the WinNonlin 5.2 program (Pharsight, USA) was used. AUC 0-t 、AUC 0-∞ 、Cmax, Tmax, and t 1 / 2 . The pharmacokinetic parameter results are expressed as mean and standard deviation (SD), and statistical processing was performed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

[0926] The test results are shown in Table 4 below.

[0927] [Table 4]

[0928]

[0929] All documents mentioned herein are incorporated herein by reference as if their contents were set forth herein. When introducing elements of the present invention or preferred embodiments thereof, the articles "a / an" and "the / said" are intended to mean that there is one or more than one element. The terms "comprising", "including", and "having" are intended to be inclusive and mean that there may be additional elements in addition to those listed. Although the present invention has been described in accordance with one or more specific embodiments, this should not be construed as limiting the details of these embodiments.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one of the following compounds:

3. A composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition for treating or preventing cancer having an EGFR mutation, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2 as an active ingredient.

5. The pharmaceutical composition according to claim 4, wherein the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon 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, blood cancer, lymphoma, skin cancer or fibroadenoma.

6. The pharmaceutical composition according to claim 5, wherein the cancer is lung cancer.

7. The pharmaceutical composition according to claim 6, wherein the lung cancer is non-small cell lung cancer.

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