E3 ligase ligand compounds, compounds exhibiting ALK and / or EGFR mutant kinase inhibitory activity, and pharmaceutical uses thereof

Abstract

One aspect of the present disclosure provides a von Hippel–Lindau (VHL) E3 ligase ligand compound that can be used in the preparation of a PROTAC compound, a PROTAC compound comprising same, and a method for preparing a PROTAC compound using the ligand compound. Another aspect of the present disclosure provides a compound with a specific chemical structure or a pharmaceutically acceptable salt thereof, that is inhibitory against ALK−overexpression, ALK−mutation, EGFR−overexpression, EGFR−mutation, and the like, that is, which has an inhibitory and / or degradative activity against specific ALK and / or EGFR proteins. The present disclosure provides pharmaceutical uses of the compounds according to the present invention, salts thereof, or compositions comprising same for the prevention or treatment of cancers exhibiting ALK and / or EGFR mutations, particularly lung cancer. The present disclosure also provides a method for treatment or prevention of ALK and / or EGFR mutation cancer, especially lung cancer, the method comprising administering an effective amount of the compound according to the present invention, a salt thereof, or a composition containing same to a subject in need of treatment.

Description

E3 ligase ligand compounds, compounds exhibiting ALK and / or EGFR mutant kinase inhibitory effects, and medicinal uses thereof

[0001] This application claims priority to Korean Patent Application No. 10-2024-0016825, filed February 2, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] One aspect of the present disclosure relates to a novel structural E3 ligase ligand compound, a PROTAC compound comprising the same, and a method for preparing a PROTAC compound using the E3 ligase ligand compound.

[0003] Another aspect of the present disclosure relates to compounds exhibiting ALK and / or EGFR mutant kinase inhibitory effects and their medicinal uses. Accordingly, the present disclosure relates to useful methods for treating diseases associated with ALK and / or EGFR proteins using compounds exhibiting ALK and / or EGFR mutant kinase inhibitory effects.

[0004] First, the von Hippel-Lindau (VHL) Cullin RING E3 ligase is an essential enzyme of the ubiquitin-proteasome system, recruiting substrates such as hypoxia-inducible factor (HIF) for ubiquitination and subsequent proteasomal degradation. The ubiquitin-proteasome pathway can be exploited using proteolysis-targeting chimeras (PROTACs), bifunctional molecules designed to simultaneously bind to E3 ligases and target proteins, inducing ubiquitination and degradation of the target protein. Small molecule ligands with high binding affinity for E3 ligases are fundamental to the development of effective PROTACs. Therefore, there is a critical need for superior E3 ligase ligands as a starting point for the development of PROTAC degraders.

[0005] These E3 ligase ligands must not only have excellent binding affinity to E3 ligase for their intended purpose, but must also be stable in the body for a certain period of time to perform their role.

[0006] Meanwhile, anaplastic lymphoma kinase (ALK) has recently been discovered in various human tumors and is being studied as a target for targeted therapy. The carcinogenic process of ALK is known to be primarily related to the ALK-NPM (Nucleophosmin) fusion gene, which is observed in anaplastic large cell lymphoma. When ALK is activated by this gene fusion, the tyrosine kinase contained in ALK behaves abnormally, causing cancer. In other words, abnormally activated ALK induces cell proliferation and prevents cell death by interfering with apoptosis.

[0007] ALK interacts with other tyrosine kinases, both normal and oncogene-activated, and activates various other pathways. In particular, within lung cancer cells, the ALK gene fuses with the EML4 (Echinoderm Microtubule-Associated Protein-Like 4) gene to produce the active tyrosine kinase, EML4-ALK, and it has been shown that the oncogenic ability of EML4-ALK is dependent on its enzymatic activity. In addition, Mosse et al. reported ALK gene amplification in approximately 26% of 491 neuroblastoma specimens (Nature. 2008 Oct 16; 455(7215): 930-935). Moreover, the ALK gene has been found to be expressed in numerous non-hematopoietic tumors, including large B-cell lymphoma, systemic myelofibroblastic sarcoma, inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyosarcoma, myofibroblastic sarcoma, breast cancer, gastric cancer, and melanoma cell lines. In addition, in the rare disease called inflammatory myelofibroblastic tumor, several types of ALK fusion proteins are frequently found, and these fusion proteins are thought to be deeply involved in the development of the tumor.

[0008] Accordingly, therapeutics targeting ALK-NPM are being developed to treat cancer by blocking the ALK activation pathway. Crizotinib (PF-02341066), developed by Pfizer, is an ATP-competitive c-Met / HGFR and ALK inhibitor and is known to be effective in treating non-small cell lung cancer. Furthermore, NVP-TAE684 and LDK-378 from Novartis and CH5424802 from Chugai are also known to reduce tumor size in neuroblastoma cell lines in addition to anaplastic large cell lymphoma cell lines.

[0009] Meanwhile, as with other kinase inhibitors, resistance to ALK inhibitors is a problem. The most common mutation observed is G1202R, a mutation in the solvent-exposed domain of ALK, which causes steric hindrance to most ALK inhibitors. Furthermore, resistance to the first-generation ALK inhibitor crizotinib develops within 1-2 years in non-small cell lung cancer. Resistance mutations are found within the TK domain of ALK, most commonly L1196M. This mutation causes steric hindrance at the binding site, reducing the efficacy of crizotinib. In addition, various ALK resistance mutations exist, which reduce the therapeutic efficacy of ALK inhibitors. Therefore, there is a need for therapeutics that exhibit inhibitory effects against various ALK mutations.

[0010] Furthermore, the epidermal growth factor receptor (EGFR) is a protein composed of a receptor portion and a tyrosine kinase portion, and it functions to transmit signals from outside the cell to inside the cell by passing through the cell membrane. EGFR plays an essential role in normal cell regulation through intracellular signal transduction. However, overexpression of EGFR or activating EGFR mutations characterized by ligand-independent tyrosine kinase activity are known to induce cancer cell growth, differentiation, angiogenesis, metastasis, and resistance by abnormally activating cell signaling systems. It has been reported that EGFR is abnormally overexpressed or frequently mutated in most solid cancer cells, and this is associated with a poor prognosis. For example, lung cancer, liver cancer, esophageal cancer, stomach 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 associated with EGFR mutations (Cancer Communications. 2020;40:43-59).

[0011] Among these, EGFR-activating mutations, such as the L858R point mutation in exon 21 of the EGFR tyrosine kinase domain or the in-frame deletion in exon 19, are known to be important causes of non-small cell lung cancer. Therefore, research is actively underway to develop anticancer agents targeting the epidermal growth factor receptor, based on the prediction that blocking cancer cell signaling through the epidermal growth factor receptor would have a superior anticancer effect.

[0012] Gefitinib, the first small-molecule EGFR tyrosine kinase inhibitor developed, is a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among the EGFR subtypes. Another drug with similar properties is erlotinib, an EGFR-targeted therapy primarily used for patients with EGFR-activating mutations, primarily for non-small cell lung cancer (NSCLC).

[0013] However, it has been reported that NSCLC patients with EGFR activating mutations who received gefitinib or erlotinib develop drug resistance after approximately 8 to 16 months, and approximately 60% of these patients develop resistance due to the EGFR T790M mutation (Helena A. Yu et al., Clin Cancer Res. 19(8), 2240, 2013).

[0014] To overcome resistance to existing EGFR inhibitors, such as gefitinib or erlotinib, irreversible inhibitors have been proposed. However, these irreversible EGFR inhibitors are also highly active against the wild-type EGFR, which also exists in normal cells. Therefore, when administered at doses sufficient to overcome resistance caused by the EGFR T790M mutation, they cause serious side effects, limiting their clinical application.

[0015] As an alternative, several drugs, including osimertinib, olmutinib, naquotinib, and avitinib, which are selective inhibitors of EGFR mutations, are in clinical development. However, according to the clinical results of osimertinib in non-small cell lung cancer patients with EGFR resistance mutations, drug resistance occurs after about 10 months due to the activation of other resistance mechanisms, and among them, the C797S mutation is known to occur at a high rate of more than 20%. The C797S mutation is a point mutation in which cysteine ​​773 (Cys773), which forms a covalent bond with irreversible inhibitors of EGFR, is changed to serine, preventing the formation of a covalent bond with irreversible inhibitors of EGFR, resulting in a decrease in drug responsiveness.

[0016] Thus, the development of EGFR-targeted therapies has shown limitations, with efficacy not lasting longer than a certain period due to the development of primary and secondary resistance. In particular, research on the EGFR C797S mutation has been limited to reports of early-stage preclinical studies, with no agents currently undergoing clinical trials. Therefore, effective treatments for this mutation are urgently needed.

[0017] In addition, it has been recently shown that the combination of ALK inhibitors and EGFR inhibitors is effective in treating patients with cancers induced by ALK mutations, etc. (WO2020-030977 A2), and therefore, substances that have inhibitory activity against both ALK mutations and EGFR mutations will be very useful in the treatment of various cancers, especially those that may develop resistance.

[0018] Therefore, one problem to be solved by the present invention is to provide a ligand compound suitable for use as an E3 ligase binding moiety in a PROTAC structure due to its excellent binding affinity for E3 ligase and high stability in the body. In addition, another problem of the present invention is to provide a PROTAC compound prepared using such an E3 ligase ligand and a method for preparing the same.

[0019] Another problem to be solved by the present invention is to provide a novel compound exhibiting inhibitory and / or degradative activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation, etc., and a pharmaceutical use thereof. Another problem to be solved by the present invention is to provide a novel compound exhibiting inhibitory and / or degradative activity against both ALK mutation and EGFR mutation, and a pharmaceutical use thereof.

[0020] E3 ligase ligand compounds and methods for producing such compounds

[0021] In order to achieve the above-described problem, one aspect of the present invention provides an E3 ligase ligand compound represented by the following chemical formula 3 or a pharmaceutically acceptable salt thereof.

[0022] [Chemical Formula 3]

[0023]

[0024] In the above chemical formula 3,

[0025] R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl.

[0026] In one preferred embodiment of the present invention, R1 of the compound of formula 3 is methyl, R2 is methyl, and R3 is C 1-6 Alkyl (preferably tert-butyl).

[0027]

[0028] Another aspect of the present invention also provides a method for producing a PROTAC (Proteolysis-targeting chimera) compound, characterized in that the compound of the above chemical formula 3 is used as a von Hippel-Lindau (VHL) E3 ligase ligand.

[0029] Preferably, in the above manufacturing method of the present invention, R1 is methyl, R2 is methyl, and R3 is C 1-6 Alkyl (preferably tert-butyl).

[0030]

[0031] That is, one aspect of the present invention provides an E3 ligase ligand having a specific structure that has excellent binding affinity to E3 ligase and excellent stability in the body, and a method for producing a PROTAC compound using such a ligand compound.

[0032] For example, the E3 ligase moiety of the present invention may be more stable to metabolism in the body due to the -Ar-N(R2)-N- structure, but the present invention is not limited to this theoretical mechanism. In the case of the existing -Ar-CH2-N- structure, it is unstable to metabolism in the body, and the overall stability of protac compounds containing it is reduced, but the E3 ligase moiety of the present invention improves this instability.

[0033]

[0034] PROTAC compounds

[0035] In order to achieve the above-mentioned problem, another aspect of the present invention is a PROTAC (Proteolysis-targeting chimera) compound having an ELP structure,

[0036] P, a ligand that binds to a target protein to be degraded by ubiquitin ligase, is linked to the E moiety, an E3 ligase ligand, through a covalent bond with L, a linker.

[0037] Here, the PROTAC compound has a structure of the following chemical formula 1, wherein E, a von Hippel-Lindau (VHL) E3 ligase ligand, is covalently linked to L as in the following chemical formula 1, and a PROTAC compound or a pharmaceutically acceptable salt thereof is provided.

[0038] [Chemical Formula 1]

[0039]

[0040] In the above chemical formula 1,

[0041] R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl.

[0042]

[0043] Another aspect of the present invention also provides a PROTAC compound having a structure represented by the following chemical formula 1a or a pharmaceutically acceptable salt thereof.

[0044] [Chemical Formula 1a]

[0045]

[0046] In the above chemical formula 1a,

[0047] R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl,

[0048] R4 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, -NH-C(O)-R8, or -NH-S(O)(O)R8 (preferably, methoxy, methyl, halogen, cyano, or -NH-S(O)(O)methyl), where R8 is hydrogen, C 1-6 Alkyl, or C 1-6 It is fluoroalkyl,

[0049] R5 is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl,

[0050] R6 is , , or , wherein R' and R” are independently hydrogen, C 1-6 Alkyl, or C 1-6 It is fluoroalkyl,

[0051] R7 is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl,

[0052] L is a linker,

[0053] m and n are independently 0, 1, 2, 3, or 4.

[0054]

[0055] Preferably, in the chemical formulas 1 and 1' of the present invention, R1 is methyl, R2 is methyl, and R3 is C 1-6 Alkyl (preferably tert-butyl).

[0056] In one aspect of the present invention, R6 of the chemical formula 1a is , , or It could be.

[0057]

[0058] The present inventors evaluated various substituents and were able to obtain a compound having a structure such as chemical formula 1a of the present disclosure, which is superior in various aspects, including ALK and / or EGFR degradation activity. In other words, the present invention provides a novel compound having superior ALK and / or EGFR degradation activity, (metabolic) stability, etc.

[0059]

[0060] Definition of Terms

[0061] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0062] If a substituent is described as "optionally substituted" or "optionally substituted," it means that the substituent is unsubstituted or substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0063] The term "alkyl" as used herein means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (where the number of carbon atoms is not particularly limited), preferably 1 to 3 carbon atoms. "Lower alkyl" means a straight-chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 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, and 3,3-diethylhexyl. In a preferred embodiment of the present invention, alkyl is methyl, ethyl, isopropyl, t-butyl.

[0064] The term "alkoxy" as used herein means -O-(alkyl) including -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)2H, -OC(CH3)3, and the like, wherein alkyl is as defined above.

[0065] In this specification, “C 1-6 ”, “C1-6”, or “C1-C6”, this means that it has 1 to 6 carbon atoms. For example, C 1-6Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0066] 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 fluorine.

[0067] As used herein, the term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and the like. In a preferred embodiment of the present invention, haloalkyl is CF3. wherein alkyl, alkoxy and halogen are as defined above.

[0068] The term "carbocycle" or "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentalene, decahydronaphthalene, etc.; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, etc.; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The cycloalkyl group may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring.

[0069] As used herein, “heterocycle” or “heterocycloalkyl” means a saturated 4- to 7-membered monocyclic, or 7- to 12-membered bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Representative heterocycles include oxiran, oxetan, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoine, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyra, morpholine, tetrahydropyridine, tetrahydropyrimidine, etc. Heterocycles include bicyclic rings in which some of the heterocycles are fused to a benzene or cyclopenta-1,3-diene ring. The heterocycles may be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spiro rings, and bridged bicyclic rings in which one or more carbon atoms of the aforementioned polycyclic rings are replaced by nitrogen, oxygen, or sulfur atoms.Examples of such include fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, etc., when the heteroatom is nitrogen; 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, Spiro rings such as 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, etc.; and bridged heterobicyclic rings such as 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, etc., but are not limited thereto.

[0070] The term "aryl" as used herein refers to a carbon-cyclic aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl (benzene), tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The carbon-cyclic aromatic group may be optionally substituted.

[0071] As used herein, "heteroaryl" is a 5 to 10 membered aromatic heterocycle ring having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and containing at least one carbon atom, including mono- and bicyclic ring systems. Representative heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, dihydroquinoline, These include isoquinoline, dihydroisoquinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, thiadiazole, tetrahydroisoquinoline, and tetrahydropyrazolopyrazine.

[0072] In this specification, * or means connected to another moiety.

[0073]

[0074] Preferably, in the PROTAC compound according to the present invention, the moiety (ALK and / or EGFR ligand) on the right side of the linker (L) has any of the following structures. When it has the following structure, the ALK and / or EGFR degrading activity is excellent, and it is more suitable for various purposes of the present invention.

[0075]

[0076] (The above structures are ligand structures with excellent binding affinity to both ALK and EGFR)

[0077]

[0078] (The above structures are ligand structures with excellent binding affinity to ALK)

[0079]

[0080] Preferably, in the chemical formula 1 or 1' according to the present invention, L provides a PROTAC compound having a structure of the following chemical formula 2 or a pharmaceutically acceptable salt thereof.

[0081] [Chemical Formula 2]

[0082]

[0083] In the above chemical formula 2,

[0084] C1 and C2 are independently a direct bond, aryl, heteroaryl, carbocycle, or heterocycle, wherein the aryl, heteroaryl, carbocycle, or heterocycle is optionally provided that one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-6 substituted with one or more of haloalkyl, or hydroxy,

[0085] D1 and D2 are independently a direct bond, -O-, -N(R9)-, -C(O)-, -CC-, -C(O)NH-, or -NHC(O)-, where R9 is H, C 1-6 alkyl, or C 1-6 It is haloalkyl,

[0086] q1, q2, q3, and q4 are independently 0, 1, 2, or 3.

[0087]

[0088] More preferably, one aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein in the above chemical formula 2, C2 is a divalent 4-7 membered monocyclic heterocycle, a 4-7 membered spiro heterocycle, or an 8-10 membered bicyclic heterocycle; q4 is 0; and D2 is a direct bond. In the PROTAC compound according to the present invention, when the linker (L) has such a structure, the ALK and / or EGFR degrading activity is excellent, and the compound is more suitable for various purposes of the present invention.

[0089]

[0090] In a more preferred embodiment of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein q1 is 1 or 2 (preferably 1), C1 and C2 are independently piperidine or piperazine, q2 is 1 or 2 (preferably 1), D1 and D2 are direct bonds, and q3 and q4 are 0 or 1 (preferably 0). In the PROTAC compound according to the present invention, when the linker (L) has this structure, the ALK and / or EGFR degrading activity is excellent, and it is more suitable for various purposes of the present invention.

[0091]

[0092] More preferably, another aspect of the present invention is a compound of formula 1 or 1', wherein L is , , , or The present invention provides a PROTAC compound or a pharmaceutically acceptable salt thereof. In the PROTAC compound of the present invention, when L is as described above, it is more preferable for various purposes of the present invention.

[0093]

[0094] Non-limiting, the compound of formula 1a according to the present disclosure is

[0095] 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)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 2),

[0096] 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 3),

[0097] 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 4),

[0098] 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 5), or

[0099] 2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 6),

[0100] or a pharmaceutically acceptable salt thereof.

[0101]

[0102] "Pharmaceutically acceptable salts" in the present invention include salts of the active compounds prepared with relatively non-toxic acids and bases, depending on the specific substituents found in the compounds mentioned herein. When the compounds of the present invention contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitably inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like, as well as salts derived from hydrochloric, hydrobromide, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acids and the like. Also included are salts of amino acids such as alginate and its analogs and analogs of organic acids such as glucuronic or galactunoric acids and their analogs.Certain specific compounds of the present invention possess both basic and acidic functionalities, allowing them to be converted into basic or acidic addition salts. Other examples of salts are well known in the art.

[0103] As used herein, the term "compound of the present invention" is meant to include not only each compound of formula 1, but also isotopic variants, clathrates, hydrates, solvates, or polymorphs thereof. The term "compound of the present invention" is also meant to include pharmaceutically acceptable salts of the compounds of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compounds of the present invention can exist as stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)). That is, when the compound of formula 1 according to the present invention or a salt thereof is a tautomeric isomer and / or a stereoisomer (e.g., a geometrical isomer and a conformational isomer), each of their separated isomers and mixtures are also included in the scope of the compound of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

[0104] As used herein, the term "isotopic variant" means a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound. For example, an isotopic variant of a compound may be radioactively labeled, for example, a hydrogen atom may be selected from hydrogen, deuterium, and tritium, and a carbon-13 (13 C), nitrogen-15( 15 N) may contain etc.

[0105] As used herein, the term "polymorph" means a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical, and / or spectral properties. Differences in physical properties include, but are not limited to, stability (e.g., heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such as faster discoloration of one polymorph than of another), mechanical properties (e.g., tablet fragments stored as a kinetically favored polymorph transform to the thermodynamically more stable polymorph), or both (tablets of one polymorph are more susceptible to degradation at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or more difficult to filter or wash than another polymorph, for example due to its shape or particle size distribution.

[0106] The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.

[0107] The term "hydrate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0108] The term "clathrate" as used herein means a compound of the present invention or a salt thereof in the form of a crystal lattice that includes spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0109] The term "purified" as used herein means that when separated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

[0110]

[0111] Medicinal uses and therapeutic methods of the compounds of the present invention

[0112] The present invention also provides a method for treating the following diseases or conditions in a subject having or susceptible to the following diseases or conditions by administering to the subject a therapeutically effective amount of one or more compounds of Formula 1a. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0113] 1. Disease or condition

[0114] The compounds of the present invention for inhibiting and / or degrading ALK and / or EGFR are useful for various therapeutic or preventive applications (e.g., cancer or psoriasis). These compounds can be used to degrade ALK and / or EGFR to reduce ALK and / or EGFR activity, and can also be used for treating or preventing the worsening of ALK and / or EGFR-related diseases. Accordingly, the present invention provides a method for degrading ALK and / or EGFR in a cell. In this method, the cell is contacted with an effective amount of a compound of the present invention. In one embodiment, the cell is present in a subject. The method of the present invention comprises administering to a subject in need of treatment or prevention a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the present invention.

[0115] In one aspect, the present invention provides a method for degrading ALK and / or EGFR in cells of an individual suffering from an ALK and / or EGFR-related disease. For example, the present invention can be used to degrade ALK and / or EGFR in cells of an individual suffering from an ALK and / or EGFR-related disease, as described below, thereby reducing ALK and / or EGFR activity. In another aspect, the present invention can be used to degrade ALK and / or EGFR in cells of a cancer, psoriasis, or the like.

[0116] In another aspect, the present invention provides a method for treating an ALK and / or EGFR-associated disease, comprising administering to a subject a therapeutically effective amount of a compound of formula 1a or a pharmaceutically acceptable salt thereof. The method comprises administering to a subject in need thereof a sufficient amount of the compound of the present invention to degrade ALK and / or EGFR, i.e., a therapeutically effective amount. In such a method, the compound of the present invention may be administered to the subject in the form of a pharmaceutical composition as described herein.

[0117] In one embodiment of the present invention, the ALK and / or EGFR-related disease is cancer or psoriasis. In another embodiment of the present invention, the cancer is a cancer having an ALK and / or EGFR mutation. The cancer is a solid cancer. The cancer may be selected from the group consisting of lung cancer, liver cancer, esophageal cancer, stomach 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, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastic tumor, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic myelofibrosis, inflammatory myofibroblastic sarcoma, or esophageal squamous cell carcinoma, but is not particularly limited thereto. In a preferred embodiment of the present invention, the cancer is lung cancer. In another preferred embodiment of the present invention, the cancer is non-small cell lung cancer.

[0118] In one aspect of the present invention, the ALK mutation is any one or more of G1202R, L1196M, C1156Y, F1174L, F1174S, G1269A, G1269S, L1152R, R1275Q, S1206R, T1151-L1152insT, or T1151M. In another aspect of the present invention, the ALK mutation is any one or more of G1269S, G1202R, and L1196M.

[0119] In one aspect of the present invention, the cancer exhibiting an EGFR mutation is, in particular, a cancer exhibiting one or more of the EGFR mutations del19, T790M, C797S, and L858R. In another aspect of the present invention, the EGFR mutation is del19 / T790M / C797S and / or T790M / C797S / L858R.

[0120] That is, the present invention provides a pharmaceutical use of a compound of chemical formula 1a or a pharmaceutically acceptable salt thereof for treating or preventing the above-described disease.

[0121] 2. Subjects

[0122] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and the like, and include mammals in utero.

[0123] In one aspect, the subject suitable for treatment according to the present invention is a human.

[0124] 3. Administration and Dosing

[0125] The compounds of the present invention are generally administered in a therapeutically effective amount.

[0126] As used herein, "effective amount" refers to an amount of a compound of the present invention sufficient to slow or minimize the progression of an ALK and / or EGFR-associated disease, or to provide a therapeutic benefit in the treatment or management of an ALK and / or EGFR-associated disease. An "effective amount" also refers to an amount sufficient to inhibit or reduce ALK and / or EGFR activity, either in vitro or in vivo.

[0127] The compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg / kg body weight / day, preferably from about 0.01 to about 50 mg / kg / day, in single or divided doses. Dosage levels below the lower end of this range may be appropriate depending on age, species, and the disease or condition being treated. In other cases, still higher dosages may be used without harmful side effects. A larger dosage may be divided into several smaller doses for administration throughout the day.

[0128]

[0129] Pharmaceutical composition of the compound of the present invention

[0130] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect of the present invention, the use of the pharmaceutical composition is for the treatment or prevention of the aforementioned ALK and / or EGFR-related diseases, preferably autoimmune diseases or cancer.

[0131] The term "pharmaceutically acceptable" means suitable for use in pharmaceutical preparations, generally considered safe for such use, and officially approved by a national regulatory agency for such use or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0132]

[0133] Pharmaceutical compositions, dosage forms and routes of administration

[0134] For the treatment of the disease or condition described above, the compound described herein or a pharmaceutically acceptable salt thereof may be administered as follows.

[0135] Oral administration

[0136] The compounds of the present invention may be administered orally, including by swallowing. Oral administration may result in the compounds of the present invention entering the gastrointestinal tract, or may be absorbed directly into the bloodstream through the mouth, for example, through buccal or sublingual administration.

[0137] Suitable compositions for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0138] Compositions for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the compositions for oral administration according to the present invention may be formulations having an immediate or modified release pattern.

[0139] Liquid formulations may include solutions, syrups, and suspensions, and these liquid compositions may be contained within soft or hard capsules. These formulations may include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations may also include one or more emulsifying and / or suspending agents.

[0140] In tablet formulations, the active ingredient drug may be present in an amount of from about 0.05% to about 95% by weight of the total weight of the tablet, more typically from about 2% to about 50% by weight of the formulation. The tablets may also contain a disintegrant, which comprises from about 0.5% to about 35% by weight, more typically from about 2% to about 25% by weight of the formulation. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0141] Suitable lubricants included for manufacturing the tablets may be present in an amount of about 0.1 wt% to about 5 wt%, and talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, etc. may be used as lubricants, but the present invention is not limited to the types of these additives.

[0142] Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. can be used as binders for manufacturing into tablets, and mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. can be used as suitable diluents for manufacturing into tablets, but the present invention is not limited to the types of these additives.

[0143] Solubilizing agents that may optionally be included in the tablet may be used in an amount of about 0.1 wt% to about 3 wt% based on the total weight of the tablet, and examples thereof include polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR. TM (Nikkol), oleic acid ester, gelucire TM ), caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, solutol HS TM Although these may be used in the pharmaceutical composition according to the present invention, the present invention is not limited to the specific types of these solubilizing agents.

[0144] Parenteral Administration

[0145] The compounds of the present invention can be administered directly into the bloodstream, muscle, or internal organs. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial injections. Suitable devices for parenteral administration include injectors (including needle and needle-less syringes) and infusion methods.

[0146] Compositions for parenteral administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or sustained release pattern.

[0147] Most parenteral formulations are liquid compositions, which are aqueous solutions containing the active ingredient, salt, buffer, isotonic agent, etc. according to the present invention.

[0148] Parenteral formulations can also be prepared in a dry form (e.g., lyophilized) or as a sterile non-aqueous solution. These formulations can be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents can also be used in the preparation of parenteral solutions.

[0149] Topical Administration

[0150] The compounds of the present invention can be administered topically, either skin-wise or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be accomplished by electroporation, iontophoresis, phonophoresis, and the like.

[0151] Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or sustained release pattern.

[0152] One aspect of the present disclosure provides a ligand compound having excellent binding affinity to E3 ligase and high stability in the body, which is suitable for use as an E3 ligase binding moiety in a PROTAC structure, a method for preparing a PROTAC compound using such an E3 ligase ligand, and a PROTAC compound comprising such a ligand compound.

[0153] Another aspect of the present disclosure provides compounds having excellent ALK and / or EGFR degrading activity and thus exhibiting various pharmacological activities, pharmaceutical compositions comprising these as active ingredients, their medicinal uses (particularly, cancer), and therapeutic methods comprising administering these to a subject in need of treatment or prevention. The compounds according to the present invention or pharmaceutically acceptable salts thereof are excellent in various aspects, such as ALK and / or EGFR degrading activity, (metabolic) stability, and physicochemical properties.

[0154] Hereinafter, the present invention will be described in detail, using examples and the like, to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0155]

[0156] Preparation of compounds of the present invention

[0157] Hereinafter, the synthetic process of some compounds of the present invention is described, and compounds not mentioned below can be prepared by a similar method by replacing the starting materials, intermediates and / or reactants.

[0158]

[0159] Example 1: Synthesis of Intermediate 1

[0160]

[0161] Step 1: Synthesis of 5-(4-bromophenyl)-4-methylthiazole (1-1)

[0162] A mixture of 4-methylthiazole (2.0 g, 20.1 mmol), 1-bromo-4-iodobenzene (5.1 g, 20.1 mmol), Pd(OAc)2 (451 mg, 2.01 mmol), and potassium acetate (3.9 g, 40.2 mmol) in dimethylacetamide (20 mL) was replaced with argon gas and stirred at 100°C overnight. The mixture was extracted by dilution with dichloromethane and water, and dried over anhydrous magnesium sulfate. After filtration and concentration, the mixture was purified by silica gel column to obtain the title compound (1.1 g, 22%).

[0163] Step 2: Synthesis of 5-(4-(2-(diphenylmethylene)hydrazinyl)phenyl)-4-methylthiazole (1-2)

[0164] (1-1) A mixture of (1.1 g, 4.41 mmol), (diphenylmethylene)hydrazine (861 mg, 4.41 mmol), Pd(OAc)2 (99 mg, 0.44 mmol), BINAP (275 mg, 0.44 mmol), and sodium tert-butoxide (808 g, 8.82 mmol) in 1,4-dioxane (15 mL) was replaced with argon gas and stirred at 100°C overnight. The mixture was extracted by dilution with ethyl acetate and water, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column to obtain the title compound (1.3 g, 81%).

[0165] Step 3: Synthesis of 5-(4-(2-(diphenylmethylene)-1-methylhydrazinyl)phenyl)-4-methylthiazole (1-3)

[0166] (1-2) The substance (1.3 g, 3.55 mmol) was dissolved in dimethylformamide (15 mL), and sodium hydride (60%, 213 mg, 5.33 mmol) was added at 0°C. After stirring for 30 minutes, iodomethane (0.33 mL, 5.33 mmol) was added, and the mixture was stirred for 2 hours. The mixture was extracted by dilution with ethyl acetate and water, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column to obtain the title compound (1.3 g, 95%).

[0167] Step 4: Synthesis of 4-methyl-5-(4-(1-methylhydrazinyl)phenyl)thiazole (1-4)

[0168] (1-3) The substance (1.2 g, 3.13 mmol) was dissolved in ethanol (22 mL), and concentrated sulfuric acid (5 mL) was added. The mixture was stirred at 85°C for 3 hours, cooled to room temperature, and extracted with ether. The aqueous layer was diluted with water and neutralized with 1 N sodium hydroxide. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography to obtain the title compound (633 mg, 92%).

[0169] 1 H NMR (400 MHz, DMSO-d6): δ 8.88 (s, 1H), 7.26 (d, 2H), 7.03 (d, 2H), 4.45 (br s, 2H), 3.06 (s, 3H), 2.42 (s, 3H)

[0170] LC / MS (ESI) m / z 220 [M+H] +

[0171]

[0172] Example 2: Synthesis of Intermediate 2

[0173]

[0174] Step 1: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate (2-1)

[0175] To a solution of intermediate 1 (623 mg, 2.84 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (658 mg, 2.84 mmol) in dimethylformamide (7 mL) was added diisopropyldiamine (1.48 mL, 8.52 mmol), and the mixture was stirred for 15 minutes. HATU (1.62 g, 4.26 mmol) was added to the reaction mixture, and the mixture was stirred overnight. The mixture was extracted with dichloromethane and water, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography to obtain the title compound (997 mg, 81%).

[0176] Step 2: Synthesis of (2S,4R)-4-hydroxy-N'-methyl-N'-(4-(4-methylthiazol-5-yl)phenyl)pyrrolidine-2-carbohydrazide hydrochloride (2-2)

[0177] (2-1) A 4N HCl 1,4-dioxane solution (10 mL) was added to a dichloromethane (10 mL) solution of the substance (997 mg, 2.3 mmol) and stirred for 1 hour. Tertiary butyl methyl ether was added to the reaction mixture, stirred for 30 minutes, and filtered to obtain the title compound (861 mg, >100%).

[0178] 1 H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.83 (br s, 1H), 7.36 (d, 2H), 6.89 (d, 2H), 4.49 (m, 1H), 4.42 (m, 1H), 3.33 (m, 1H), 3.17 (s, 3H), 3.14 (m, 2H), 2.43 (s, 3H), 2.38 (m, 1H), 2.04 (m, 1H)

[0179]

[0180] Example 3: Synthesis of intermediate 3

[0181]

[0182] Step 1: Synthesis of tert-butyl ((S)-1-(2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (3-1)

[0183] To a solution of intermediate 2 (760 mg, 2.06 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (476 mg, 2.06 mmol) in dimethylformamide (5 mL) was added diisopropyldiamine (1.1 mL, 6.8 mmol) and stirred for 15 minutes. HATU (1.2 g, 3.09 mmol) was added to the reaction mixture and stirred for 2 hours. The mixture was extracted with ethyl acetate and water and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography to obtain the title compound (1.0 g, 92%).

[0184] Step 2: Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N'-methyl-N'-(4-(4-methylthiazol-5-yl)phenyl)pyrrolidine-2-carbohydrazide hydrochloride (3-2)

[0185] (3-1) A 4N HCl 1,4-dioxane solution (1 mL) was added to a solution of the substance (107 mg, 0.2 mmol) in dichloromethane (1 mL) and stirred for 2 hours. The reaction mixture was concentrated and dried under vacuum to obtain the title compound (98.5 mg, >100%), which was used in the next reaction without further purification.

[0186] 1 H NMR (400 MHz, DMSO-d6): δ 10.5 (s, 1H), 8.92 (s, 1H), 8.11 (m, 3H), 7.26 (d, 2H), 6.95 (d, 2H), 4.51 (m, 1H), 4.43 (m, 2H), 3.94 (m, 2H), 3.12 (s, 3H), 2.42 (s, 3H), 2.16 (m, 1H), 1.96 (m, 1H), 1.01 (s, 9H)

[0187]

[0188] Example 4: Synthesis of N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (1)

[0189]

[0190] To a solution of intermediate 3 (58 mg, 0.12 mmol) and acetic acid (6.9 mL, 0.12 mmol) in dimethylformamide (1.2 mL) was added diisopropyldiamine (0.063 mL, 0.39 mmol), and the mixture was stirred for 15 minutes. HATU (68 mg, 0.18 mmol) was added to the reaction mixture, and the mixture was stirred for 2 hours. The mixture was extracted with dichloromethane and water, and dried over anhydrous magnesium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography to obtain the title compound (28 mg, 48%).

[0191] 1 H NMR (400 MHz, DMSO-d6): δ 10.3 (s, 1H), 8.90 (s, 1H), 8.03 (d, 1H), 7.24 (d, 2H), 7.00 (d, 2H), 5.19 (d, 1H), 4.53 (d, 1H), 4.38 (m, 2H), 3.65 (m, 2H), 3.11 (s, 3H), 2.42 (s, 3H), 2.06 (m, 1H), 1.95 (m, 1H), 1.89 (s, 3H), 0.92 (s, 9H)

[0192] LC / MS (ESI) m / z 488 [M+H] +

[0193]

[0194] Example 5: Synthesis of intermediate 4

[0195]

[0196] Step 1: Preparation of benzyl 4-((4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (5-1)

[0197] A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (540 mg, 3.16 mmol), benzyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.0 g, 3.16 mmol), and potassium carbonate (655 mg, 43.24 mmol) in N,N-dimethylformamide (6.5 mL) was stirred at 65°C overnight. Saturated aqueous NH4Cl solution was added to the reaction mixture, stirred for 5 minutes, and extracted with water and ethyl acetate. The organic layer was washed with brine and water successively, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (903 mg, 61%).

[0198] Step 2: Preparation of benzyl 4-((4-(4-amino-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (5-2)

[0199] (5-1) To a solution of the substance (900 mg, 1.92 mmol) in 1,4-dioxane (15 mL) was added a solution of NH4Cl (513 mg, 9.60 mmol) in H2O (5 mL), and the mixture was replaced with argon. Zn (628 mg, 9.60 mmol) was added and stirred at 70°C. After 19 hours, the mixture was filtered through Celite and concentrated. The residue was diluted with aqueous sodium chloride solution, made alkaline with aqueous saturated sodium bicarbonate 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, yield 99%).

[0200] Step 3: Preparation of benzyl 4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (5-3)

[0201] (5-2) A mixture of material (830 mg, 1.89 mmol), N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (657 mg, 1.89 mmol), BINAP (118 mg, 0.19 mmol), and potassium carbonate (523 mg, 3.78 mmol) in 1,4-dioxane (9 mL) was replaced with argon gas, and Pd(OAc)2 (43 mg, 0.19 mmol) was added. The mixture was stirred under reflux overnight, cooled to room temperature, diluted with ethyl acetate and brine, and extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was purified by silica gel column to obtain the title compound (1.0 g, 71%).

[0202] Step 4: Preparation 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 (5-4)

[0203] (5-3) A tetrahydrofuran / ethanol (8 / 8 mL) solution of the substance (800 mg, 1.06 mmol) was replaced with argon gas, and 10% Pd / C (160 mg) was added. The mixture was stirred for 6 hours after replacing with hydrogen gas, filtered, and concentrated to obtain the labeled compound (617 mg, 94%).

[0204] 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (br s, 1H), 8.27 (m, 1H), 8.12 (br s, 1H), 7.58 (dd, 1H), 7.38 (d, 1H), 7.25 (t, 1H), 7.16 (dd, 1H), 6.62 (d, 1H), 6.43 (dd, 1H), 3.75 (s, 3H), 3.18 (s, 3H), 3.13 (m, 4H), 3.10 (s, 3H), 2.90 (m, 2H), 2.49 (m, 4H), 2.44 (m, 2H), 2.15 (d, 2H), 1.63 (m, 3H), 0.97 (m, 2H)

[0205]

[0206] Example 6: Synthesis of 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)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (2)

[0207]

[0208] Step 1: Preparation of tert-butyl-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)acetate (6-1)

[0209] To a solution of tert-butyl 2-bromoacetate (26 mg, 0.13 mmol) and intermediate 4 (82 mg, 0.13 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (60 mL, 0.33 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with dichloromethane and dilute aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (91 mg, yield 94%).

[0210] Step 2: Preparation of 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)acetic acid hydrochloride (6-2)

[0211] (6-1) A 4N HCl 1,4-dioxane solution (0.8 mL) was added to a dichloromethane (1 mL) solution of the substance (94 mg, 0.13 mmol) and stirred at 40°C for 3 hours. The reaction mixture was concentrated and vacuum-dried to obtain the title compound, which was used in the following reaction.

[0212] Step 3: Synthesis of 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)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (6-3)

[0213] (6-2) To a mixture of the substance (103 mg, 0.15 mmol) and intermediate 3 (72 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (0.88 mL, 1.08 mmol), stirred for 5 minutes, and then HATU (68 mg, 0.18 mmol) was added. After stirring for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound (86 mg, 52%).

[0214] 1H NMR (400 MHz, DMSO-d6): δ 10.34 (br s, 1H), 8.90 (s, 1H), 8.28 (s, 1H), 8.27 (m, 1H), 8.10 (s, 2H), 7.82 (d, 1H), 7.57 (d, 1H), 7.39 (d, 1H), 7.25 (m, 2H), 7.16 (t, 1H), 6.99 (m, 2H), 6.61 (d, 1H), 6.43 (dd, 1H), 5.19 (d, 1H), 4.50 (d, 1H), 4.42 (m, 2H), 3.76 (s, 3H), 3.64 (m, 2H), 3.18 (s, 3H), 3.12 (s, 3H), 3.11 (m, 4H), 3.10 (s, 3H), 3.05 (d, 1H), 2.92 (d, 1H), 2.84 (m, 2H), 2.47 (m, 4H), 2.42 (s, 3H), 2.19 (d, 2H), 2.12 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.56 (m, 1H), 1.20 (m, 2H), 0.94 (s, 9H)

[0215] LC / MS (ESI) m / z 1100 [M+H] +

[0216]

[0217] Example 7: Synthesis of intermediate 5

[0218]

[0219] Step 1: Preparation of benzyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (7-1)

[0220] The title compound (14.0 g, yield 72%) was obtained using a method similar to the first-step synthesis method of Example 5, using 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (6.5 g, 35.11 mmol) instead of 4-fluoro-2-methoxy-1-nitrobenzene.

[0221] Step 2: Preparation of benzyl 4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (7-2)

[0222] (7-1) The title compound (718 mg, yield 99%) was obtained using a material (794 mg, 1.60 mmol) and a method similar to the two-step synthesis method of Example 5.

[0223] Step 3: Preparation of benzyl 4-((1-(4-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (7-3)

[0224] (7-2) To a solution of the substance (718 mg, 1.58 mmol) and N-(2-((2,5-dichloropyrimidin-4yl)amino)phenyl)-N-methylmethanesulfonamide (677 mg, 1.90 mmol) in isopropanol (16 mL) was added methanesulfonic acid (0.20 mL, 3.23 mmol), and the mixture was refluxed overnight. The mixture was diluted with dichloromethane and aqueous sodium hydroxide solution, extracted, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by column chromatography to obtain the title compound (1.0 g, 83%).

[0225] Step 4: Preparation 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 (7-4)

[0226] (7-3) The title compound (800 mg, yield >100%) was obtained using a material (1.0 g, 1.31 mmol) and a method similar to the 4-step synthesis method of Example 5 above.

[0227] 1H NMR (400 MHz, CDCl3): δ 8.79 (br s, 2H), 8.33 (br s, 1H), 8.23 ​​(m, 1H), 8.14 (s, 1H), 8.07 (br s, 1H), 7.60 (dd, 1H), 7.45 (s, 1H), 7.27 (t, 1H), 7.19 (td, 1H), 6.72 (s, 1H), 3.77 (s, 3H), 3.24 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.87 (m, 2H), 2.85 (m 4H), 2.53 (m, 4H), 2.22 (m, 2H), 2.12 (s, 3H), 1.86 (m, 3H), 1.30 (m, 2H)

[0228]

[0229] Example 8: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (3)

[0230]

[0231] Step 1: Synthesis of tert-butyl-2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (8-1)

[0232] The title compound (120 mg, yield 67%) was obtained using intermediate 5 (150 mg, 0.24 mmol) instead of intermediate 4 and using a method similar to the first-step synthesis method of Example 6.

[0233] Step 2: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid hydrochloride (8-2)

[0234] (8-1) The material (120 mg, 0.16 mmol) was used, and the title compound was obtained using a method similar to the two-step synthesis method of Example 6 and used in the following reaction.

[0235] Step 3: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (8-3)

[0236] (8-2) The title compound (29 mg, yield 59%) was obtained using a material (30 mg, 0.04 mmol) and a method similar to the three-step synthesis method of Example 6.

[0237] 1H NMR (400 MHz, DMSO-d6): δ 10.36 (br s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 8.22 (m, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.42 (s, 1H), 7.26 (m, 3H), 7.19 (td, 1H), 7.00 (m, 2H), 6.72 (s, 1H), 5.21 (d, 1H), 4.50 (d, 1H), 4.41 (m, 2H), 3.76 (s, 3H), 3.63 (m, 2H), 3.18 (s, 3H), 3.12 (s, 3H), 3.10 (s, 3H), 3.05 (d, 1H), 2.89 (d, 1H), 2.83 (m, 6H), 2.47 (m, 4H), 2.42 (s, 3H), 2.20 (d, 2H), 2.11 (s, 3H), 2.10 (m, 3H), 1.96 (m, 1H), 1.76 (m, 2H), 1.56 (m, 1H), 1.20 (m, 2H), 0.93 (s, 9H)

[0238] LC / MS (ESI) m / z 1114 [M+H] +

[0239]

[0240] Example 9: Synthesis of intermediate 6

[0241]

[0242] Step 1: Preparation of benzyl 4-((4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (9-1)

[0243] To a solution of benzyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate dihydrochloride (1.0 g, 2.64 mmol) and 1,2-difluoro-4-methoxy-5-nitrobenzene (677 mg, 2.64 mmol) in acetonitrile (15 mL) was added triethylamine (1.8 mL, 7.92 mmol), and the mixture was stirred at 80°C overnight. The mixture was extracted by dilution with ethyl acetate and diluted aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by column chromatography to obtain the title compound (1.3 g, 99%).

[0244] Step 2: Preparation of benzyl 4-((4-(4-amino-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (9-2)

[0245] (9-1) The title compound (1.12 g, yield 94%) was obtained using a material (1.27 g, 2.61 mmol) and a method similar to the two-step synthesis method of Example 5.

[0246] Step 3: Preparation of benzyl 4-((4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (9-3)

[0247] (9-2) The title compound (1.03 g, yield 55%) was obtained using a similar method to the three-step synthetic method of Example 5 using the material (1.12 g, 2.45 mmol) and 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (1.12 g, 2.45 mmol).

[0248] Step 4: 5-chloro-N 2 -(5-Fluoro-2-methoxy-4-(4-(piperidin-4-ylmethyl)piperizin-1-yl)phenyl)-N 4 Preparation of -(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (9-4)

[0249] (9-3) The title compound (804 mg, yield 95%) was obtained using a material (1.03 g, 1.34 mmol) and a method similar to the 4-step synthesis method of Example 5.

[0250] 1 H NMR (400 MHz, DMSO-d6): δ 9.50 (br s, 1H), 8.53 (m, 1H), 8.26 (s, 1H), 8.25 (s, 1H), 7.83 (dd, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.36 (td, 1H), 6.67 (d, 1H), 3.80 (s, 3H), 3.44 (m, 1H), 3.20 (m, 2H), 3.02 (m, 4H), 2.79 (m 2H), 2.50 (m, 4H), 2.20 (d, 2H), 1.82 (m, 3H), 1.21 (m, 2H), 1.15 (d, 6H)

[0251]

[0252] Example 10: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (4)

[0253]

[0254] Step 1: Synthesis of tert-butyl-2-(4-((4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate (10-1)

[0255] Intermediate 6 (150 mg, 0.24 mmol) was used instead of intermediate 4, and the title compound (130 mg, yield 73%) was obtained using a method similar to the first-step synthesis method of Example 6.

[0256] Step 2: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid hydrochloride (10-2)

[0257] (10-1) The material (130 mg, 0.17 mmol) was used, and the title compound was obtained using a method similar to the two-step synthesis method of Example 6 and used in the following reaction.

[0258] Step 3: Synthesis of 2-(4-((4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (10-3)

[0259] (10-2) The title compound (28 mg, yield 58%) was obtained using a material (30 mg, 0.04 mmol) and a method similar to the three-step synthesis method of Example 6.

[0260] 1H NMR (400 MHz, DMSO-d6): δ 10.36 (br s, 1H), 9.50 (s, 1H), 8.90 (s, 1H), 8.54 (m, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.83 (m, 2H), 7.65 (t, 1H), 7.56 (d, 1H), 7.37 (t, 1H), 7.26 (m, 2H), 7.01 (m, 2H), 6.67 (d, 1H), 5.21 (d, 1H), 4.50 (d, 1H), 4.41 (m, 2H), 3.79 (s, 3H), 3.63 (m, 2H), 3.44 (m, 1H), 3.12 (s, 3H), 3.05 (d, 1H), 3.00 (m, 4H), 2.90 (d, 1H), 2.86 (m, 2H), 2.47 (m, 4H), 2.42 (s, 3H), 2.20 (d, 2H), 2.10 (m, 3H), 1.95 (m, 1H), 1.76 (m, 2H), 1.55 (m, 1H), 1.15 (d, 6H), 1.20 (m, 2H), 0.93 (s, 9H)

[0261] LC / MS (ESI) m / z 1117 [M+H] +

[0262]

[0263] Example 11: Synthesis of intermediate 7

[0264]

[0265] Step 1: Preparation of benzyl 4-((4-(5-methoxy-2-(methylsulfonamido)-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (11-1)

[0266] The title compound (3.5 g, yield 88%) was obtained using N-(2-fluoro-4-methoxy-5-nitrophenyl)methanesulfonamide (1.8 g, 7.05 mmol) and a method similar to the first-step synthesis method of Example 9.

[0267] Step 2: Preparation of benzyl 4-((4-(4-amino-5-methoxy-2-(methylsulfonamido)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (11-2)

[0268] (11-1) The title compound (3.0 g, yield 91%) was obtained using a material (3.5 g, 6.23 mmol) and a method similar to the two-step synthesis method of Example 5.

[0269] Step 3: N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-((1-(2-oxo-2-phenyl-1l 2 Preparation of (ethyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)methanesulfonamide (11-3)

[0270] (11-2) Using the material (700 mg, 1.32 mmol) and 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (479 mg, 1.38 mmol), the title compound (530 mg, yield 48%) was obtained using a method similar to the three-step synthetic method of Example 5.

[0271] Step 4: Preparation of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)methanesulfonamide (11-4)

[0272] (11-3) The title compound (440 mg, yield 100%) was obtained using a material (530 mg, 0.63 mmol) and a method similar to the 4-step synthesis method of Example 5 above.

[0273] 1H NMR (400 MHz, CDCl3): δ 9.61 (br s, 1H), 8.52 (d, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 7.90 (dd, 1H), 7.68 (td, 1H), 7.41 (s, 1H), 7.26 (td, 1H), 6.80 (s, 1H), 3.88 (s, 3H), 3.43 (m, 2H), 3.24 (m, 1H), 2.89 (s, 3H), 2.80-2.85 (m, 6H), 2.59 (m, 4H), 2.31 (d, 2H), 1.99 (m, 2H), 1.75 (m, 1H), 1.55 (m, 2H), 1.30 (d, 6H)

[0274]

[0275] Example 12: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (5)

[0276]

[0277] Step 1: Synthesis of tert-butyl-2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (12-1)

[0278] The title compound (129 mg, yield 75%) was obtained using intermediate 7 (150 mg, 0.21 mmol) instead of intermediate 4 and using a method similar to the first-step synthesis method of Example 6.

[0279] Step 2: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (12-2)

[0280] (12-1) The material (123 mg, 0.15 mmol) was used, and the title compound was obtained using a method similar to the two-step synthesis method of Example 6 and used in the following reaction.

[0281] Step 3: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (12-3)

[0282] (12-2) The title compound (34 mg, yield 72%) was obtained using a material (30 mg, 0.04 mmol) and a method similar to the three-step synthesis method of Example 6.

[0283] 1H NMR (400 MHz, DMSO-d6): δ 10.36 (br s, 1H), 9.56 (s, 1H), 8.89 (s, 1H), 8.58 (m, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.66 (t, 1H), 7.56 (s, 1H), 7.30 (d, 1H), 7.26 (m, 2H), 7.00 (m, 2H), 6.93 (s, 1H), 5.21 (d, 1H), 4.50 (d, 1H), 4.40 (m, 2H), 3.77 (s, 3H), 3.66 (m, 2H), 3.44 (m, 1H), 3.12 (s, 3H), 3.05 (d, 1H), 2.98 (s, 1H), 2.88 (m, 7H), 2.51 (m, 4H), 2.42 (s, 3H), 2.21 (d, 2H), 2.10 (m, 3H), 1.95 (m, 1H), 1.77 (m, 2H), 1.55 (m, 1H), 1.16 (d, 6H), 1.20 (m, 2H), 0.93 (s, 9H)

[0284] LC / MS (ESI) m / z 1192 [M+H] +

[0285]

[0286] Example 13: Synthesis of Intermediate 8

[0287]

[0288] Step 1: Preparation of benzyl 4-((4-(2-cyano-5-methoxy-4-nitrophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (13-1)

[0289] The title compound (4.3 g, yield 89%) was obtained using 2-fluoro-4-methoxy-5-nitrobenzonitrile (1.9 g, 9.84 mmol) and a method similar to the first-step synthesis method of Example 9.

[0290] Step 2: Preparation of benzyl 4-((4-(4-amino-2-cyano-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (13-2)

[0291] (13-1) The title compound (3.5 g, yield 88%) was obtained using a material (4.3 g, 8.71 mmol) and a method similar to the two-step synthesis method of Example 5.

[0292] Step 3: Preparation of benzyl 4-((4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (13-3)

[0293] (13-2) Using the material (500 mg, 1.08 mmol) and (2-((2,5-dichloro-4-yl)amino)phenyl)dimethylphosphine oxide (341 mg, 1.08 mmol), the title compound (470 mg, yield 59%) was obtained using a method similar to the three-step synthetic method of Example 5.

[0294] 1 H NMR (400 MHz, DMSO-d6): δ 11.24 (br s, 1H), 8.42 (m, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.57 (dd, 1H), 7.45 (m, 1H), 7.31-7.37 (m, 5H), 7.15 (m, 1H), 6.77 (s, 1H), 5.07 (s, 2H), 4.01 (m, 2H), 3.89 (s, 3H), 3.17 (m, 4H), 2.85 (m, 2H), 2.55 (m, 4H), 2.22 (d, 2H), 1.76 (m, 9H), 1.01 (m, 2H)

[0295] Step 4: Preparation of (5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)benzonitrile (13-4)

[0296] (13-3) The title compound (416 mg, yield 100%) was obtained using a material (465 mg, 0.63 mmol) and a method similar to the 4-step synthesis method of Example 5 above.

[0297]

[0298] Example 14: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (6)

[0299]

[0300] Step 1: Synthesis of tert-butyl-2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetate (14-1)

[0301] The title compound (132 mg, yield 73%) was obtained using intermediate 8 (150 mg, 0.25 mmol) instead of intermediate 4 and a method similar to the first-step synthesis method of Example 6.

[0302] Step 2: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)acetic acid hydrochloride (14-2)

[0303] (14-1) The material (125 mg, 0.17 mmol) was used, and the title compound was obtained using a method similar to the two-step synthesis method of Example 6 and used in the following reaction.

[0304] Step 3: Synthesis of 2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (14-3)

[0305] (14-2) The title compound (25 mg, yield 50%) was obtained using a material (30 mg, 0.045 mmol) and a method similar to the three-step synthesis method of Example 6.

[0306] 1 H NMR (400 MHz, DMSO-d6): δ 11.22 (br s, 1H), 10.36 (s, 1H), 8.89 (s, 1H), 8.41 (m, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.83 (d, 1H), 7.56 (dd, 1H), 7.45 (t, 1H), 7.26 (m, 2H), 7.14 (t, 1H), 6.99 (m, 2H), 6.76 (s, 1H), 5.21 (d, 1H), 4.50 (d, 1H), 4.41 (m, 2H), 3.89 (s, 3H), 3.14 (m, 4H), 3.12 (s, 3H), 3.05 (d, 1H), 2.90 (d, 1H), 2.86 (m, 2H), 2.54 (m, 4H), 2.42 (s, 3H), 2.21 (d, 2H), 2.14 (m, 3H), 1.96 (m, 1H), 1.79 (s, 3H), 1.76 (s, 3H), 1.72 (m, 2H), 1.56 (m, 1H), 1.20 (m, 2H), 0.93 (s, 9H)

[0307] LC / MS (ESI) m / z 1094 [M+H] +

[0308]

[0309] Evaluation of the compounds of the present invention

[0310] Experimental Example 1: Evaluation of E3 Ligase Binding Ability

[0311] In this experimental example, it was confirmed whether the compound obtained in the above example exhibited E3 ligase binding activity. To this end, E3 ligase binding activity was evaluated by Eurofins DiscoverX Corporation (CA, USA). A simple description of the test method is as follows.

[0312] E3 ligase was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate an affinity resin. The liganded beads were treated with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding. Binding reactions were performed by mixing E3 ligase, ligand affinity beads, and test compounds in 1X binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kds were determined using an 11-point, 3-fold multiplex dilution series with three DMSO control points. All compounds for Kd measurements were dispensed into 100% DMSO by acoustic transfer (non-contact dispensing). The compounds were then diluted to a final DMSO concentration of 0.9%. All reactions were performed in polypropylene 384-well plates, each with a final volume of 0.02 ml. The assay plates were incubated at room temperature for 1 h, and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM biotinylated affinity ligand) and incubated at room temperature for 30 min. The E3 ligase concentration in the eluate was measured by qPCR.

[0313] The results of the above experiment are shown in the table below.

[0314] Compound Kd (nM) Compound 142VHL41

[0315] * Control substance: VHL

[0316]

[0317] Refining

[0318] Experimental Example 2: Evaluation of EGFR protein degradation in cells

[0319] mutant EGFR del19+T790M+C797S The ability of the compounds of the present invention to degrade mutant EGFR protein was confirmed in Ba / F3 cells expressing EGFR. The degree of EGFR protein degradation was confirmed through a Western blot test using an EGFR selective antibody.

[0320] Specifically, Ba / F3 cells expressing EGFR were cultured in RPMI 1640 (Welgene, Daegu, Korea) containing 10% fetal bovine serum (FBS, Welgene, Daegu, Korea). The compound of the present invention was used to treat EGFR del19+T790M+C797S Cells expressing EGFR were treated with 0.1 μM and 1 μM concentrations for 24 hours, respectively. After washing twice with DPBS (Dulbecco's Phosphate Buffered Saline), 10 μg of cell lysate was subjected to SDS-PAGE. The proteins separated on the gel were transferred to a nitrocellulose membrane, and the expression level of EGFR protein was confirmed using an EGFR antibody (Cell Signaling Technology, CA, USA). The EGFR band separated by Western blotting was quantitatively analyzed using ChemiDoc MP (Bio-Rad, Hercules, CA, USA).

[0321] The results of the above experiment are shown in Table 2 below.

[0322]

[0323] Experimental Example 3: Evaluation of ALK protein degradation in cells

[0324] The ability of the compounds of the present invention to degrade mutant ALK protein was confirmed in Ba / F3 cells expressing the mutant ALK L1196M. The degree of ALK protein degradation was confirmed through Western blot analysis using an ALK-selective antibody.

[0325] Specifically, Ba / F3 cells expressing ALK L1196M were cultured in RPMI 1640 (Welgene, Daegu, Korea) containing 10% fetal bovine serum (FBS; Welgene, Daegu, Korea). The cells expressing ALK L1196M were treated with the compound of the present invention at concentrations of 0.1 μM and 1 μM for 24 hours, respectively. After washing twice with DPBS (Dulbecco's Phosphate-buffered saline), 20 μg of cell lysate was subjected to SDS-PAGE. The proteins separated on the gel were transferred to a nitrocellulose membrane, and the expression level of ALK protein was confirmed using an ALK antibody (Cell Signaling Technology, CA, USA). The ALK band separated by Western blotting was quantitatively analyzed using ChemiDoc MP (Bio-Rad, Hercules, CA, USA).

[0326] The results of the above experiment are shown in Table 2 below.

[0327]

[0328] ++: Protein decomposition >80%

[0329] +: Protein decomposition 20-80%

[0330] - : Protein degradation <20%

Claims

1. It is a PROTAC (Proteolysis-targeting chimera) compound with an ELP structure. P, a ligand that binds to a target protein to be degraded by ubiquitin ligase, is linked to the E moiety, an E3 ligase ligand, through a covalent bond with L, a linker. Here, the PROTAC compound is a compound having a structure of the following chemical formula 1, wherein E, a von Hippel-Lindau (VHL) E3 ligase ligand, is covalently linked to L as in the following chemical formula 1, or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] In the above chemical formula 1, R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl.

2. In paragraph 1, the chemical formula 1 is a compound having a structure of the following chemical formula 1a or a pharmaceutically acceptable salt thereof. [Chemical Formula 1a] In the above chemical formula 1a, R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl, R4 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, -NH-C(O)-R8, or -NH-S(O)(O)R8, where R8 is hydrogen, C 1-6 Alkyl, or C 1-6 It is fluoroalkyl, R5 is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl, R6 is , , or , wherein R' and R” are independently hydrogen, C 1-6 Alkyl, or C 1-6 It is fluoroalkyl, R7 is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is haloalkyl, L is a linker, m and n are independently 0, 1, 2, 3, or 4.

3. In paragraph 1 or 2, R1 is methyl, R2 is methyl, and R3 is C 1-6 An alkyl compound or a pharmaceutically acceptable salt thereof.

4. In paragraph 1 or 2, L is a compound represented by the following chemical formula 2 or a pharmaceutically acceptable salt thereof. [Chemical Formula 2] In the above chemical formula 2, C1 and C2 are independently a direct bond, aryl, heteroaryl, carbocycle, or heterocycle, wherein the aryl, heteroaryl, carbocycle, or heterocycle is optionally provided that one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-6 substituted with one or more of haloalkyl, or hydroxy, D1 and D2 are independently a direct bond, -O-, -N(R9)-, -C(O)-, -CC-, -C(O)NH-, or -NHC(O)-, where R9 is H, C 1-6 alkyl, or C 1-6 It is haloalkyl, q1, q2, q3, and q4 are independently 0, 1, 2, or 3.

5. In the fourth paragraph, in the chemical formula 2 C2 is a bivalent 4-7 membered monocyclic heterocycle, a 4-7 membered spiro heterocycle, or an 8-10 membered bicyclic heterocycle, q4 is 0, D2 is a direct bond, a compound or a pharmaceutically acceptable salt thereof.

6. In paragraph 4, L is , , , or A person, a compound or a pharmaceutically acceptable salt thereof.

7. In the second paragraph, the chemical formula 1a is 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)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 2), 2-(4-((1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 3), 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 4), 2-(4-((1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(methylsulfonamido)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 5), or A compound or a pharmaceutically acceptable salt thereof, which is 2-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-cyano-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-(2-methyl-2-(4-(4-methylthiazol-5-yl)phenyl)hydrazine-1-carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)acetamide (Compound 6).

8. A composition comprising a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for preventing or treating cancer or psoriasis having ALK and / or EGFR mutations, comprising a compound of any one of claims 2 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

10. A pharmaceutical composition according to claim 9, wherein the cancer is lung cancer, liver cancer, esophageal cancer, stomach 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, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastic tumor, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic myelofibrosis, inflammatory myofibroblastic sarcoma, or esophageal squamous cell carcinoma.

11. A pharmaceutical composition according to claim 10, wherein the cancer is lung cancer.

12. A method for treating or preventing cancer or psoriasis having ALK and / or EGFR mutations, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 2 to 7 or a pharmaceutically acceptable salt thereof.

13. In the 12th paragraph, the cancer is lung cancer, liver cancer, esophageal cancer, stomach 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, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastic tumor, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic myelofibrosis, inflammatory myofibroblastic sarcoma, or esophageal squamous cell carcinoma.

14. A method according to claim 13, wherein the cancer is lung cancer.

15. A method for producing a PROTAC compound, characterized in that the compound of the following chemical formula 3 is used as a von Hippel-Lindau (VHL) E3 ligase ligand. [Chemical Formula 3] In the above chemical formula 3, R1, R2 and R3 are independently hydrogen, halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl.

16. In the 15th paragraph, R1 is methyl, R2 is methyl, and R3 is C 1-6 Method for producing alkylene.

Images