Protac compound

Abstract

Provided is a novel PROTAC compound having an activity to induce the decomposition of BRD4.　Specifically provided is a compound having a structure represented by general formula (I) E3LLM-L-BETLM, or a salt or solvate of the compound.

Description

PROTAC compound

[0001] The present invention relates to a PROTAC compound in which an E3 ligand is linked to a ligand of a BET family protein via a linker.

[0002] It is estimated that approximately one in two people in Japan suffers from allergy-related diseases, and various anti-allergy compounds have been developed to date depending on the cause and symptoms. However, as the condition can become chronic or even fatal due to severe illness, further development of anti-allergy drugs is important.

[0003] In response to such demand, the present inventors have focused on the allergy-inducing cytokine TSLP and reported the following compound that inhibits its production (Patent Document 1). The present inventors have also reported that this compound targets BET family proteins (BRD2, BRD3, BRD4) and exerts anti-allergic effects through this (Non-Patent Document 1).

[0004] Furthermore, Juncheng Chen et al. have reported that BET family proteins are transcription factors involved in cancer and inflammation (Non-Patent Document 3).

[0005] In recent years, PROTACs have emerged as a drug discovery modality that induces the degradation of disease-causing proteins, and PROTACs that selectively induce the degradation of BRD4 have been developed. For example, Ciulli Alessio et al. have developed and commercially marketed a compound called MZ-1 shown below as a PROTAC compound that has BRD4 degradation activity (Patent Document 2). Furthermore, Jing Lu et al. have developed a compound called ARV-825 shown below as a PROTAC compound having BRD4 degradation activity (Non-Patent Document 2). Furthermore, Crew Andrew et al. have disclosed the following compound as a PROTAC compound having BRD4 degradation activity (Patent Document 4).

[0006] WO2016 / 159280A1 WO2016 / 146985A1 Special Table 2018-50946 Special Table 2017-513862

[0007] Ryosuke Segawa et al. , Biochem. Pharmacol. 2021, 194, 114819 Jing Lu et al. , Chemistry and Biology (2015) vol. 22, pp. 755-763 Juncheng Chen et al. , Journal of Medical Chemistry 2022, 65, 5184-5211

[0008] An object of the present invention is to provide novel PROTAC compounds that have the activity of inducing the degradation of BRD4.

[0009] The present inventors attempted to create novel PROTAC compounds that induce the degradation of BET family proteins, and found that the activity of inducing the degradation of a desired BET family protein can be obtained by linking a specific E3 ligase ligand to a specific BET family protein ligand via a specific linker, thereby completing the present invention.

[0010] More specifically, in one embodiment, the present invention provides: [1] a compound having a structure of the following general formula (I): E3LLM-L-BETLM... (I), or a salt or solvate thereof: [In formula (I), BETLM is a group represented by formula (II): (In formula (II), R １ , R ２ and R ３ each independently represents hydrogen or an alkyl group having 1 to 10 carbon atoms; and E3LLM is a BARD4 ligand module represented by formula (III): (Wherein, W is CHR Ｗ１ (R Ｗ１ is hydrogen or an alkyl group having 1 to 10 carbon atoms), C(O), S(O) ２ , and N.R. Ｗ２ (R Ｗ２ is hydrogen or alkyl having 1 to 10 carbon atoms; １ and X ２ are each independently —CHR Ｘ１ (R Ｘ１is hydrogen or alkyl having 1 to 10 carbon atoms), C(O), C(S), and NR Ｘ２ (R Ｘ２ is hydrogen or alkyl having 1 to 10 carbon atoms; Z is -CHR Ｚ１ (R Ｚ１ is hydrogen or alkyl having 1 to 10 carbon atoms), C(O), C(S), and NR Ｚ２ (R Ｚ２ is hydrogen, or alkyl having 1 to 10 carbon atoms; G is independently hydrogen, alkyl having 1 to 10 carbon atoms, OH, optionally R Ｇ１ 3- to 8-membered heterocyclyl optionally substituted with, and optionally R Ｇ２ 5- or 6-membered aryl, preferably phenyl, optionally substituted with R Ｇ１ and R Ｇ２ are each independently selected from the group consisting of hydrogen or alkyl having 1 to 10 carbon atoms; ４ and R ５ are independently hydrogen, alkyl having 1 to 10 carbon atoms, and optionally R ６ 3- to 8-membered cycloalkyl (R ６ is selected from the group consisting of: (CR Ｌ１ R Ｌ２ )n (n is an integer from 1 to 20), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and (O—(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3, and m is an integer of 1 to 10), Ｌ１ , and R Ｌ２ are each independently hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC １－８ Alkyl, NHC １－８ Alkyl, N(C１－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ cycloalkyl) ２ , N(C １－８ cycloalkyl)(C １－８ alkyl), OH, NH ２ , SH, S(O) ２ C １－８ Alkyl, P(O)(OC １－８ alkyl) (C １－８ alkyl), P(O)(OC １－８ alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH═CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , SF ５ , S(O) ２ NHC １－８ Alkyl, S(O) ２ N (C １－８ alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ alkyl), N(C １－８ alkyl)C(O)N(C １－８ alkyl) ２,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ alkyl) ２ , NHC(O)NH ２ , N(C １－８ alkyl)S(O) ２ NH (C １－８ alkyl), N(C １－８ alkyl)S(O) ２ N (C １－８ alkyl) ２ , NHS(O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ alkyl) ２ , or NHS(O) ２ NH ２ and the minimum number of atoms connecting both ends is 13 to 20.

[0011] In a preferred embodiment, the present invention also provides the following compound, or a salt or solvate thereof: [2] L is (CR Ｌ１ R Ｌ２ )n (n is an integer of 3 to 20). [3] The compound or salt or solvate thereof according to [1] or [2], wherein L represents a linker structure having a minimum number of atoms connecting both ends of the linker structure of 14 to 17. [4] L represents a linker structure represented by the formula: (In the formula, L １ (CR Ｌ１ R Ｌ２ )n (n is an integer from 1 to 20), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and (O—(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and optionally CR Ｌ１ =CR Ｌ２ , C≡C, O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２NR Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(R Ｌ３ ), N(R Ｌ３ )C(O)N(R Ｌ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), Si(R Ｌ１ ) (R Ｌ２ ), and optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ cycloalkyl, optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ heterocyclyl, optionally R Ｌ１ and / or R Ｌ２ a 5- or 6-membered monocyclic aromatic hydrocarbon optionally substituted with R Ｌ１ and / or R Ｌ２ and one or a combination of two or more of a 5- or 6-membered monocyclic aromatic heterocycle optionally substituted with R Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ cycloalkyl) ２ , N(C １－８ cycloalkyl)(C １－８ alkyl), OH, NH ２ , SH, S(O) ２ C １－８ Alkyl, P(O)(OC１－８ alkyl) (C １－８ alkyl), P(O)(OC １－８ alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH═CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , SF ５ , S(O) ２ NHC １－８ Alkyl, S(O) ２ N (C １－８ alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ alkyl), N(C １－８ alkyl)C(O)N(C １－８ alkyl) ２ ,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ alkyl) ２ , NHC(O)NH ２ , N(C １－８ alkyl)S(O) ２ NH (C １－８ alkyl), N(C １－８ alkyl)S(O) ２ N (C １－８ alkyl) ２ , NHS(O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ alkyl)２ , or NHS(O) ２ NH ２ [5] The compound according to any one of [1] to [3], or a salt or solvate thereof, wherein L １ (CR Ｌ１ R Ｌ２ )n (n is an integer from 3 to 10) and (C≡C)n (n is 1 or 2), or optionally R Ｌ１ and / or R Ｌ２ and one or a combination of two or more of 5- or 6-membered monocyclic aromatic heterocycles optionally substituted by (CR Ｌ１ R Ｌ２ )n (n is an integer of 1 to 3) and preferably in this order, Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms. １ is represented by the following general formula (VI) or (VII): ２ -L ３ -L ４ ... (VI) L ２ -XL ４ ...(VII) (in the formula, L ２ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as described in [4], preferably as described in [5], and n is an integer from 3 to 10; L ３ is (C≡C)n (n is 1 or 2), and X is Ar １ -Ar ２ , Het １ -Ar １ , Ar １ -Het １ , or Het １ -Het ２ and Ar １is a 5- or 6-membered monocyclic aromatic hydrocarbon or a 10- to 12-membered bicyclic fused aromatic hydrocarbon, and Ar ２ is a bond, a 5- or 6-membered monocyclic aromatic hydrocarbon, or a 10- to 12-membered bicyclic fused aromatic hydrocarbon; Het １ is a 5- or 6-membered monocyclic aromatic heterocycle, Het ２ is a bond, a 5- or 6-membered monocyclic aromatic heterocycle, or a 10- to 12-membered bicyclic fused aromatic heterocycle; L ４ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as described in [4], preferably as described in [5], n is an integer of 1 to 3, and L ２ is bonded to C(O) of formula (IV) or formula (IV′), and L ４ is bonded to O in formula (IV) or formula (IV'), or a salt or solvate thereof. [7] L ２ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as described in [4], preferably as described in [5], and n is an integer from 3 to 8, ３ is (C≡C)n (n is 1 or 2), and X is Het １ -Het ２ and Het １ is a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen atoms or sulfur atoms as ring-constituting atoms, and Het ２ [8] The compound according to [6], or a salt or solvate thereof, wherein X is a bond or a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen atoms as ring-constituting atoms. １ -Het ２ and Het １ is a 5-membered monocyclic aromatic heterocycle having two or more nitrogen atoms as ring-constituting atoms, and Het ２[9] The compound according to [7], or a salt or solvate thereof, wherein X is a bond or a 6-membered monocyclic aromatic heterocycle having one nitrogen atom as a ring-constituting atom. １ wherein Het １

[10] The compound according to [8], or a salt or solvate thereof, wherein X is a 5-membered monocyclic aromatic heterocycle having 2 or 3 nitrogen atoms as ring-constituting atoms. １ and Het １

[11] The compound according to [8], or a salt or solvate thereof, wherein L is a 5-membered monocyclic aromatic heterocycle having one sulfur atom as a ring-constituting atom.

[12] The compound according to any one of [4] to [9], or a salt or solvate thereof, wherein L １ is represented by the following general formula (XI) or (XII): [wherein n is an integer of 3 to 10, m is 0 or 1, and l is an integer of 0 to 10, and is bonded to C(O) in formula (IV) or (V) at the left end and to O in formulas (IV) and (V) at the right end.] The compound according to any one of [4] to

[11] , or a salt or solvate thereof, wherein L1 is a compound represented by the following general formula (XIII): [wherein n is an integer of 3 to 10, m is 0 or 1, and 1 is an integer of 0 to 10, and is bonded to C(O) in formula (XIII) or (XIV) at the left end and to O in formula (XIII) or (XIV) at the right end.] The compound according to any one of [4] to

[11] , or a salt or solvate thereof, wherein 1 is an integer of 1 or 2.

[14] The compound according to

[12] or

[13] , or a salt or solvate thereof, wherein 1 is an integer of 1 or 2.

[15]

[16] A compound selected from the group consisting of:

[17] A compound represented by the formula: A compound represented by the formula:

[0012] In another preferred embodiment, the present invention also provides a pharmaceutical use of the compound or a salt or solvate thereof. More specifically, the present invention provides the following pharmaceutical compositions, uses of the compound or a salt thereof for preparing a medicament, and methods for preventing or treating allergies or cancer.

[18] A pharmaceutical composition comprising the compound or a salt or solvate thereof according to any one of [1] to

[17] .

[19] The pharmaceutical composition according to

[18] , further comprising a pharmaceutically acceptable carrier.

[20] Use of the compound or a salt or solvate thereof according to any one of [1] to

[17] , or the pharmaceutical composition according to

[18] or

[19] , for preparing a medicament.

[21] The compound or a salt or solvate thereof according to any one of [1] to

[17] , or the pharmaceutical composition according to

[18] or

[19] , for preventing or treating allergies.

[22] The compound or a salt or solvate thereof, or the pharmaceutical composition according to

[21] , wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma, and allergic rhinitis.

[23] Use of the compound according to any one of [1] to

[17] or a salt or solvate thereof, or the pharmaceutical composition according to

[18] or

[19] , for preparing a medicament for preventing or treating allergies.

[24] The use according to

[23] , wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma, and allergic rhinitis.

[25] A method for preventing or treating allergies, comprising administering a therapeutically effective amount of the compound according to any one of [1] to

[17] or a salt or solvate thereof, or a therapeutically effective amount of the pharmaceutical composition according to

[18] or

[19] , to a patient in need thereof.

[26] The method according to

[25] , wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma, and allergic rhinitis.

[27] The compound according to any one of [1] to

[17] or a salt or solvate thereof, or the pharmaceutical composition according to

[18] or

[19] , for treating cancer.

[28] Use of the compound according to any one of [1] to

[17] or a salt or solvate thereof, or the pharmaceutical composition according to

[18] or

[19] , for preparing a medicament for treating cancer.

[29] A method for treating cancer, comprising administering a therapeutically effective amount of the compound according to any one of [1] to

[17] or a salt or solvate thereof, or a therapeutically effective amount of the pharmaceutical composition according to

[18] or

[19] , to a patient in need thereof.

[0013] Here, definitions of some terms used in the present specification are provided. "PROTAC" is an abbreviation for Proteolysis Targeting Chimera and refers to a compound that induces targeted protein degradation. The compound of the present invention is a PROTAC that links an E3 ligase ligand and a BET ligand via a linker and induces the degradation of BET family proteins. "E3 ligase" is a type of "ubiquitin ligase" and is a protein of the ubiquitin ligase family that promotes the transfer of ubiquitin to a specific substrate protein, thereby polyubiquitinating the substrate protein and targeting the substrate protein for degradation. "BET (bromodomain and extraterminal domain)" proteins are proteins consisting of repeated bromodomain sequences and specific terminal sequences that recognize acetylated histones and regulate gene transcription through the recruitment of transcription factors. Known BET proteins include BRD2, BRD3, BRD4 (also known as MCAP), and BRDT, and these BET proteins are thought to play important roles in cellular processes such as inflammation-related gene expression, cell division, and virus / host interactions.

[0014] The terms "alkyl" and "alkyl group" mean a straight or branched chain saturated hydrocarbon group having the general formula: -C ｎ H ２ｎ＋１The term "alkyl" is used alone to represent a substituent or as part of a larger substituent or structure. Examples of alkyl include methyl, ethyl, propyl (e.g., propan-1-yl, propan-2-yl (or isopropyl)), butyl (e.g., 2-methylpropan-2-yl (or tert-butyl), butan-1-yl, butan-2-yl), pentyl (e.g., pentan-1-yl, pentan-2-yl, pentan-3-yl), 2-methylbutan-1-yl, 3-methylbutan-1-yl, hexyl (e.g., hexan-1-yl), heptyl, octyl, nonyl, decyl, and the like.

[0015] The terms "alkenyl" and "alkenyl group" refer to a straight- or branched-chain unsaturated hydrocarbon group having one double bond. The term "alkenyl" may be used alone to represent a substituent or as part of a larger substituent or structure. Examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, and 5-hexenyl.

[0016] The terms "alkynyl" and "alkynyl group" refer to a straight or branched chain unsaturated hydrocarbon group having one triple bond. The term "alkynyl" may be used alone to represent a substituent or as part of a larger substituent or structure. Examples of alkynyl include 2-propynyl, 2-butynyl, and 1,3-hexadien-5-ynyl.

[0017] The term "alkylene," when used, includes -(CH ２ ) ｎ- (where n is, for example, an integer of 1 to 10). "Alkenylene" refers to a divalent group formed by the loss of two hydrogen atoms from an aliphatic hydrocarbon having one double bond in the molecule. "Alkynylene" refers to a divalent group formed by the loss of two hydrogen atoms from an aliphatic hydrocarbon having one triple bond in the molecule.

[0018] The term "alkoxy" refers to a radical of the formula -OR, where R is alkyl, and may represent a substituent by itself or may represent a part of a larger substituent or structure. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., 1-propoxy, 2-propoxy), butoxy (e.g., 1-butoxy, 2-butoxy, 2-methyl-2-propoxy), pentyloxy (1-pentyloxy, 2-pentyloxy), hexyloxy (1-hexyloxy, 3-hexyloxy), and the like.

[0019] The term "aromatic hydrocarbon" refers to a hydrocarbon group having a monocyclic or polycyclic ring structure composed of carbon atoms with alternating single and double bonds and delocalized electrons, and is used alone to represent a substituent or as part of a larger substituent or structure. The term "aromatic hydrocarbon" can refer to a monovalent group alone or to a divalent group as part of a larger substituent or structure. When referring to a monovalent group, the term "aromatic hydrocarbon" is used interchangeably with the term "aryl." The term "x to y-membered aromatic hydrocarbon" refers to an aromatic hydrocarbon whose ring is composed of x to y carbon atoms. Aromatic hydrocarbons include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, and the like.

[0020] The term "aromatic heterocycle" means a monocyclic or polycyclic group having a ring structure with alternating single and double bonds, resulting in electron delocalization, and containing heteroatoms other than carbon atoms as ring atoms. The term "aromatic heterocycle" can refer to a monovalent group alone or to a divalent group as part of a larger substituent or structure. When referring to a monovalent group alone, the term "aromatic heterocycle" is used interchangeably with the term "heteroaryl." The term "x-y membered aromatic heterocycle" means an aromatic heterocycle whose ring is composed of x-y atoms (including carbon and heteroatoms other than carbon atoms). Examples of aromatic heterocycles include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; and benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyridine, and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as pyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0021] The term "heterocyclyl" refers to a monocyclic or polycyclic group having a saturated ring structure containing heteroatoms other than carbon atoms as ring constituent atoms, and is used alone as a substituent or as part of a larger substituent or structure. When alone representing a substituent, the term "heterocyclyl" refers to a monovalent group, but when used as part of a larger substituent or structure, it can refer to a divalent group. The term "x to y-membered heterocyclyl" refers to a heterocyclyl whose ring consists of x to y atoms (including heteroatoms other than carbon and carbon atoms). Polycyclic heterocyclyls include bicyclic and tricyclic heterocyclyls. Polycyclic heterocyclyls also include bridged rings and spirocyclic rings. "Heterocyclyl" typically includes saturated heterocyclic groups containing one or more (e.g., 1 to 3) heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Heterocyclyls containing one heteroatom include aziridinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, including but not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl. Heterocyclyls containing two heteroatoms include dioxolanyl, oxathiolanyl, thiazolidinyl, dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl. Heterocyclyls containing three heteroatoms include triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl.Bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, phenanthridinyl, Indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0022] The term "cycloalkyl" is used interchangeably with the term "alicyclic saturated hydrocarbon" and refers to a monocyclic or polycyclic saturated cyclic hydrocarbon group. Furthermore, the term "cycloalkyl" may be used alone to represent a substituent or as part of a larger substituent or structure; when alone representing a substituent, it refers to a monovalent group, but when used as part of a larger substituent or structure, it may refer to a divalent or higher-valent group. The term "x to y-membered cycloalkyl" refers to a monocyclic or polycyclic saturated cyclic hydrocarbon group whose ring consists of x to y carbon atoms. Polycyclic cycloalkyls include bicyclic and tricyclic cycloalkyls. Polycyclic cycloalkyls also include bridged ring hydrocarbons and spiro hydrocarbons. Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctadienyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, and the like.

[0023] The term "carboxy" refers to the group --C(O)OR, where R is, for example, hydrogen, alkyl, aryl, or heteroaryl.

[0024] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, or iodine and are used to represent a substituent alone or as part of a larger substituent or structure. "Halide" and "halide" refer to compounds to which a halogen has been added, such as fluoride, chloride, bromide, and iodide.

[0025] The term "cycloalkoxy" refers to a group of the formula: -OR (where R is cycloalkyl), and may represent a substituent alone or may represent a part of a larger substituent or structure. When the term "cycloalkoxy" represents a substituent alone, it represents a monovalent group, but when used as part of a larger substituent or structure, it may refer to a divalent or higher valent group. In addition, the term "x to y-membered cycloalkoxy" refers to a cycloalkyl in which the cycloalkyl ring is composed of x to y carbon atoms. Examples of "cycloalkoxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0026] The term "alkylthio" refers to a group of the formula: -SR, where R is alkyl, either alone as a substituent or as part of a larger substituent or structure. When alone as a substituent, the term "alkylthio" refers to a monovalent group, but when used as part of a larger substituent or structure, it can refer to a divalent or higher valent group. ｘ－ｙ The term "alkylthio" means an alkylthio group having x to y carbon atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, and the like.

[0027] The terms "alkylsulfonyl," "cycloalkylsulfonyl," and "heterocyclosulfonyl" refer to groups of the formula: -S(O) ２"Alkyl sulfonyl" refers to a group represented by -R (wherein R is alkyl, cycloalkyl, or heterocyclyl, respectively), which may represent a substituent alone or may represent a part of a larger substituent or structure. Examples of "alkylsulfonyl groups" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. The term "arylsulfonyl" is used in the same manner as above, and examples of "arylsulfonyl" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0028] The terms "alkylcarbonyl," "cycloalkylcarbonyl," and "heterocyclocarbonyl" refer to groups of the formula -C(O)-R, where R is alkyl, cycloalkyl, and heterocyclyl, respectively, and may represent a substituent alone or a part of a larger substituent or structure. The term "x to y-membered cycloalkylcarbonyl" refers to a cycloalkylcarbonyl in which the cycloalkyl ring is made up of x to y carbon atoms, and the term "x to y-membered heterocyclocarbonyl" refers to a heterocyclocarbonyl in which the heterocyclo ring is made up of x to y atoms (including heteroatoms other than carbon and carbon atoms). Examples of "alkylcarbonyl" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, and the like.

[0029] The term "ester" refers to an ester of the formula: -R-C(O)O-R'-, where R is C １－３ The term "ether" refers to a structure represented by the formula -R-O-R'- (R and R' are each substituents such as an alkyl group or an aromatic hydrocarbon group), and "ether compound" refers to a compound having an ether.

[0030]

[0049] Figure 1 shows a Western blot image of a cell treatment solution obtained by treating KCMH-1 cells for 24 hours with a dimethyl sulfoxide solution containing the compound (MZ-1) of Comparative Example 8, the compound (TKP-3) of Example 2, the compound (TKP-1) of Comparative Example 1, or the compound (TKP-2) of Comparative Example 2 at a concentration of 10 μM.

[0050] Figure 1 shows a Western blot image of a cell treatment solution obtained by treating KCMH-1 cells for 2 hours with the compound (MZ-1) of Comparative Example 8, the compound (TKP-5) of Example 1, the proteasome inhibitor MG132, the compound (MZ-1) of Comparative Example 8 and MG132, or the compound (TKP-5) and MG132 of Example 1. The figure shows a Western blot image of the cell treatment solution obtained by treating KCMH-1 cells for 24 hours with a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1), the compound of Comparative Example 2 (TKP-2), the compound of Comparative Example 1 (TKP-1), the compound of Example 2 (TKP-3), the compound of Comparative Example 3 (TKP-4), the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), the compound of Comparative Example 4 (TKP-7), the compound of Comparative Example 5 (TKP-8), the compound of Example 4 (TKP-9), the compound of Example 5 (TKP-10), or the compound of Example 6 (TKP-11) at a concentration of 10 μM. 1 is a graph showing the results of measuring the TSLP concentration in the culture supernatant obtained by treating KCMH-1 cells for 24 hours with dimethyl sulfoxide solutions containing the compound of Comparative Example 8 (MZ-1), the compound of Example 1 (TKP-5), the compound of Example 9 (TKP-16), or the compound of Example 10 (TKP-17), at different concentrations of 0.1, 0.3, and 1 μM for each compound. The graph shows Western blot images of the cell treatment solution obtained by treating KCMH-1 cells for 24 hours with dimethyl sulfoxide solutions containing the compound of Comparative Example 8 (MZ-1), the compound of Example 1 (TKP-5), the compound of Example 9 (TKP-16), or the compound of Example 10 (TKP-17), at different concentrations of 0.1, 0.3, and 1 μM for each compound. 1 is a graph showing the results of measuring the TSLP concentration in the culture supernatant obtained by treating KCMH-1 cells for 2 hours with a dimethyl sulfoxide solution containing the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), or the compound of Example 8 (TKP-14) at a concentration of 1 μM.1 is a graph showing the results of measuring the TSLP concentration in the culture supernatant obtained by treating KCMH-1 cells for 24 hours with dimethyl sulfoxide solutions containing the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), or the compound of Example 8 (TKP-14), at different concentrations of 0.1, 0.3, and 1 μM for each compound. FIG. 1 shows a Western blot image of the cell treatment solution obtained by treating KCMH-1 cells for 24 hours with dimethyl sulfoxide solutions containing the compound of Comparative Example 8 (MZ-1) or the compound of Example 1 (TKP-5), at concentrations of 0.01, 0.03, 0.1, 0.3, or 1 μM.

[0039] Figure 1 shows a Western blot image of a cell treatment solution obtained by adding a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1) or the compound of Example 1 (TKP-5) at a concentration of 1 μM and treating KCMH-1 cells for 2, 4, 8, 12, or 24 hours.

[0040] Figure 1 shows a Western blot image of a cell treatment solution obtained by adding a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1) or the compound of Example 1 (TKP-5) at a concentration of 1 μM and treating KCMH-1 cells for 2 hours, followed by holding the cells in compound-free medium for 0, 4, 8, 12, or 24 hours.

[0050] Figure 1 shows a Western blot image of a cell treatment solution obtained by adding a dimethyl sulfoxide solution containing the compound of Example 1 (TKP-5), the compound of Example 11 (TKP-21), or the compound of Example 12 (TKP-22) at a concentration of 1 μM and treating KCMH-1 cells for 24 hours. 1 shows a Western blot image of the cell treatment solution obtained by treating KCMH-1 cells for 24 hours with a dimethyl sulfoxide solution containing the compound of Example 13 (TKP-33) at a concentration of 0.01, 0.1, or 1.0 μM.

[0031] The present invention will be described in detail below with reference to the preferred embodiments, but the present invention should not be understood as being limited to the following embodiments.

[0032] In one embodiment, the present invention relates to a PROTAC compound in which a specific E3 ligand is linked to a specific BET family protein ligand via a specific linker, and the PROTAC compound exhibits the activity of inducing degradation of BET family proteins. Therefore, in another embodiment, the present invention relates to a pharmaceutical use of the PROTAC compound, as described in detail below.

[0033] 1. PROTAC Compound The PROTAC compound according to one embodiment of the present invention is a compound having a structure represented by general formula (I): E3LLM-L-BETLM ... (I) or a salt thereof.

[0034] In the above formula (I), BETLM is a compound represented by the formula (II): The ligand module of the BET family protein (BARD4 ligand module) is represented by the formula: １ , R ２ and R ３ are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms, and R １ and R ２ At least one of R is an alkyl group having 1 to 10 carbon atoms. １ , R ２ and R ３ are each independently hydrogen or an alkyl group having 1 to 3 carbon atoms, and R １ and R ２ At least one of R is an alkyl group having 1 to 3 carbon atoms. １ and R ２ is an alkyl group having 1 to 3 carbon atoms, and R ３is hydrogen. Examples of alkyl groups having 1 to 10 carbon atoms include methyl, ethyl, propyl (e.g., propan-1-yl, propan-2-yl (or isopropyl)), butyl (e.g., 2-methylpropan-2-yl (or tert-butyl), butan-1-yl, butan-2-yl), pentyl (e.g., pentan-1-yl, pentan-2-yl, pentan-3-yl), 2-methylbutan-1-yl, 3-methylbutan-1-yl, hexyl (e.g., hexane-1-yl), heptyl, octyl, nonyl, and decyl. Examples of alkyl groups having 1 to 3 carbon atoms include methyl, ethyl, and propyl (e.g., propan-1-yl, propan-2-yl (or isopropyl)).

[0035] In the above formula (I), E3LLM is represented by formula (III): where W is a CHR Ｗ１ (R Ｗ１ is hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms), C(O), S(O) ２ , and N.R. Ｗ２ , (R Ｗ２ is selected from the group consisting of hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, and is preferably C(O). １ and X ２ are each independently CHR Ｘ１ (R Ｘ１ is hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms), C(O), C(S), S(O) ２ , and N.R. Ｘ２ , (R Ｘ２ is hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms), and preferably CHR Ｘ１ (R Ｘ１is hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms) or C(O), more preferably C(O). Ｚ１ (R Ｚ１ is hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms), C(O), C(S), S(O) ２ , and N.R. Ｚ２ (R Ｚ２ is selected from the group consisting of hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, and preferably C(O). In the formula, G is independently hydrogen, an alkyl group having 1 to 10 carbon atoms, OH, and optionally R Ｇ１ 3- to 8-membered heterocyclyl optionally substituted with, and R Ｇ２ a benzene ring optionally substituted with R Ｇ１ and R Ｇ２ are each independently hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms. G is preferably hydrogen or an alkyl group having 1 to 10 carbon atoms, more preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, and particularly preferably H. In the formula, R ４ and R ５ are independently hydrogen, an alkyl group having 1 to 10 carbon atoms, and optionally R ６ 3- to 8-membered, preferably 3- to 6-membered cycloalkyl (R ６ is selected from the group consisting of hydrogen or an alkyl group having 1 to 10 carbon atoms, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, and halogen (preferably Cl and F). ４ and R ５are preferably each independently hydrogen or an alkyl group having 1 to 3 carbon atoms, and particularly preferably hydrogen. As will be shown in the Examples below, the present inventors have confirmed that when E3LLM was used as the VHL ligand constituting PROTAC described in Non-Patent Document 2, which is also known as an E3 ligase ligand, the desired PROTAC activity could not be obtained.

[0036] In an embodiment of the present invention, the above-mentioned E3 ligase ligand module (E3LLM) and BET family protein ligand module (BETLM) are chemically linked via a specific linker, thereby functioning as a PROTAC.

[0037] As shown in the Examples below, the present inventors have also conducted various studies on linkers linking BETLM and E3LLM, and have found that BRD4 degradation-inducing activity can be achieved by linking them via a linker having a structure in which the minimum number of atoms linking both ends is 13 to 20. In this specification, the "minimum number of atoms linking both ends" refers to the number of atoms constituting a line, when a line is imagined that connects both ends bound to BETLM and E3LLM, respectively, with the minimum number of consecutive atoms, in the linker structure. For example, In this case, the "minimum number of atoms" is 8. In this case, the "minimum number of atoms connecting both ends" is 7. The "minimum number of atoms connecting both ends" is a simple indicator that alternatively indicates the distance between the E3 ligase ligand module (E3LLM) and the BET family protein ligand module (BETLM), and is an important factor for the E3 ligase ligand (E3LL) and the BET family protein ligand (BETL) to exert their respective functions, as will be shown in the Examples below.

[0038] As will be shown in the examples below, the minimum number of atoms connecting both ends is preferably 13 to 20, more preferably 14 to 17, and particularly preferably 14 to 16.

[0039] In a preferred embodiment, the linker has the following formula (IV) or formula (IV'): It has the structure shown by:

[0040] L １ can be composed of various atoms and structures, for example, (CR Ｌ１ R Ｌ２ ) n (n is an integer from 1 to 20), CR Ｌ１ =CR Ｌ２ , C≡C, ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), (O-(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3 and m is an integer of 1 to 10), O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２ NR Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(R Ｌ３ ), N(R Ｌ３ )C(O)N(R Ｌ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), Si(R Ｌ１ ) (R Ｌ２ ), and optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ cycloalkyl, optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ heterocyclyl, optionally R Ｌ１ and / or R Ｌ２ 5- or 6-membered aryl optionally substituted with R Ｌ１ and / or R Ｌ２ In each formula, R may be composed of one or more 5- or 6-membered heteroaryls optionally substituted with Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC１－８ Alkyl, NHC １－８ Alkyl, N(C １－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ cycloalkyl) ２ , N(C １－８ cycloalkyl)(C １－８ alkyl), OH, NH ２ , SH, S(O) ２ C １－８ Alkyl, P(O)(OC １－８ alkyl) (C １－８ alkyl), P(O)(OC １－８ alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH═CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , SF ５ , S(O) ２ NHC １－８ Alkyl, S(O) ２ N (C １－８ alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ alkyl), N(C １－８alkyl)C(O)N(C １－８ alkyl) ２ ,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ alkyl) ２ , NHC(O)NH ２ , N(C １－８ alkyl)S(O) ２ NH (C １－８ alkyl), N(C １－８ alkyl)S(O) ２ N (C １－８ alkyl) ２ , NHS(O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ alkyl) ２ , or NHS(O) ２ NH ２ and preferably hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, or C １－８ Alkoxy, preferably hydrogen, halogen, OH, NH ２ , SH, or C １－５ alkyl, more preferably hydrogen, OH, or a carbon number C １－３ It is preferably alkyl, and particularly preferably hydrogen.

[0041] Preferably, L １ (CR Ｌ１ R Ｌ２ ) n (n is an integer from 1 to 20), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and (O—(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and optionally CR Ｌ１ =CR Ｌ２ , C≡C, O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２ NR Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(RＬ３ ), N(R Ｌ３ )C(O)N(R Ｌ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), Si(R Ｌ１ ) (R Ｌ２ ), and optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ cycloalkyl, optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ heterocyclyl, optionally R Ｌ１ and / or R Ｌ２ 5- or 6-membered aryl optionally substituted with R Ｌ１ and / or R Ｌ２ and a combination of two or more of 5- or 6-membered heteroaryls optionally substituted with R. Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ cycloalkyl) ２ , N(C １－８ cycloalkyl)(C １－８ alkyl), OH, NH ２ , SH, S(O) ２ C １－８ Alkyl, P(O)(OC １－８ alkyl) (C １－８ alkyl), P(O)(OC１－８ alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH═CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , SF ５ , S(O) ２ NHC １－８ Alkyl, S(O) ２ N (C １－８ alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ alkyl), N(C １－８ alkyl)C(O)N(C １－８ alkyl) ２ ,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ alkyl) ２ , NHC(O)NH ２ , N(C １－８ alkyl)S(O) ２ NH (C １－８ alkyl), N(C １－８ alkyl)S(O) ２ N (C １－８ alkyl) ２ , NHS(O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ alkyl) ２ , or NHS(O) ２ NH ２and preferably hydrogen, halogen, OH, NH ２ , S.H., C. １－８ Alkyl, or carbon C １－８ Alkoxy, preferably hydrogen, halogen, OH, NH ２ , SH, or C １－５ alkyl, more preferably hydrogen, OH, or a carbon number C １－３ It is preferably alkyl, and particularly preferably hydrogen.

[0042] L １ is more preferably (CR Ｌ１ R Ｌ２ )n (n is an integer from 3 to 10), and (C≡C)n (n is 1 or 2), and / or optionally R Ｌ１ and / or R Ｌ２ one or a combination of two or more of 5- or 6-membered heteroaryl optionally substituted with (C≡C)n (n is 1 or 2), and optionally R Ｌ１ and / or R Ｌ２ or a combination of two or more of 5- or 6-membered monocyclic aromatic heterocycles optionally substituted with R Ｌ１ and / or R Ｌ２ and one or a combination of two or more of 5- or 6-membered monocyclic aromatic heterocycles optionally substituted by (CR Ｌ１ R Ｌ２ )n (n is an integer of 1 to 3), and are preferably linked in this order. Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms, and preferably hydrogen, halogen, OH, NH ２ , SH, or an alkyl group having 1 to 5 carbon atoms, more preferably hydrogen, OH, or an alkyl group having 1 to 3 carbon atoms, and particularly preferably hydrogen.

[0043] L １ More preferably, L is a structure represented by the following general formula (VI) or (VII):２ -L ３ -L ４ ... (VI) L ２ -XL ４ ...(VII) In the formula, L ２ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ are as described above, and preferably each independently represents hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms, and more preferably hydrogen, halogen, OH, NH ２ , SH, or an alkyl group having 1 to 5 carbon atoms, more preferably hydrogen, OH, or an alkyl group having 1 to 3 carbon atoms, particularly preferably hydrogen. n is an integer of 2 to 10, preferably 3 to 8, and more preferably 4 to 7.

[0044] L in the ceremony ４ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ are as described above, and preferably each independently represents hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms, and more preferably hydrogen, halogen, OH, NH ２ , SH, or an alkyl group having 1 to 5 carbon atoms, more preferably hydrogen, OH, or an alkyl group having 1 to 3 carbon atoms, and particularly preferably hydrogen. n is an integer of 1 to 5, preferably an integer of 1 to 3, and particularly preferably 1. ２ is bonded to C(O) of formula (IV) or formula (IV′), and L ４ is bonded to O in formula (IV) or formula (IV').

[0045] L in the ceremony ３ is (C≡C)n (n is 1 or 2), or C≡C-Het １ -Het ２ and preferably (C≡C) ２ or C≡C-Het １-Het ２ is.

[0046] In the formula, X is Ar １ -Ar ２ , Het １ -Ar １ , Ar １ -Het １ , or Het １ -Het ２ Ar １ is a 5- or 6-membered monocyclic aromatic hydrocarbon or a 10- to 12-membered bicyclic fused aromatic hydrocarbon, and is a 5- or 6-membered monocyclic aromatic hydrocarbon, preferably a benzene ring. ２ Het is a bond, a 5- or 6-membered monocyclic aromatic hydrocarbon, or a 10- to 12-membered bicyclic fused aromatic hydrocarbon, preferably a bond or a 5- or 6-membered monocyclic aromatic hydrocarbon, more preferably a bond or a benzene ring, and particularly preferably a bond. １ is a 5- or 6-membered monocyclic aromatic heterocycle, preferably a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen or sulfur atoms as ring-constituting atoms, more preferably a 5-membered monocyclic aromatic heterocycle having two or more nitrogen atoms or one sulfur atom as ring-constituting atoms, even more preferably a 5-membered monocyclic aromatic heterocycle having two or three nitrogen atoms or one sulfur atom as ring-constituting atoms, and particularly preferably a triazole, particularly 1,2,3-triazole, or thiophene. ２ represents a bond, a 5- or 6-membered monocyclic aromatic heterocycle, or a 10- to 12-membered bicyclic fused aromatic heterocycle, preferably a bond or a 5- or 6-membered monocyclic aromatic heterocycle, more preferably a bond or a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen atoms as ring-constituting atoms, even more preferably a bond or a 6-membered monocyclic aromatic heterocycle having one or two nitrogen atoms as ring-constituting atoms, still more preferably a bond or pyridine, and particularly preferably a bond.

[0047] In the embodiment of formula (VII), X is preferably Het １ -Het ２ In embodiments of formula (VI) and (VII), Het １ is a 5- or 6-membered monocyclic aromatic heterocycle, preferably a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen or sulfur atoms as ring-constituting atoms, more preferably a 5-membered monocyclic aromatic heterocycle having two or more nitrogen atoms or one sulfur atom as ring-constituting atoms, even more preferably a 5-membered monocyclic aromatic heterocycle having two or three nitrogen atoms or one sulfur atom as ring-constituting atoms, and particularly preferably a triazole, particularly 1,2,3-triazole, or thiophene. ２ is a bond or a 5- or 6-membered monocyclic aromatic heterocycle, preferably a bond or a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen atoms as ring-constituting atoms, more preferably a bond or a 6-membered monocyclic aromatic heterocycle having one or two nitrogen atoms as ring-constituting atoms, even more preferably a bond or pyridine, and particularly preferably a bond.

[0048] In a preferred embodiment, L has the formula: The linker is particularly preferably a linker having the structure (substituted at the meta or para position) represented by the formula: It is a linker having the structure (substituted at the para position) represented by the formula:

[0049] L １ is particularly preferably represented by the following general formula (XI) or (XII): In the formula, n is an integer of 3 to 10, preferably an integer of 3 to 8. m is 0 or 1, preferably 0. l is an integer of 0 to 10, preferably 1 to 3, particularly preferably 1, and is bonded to C(O) in formulas (IV), (V) and (VI) at the left end and to O in formulas (IV), (V) and (VI) at the right end.

[0050] Specific examples of the compound represented by formula (I) include: and in particular compounds selected from the group consisting of the following formula: Preferred is a compound represented by the following formula:

[0051] 2. Production Method The compound of formula (I) can be synthesized by known reactions such as click reaction, in-yne heterocoupling reaction, condensation reaction of an amine with a carboxylic acid, condensation reaction of an amine with a carboxylic acid derivative, alkylation reaction, synthesis of an ether by reaction of a hydroxyl group with a halide, halo-yne coupling reaction, [3+2] cycloaddition reaction, and [4+2] cycloaddition reaction, and each reaction is described in detail, for example, in Experimental Chemistry Lectures (Maruzen), 5th Edition, Vol. 13 to 19, edited by the Chemical Society of Japan. The contents of that publication are incorporated herein by reference.

[0052] Representative synthesis schemes for compound (I) include a click reaction shown in the following reaction scheme, and a reaction between an E3 ligase ligand (E3LL) derivative and a BET family protein ligand (BETL) derivative by in-in heterocoupling reaction. Halo in each formula is halogen. １ , R ２ and R ３ is as shown in formula (II). １ , X ２ , Z., G., R. ４ and R ５ is as described in formula (III). １ ' is (CR Ｌ１ R Ｌ２ ) n (n is an integer from 1 to 10), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and (O—(CR Ｌ１ R Ｌ２)n)m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and optionally at least one of O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２ NR Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(R Ｌ３ ), N(R Ｌ３ )C(O)N(R Ｌ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), and Si(R Ｌ１ ) (R Ｌ２ In each formula, R Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are as described in formula (IV), and preferably each independently represents hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms. １ ' is preferably (CR Ｌ１ R Ｌ２ ) n (n is an integer from 3 to 10).

[0053] L in each formula ２ ' is (CR Ｌ１ R Ｌ２ ) n (n is an integer of 1 to 3), CR Ｌ１ =CR Ｌ２ , ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer of 1 to 3, and m is an integer of 1 to 3), (O-(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3 and m is an integer of 1 to 3), O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２ NR Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(R Ｌ３ ), N(R Ｌ３ )C(O)N(RＬ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), Si(R Ｌ１ ) (R Ｌ２ ), and optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ cycloalkyl, optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ heterocyclyl, optionally R Ｌ１ and / or R Ｌ２ 5- or 6-membered aryl optionally substituted with R Ｌ１ and / or R Ｌ２ In each formula, R may be composed of one or a combination of two or more selected from the group consisting of 5- or 6-membered heteroaryls optionally substituted with Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are as described in formula (IV), and preferably each independently represents hydrogen, halogen, OH, NH ２ , SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms, and more preferably hydrogen, halogen, OH, NH ２ , SH, or an alkyl group having 1 to 5 carbon atoms, more preferably hydrogen, OH, or an alkyl group having 1 to 3 carbon atoms, and particularly preferably hydrogen. ２ ' is preferably (CR Ｌ１ R Ｌ２ ) n (n is an integer of 1 to 3) and R Ｌ１ and / or R Ｌ２ and more preferably, (Het)m-Alk (wherein Het is R Ｌ１ and / or R Ｌ２ wherein m is 0 or 1; and Alk is (CR Ｌ１ R Ｌ２)n (n is an integer of 1 to 3), preferably (CH ２ ) n (n is an integer of 1 to 2).

[0054] Furthermore, as will be demonstrated in the Examples below, derivatives of the ligand (BETL) of the BET family protein can be synthesized, for example, according to the following scheme.

[0055] Furthermore, as will be demonstrated in the Examples below, derivatives (azide compounds) of the E3 ligase ligand (E3LL) can also be synthesized, for example, according to the following scheme.

[0056] 3. Salts The compounds of the present invention include salts of the compound of Formula (I), and salts of the compound of Formula (I) include acid addition salts and salts with bases. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate; organic acid salts such as oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; and acidic amino acid salts such as glutamate and aspartate. Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt, and calcium salt; salts with organic bases such as pyridine salt and triethylamine salt; and salts with basic amino acids such as lysine and arginine. These salts can be formed using methods well known in the art.

[0057] 4. Solvates (Hydrates) and Geometric Isomers The compound of formula (I) and its salts may exist in the form of solvates, including hydrates, and these solvates are also encompassed by the compounds of the present invention. Examples of solvents that form solvates include water, alcohols such as ethanol and propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone, and dimethyl sulfoxide.

[0058] Furthermore, the compound of formula (I) and its salts may exhibit geometric isomerism because it has a carbon-carbon double bond in the divalent group -CH=CH-(C=O)- connecting the two benzene rings. Therefore, unless otherwise specified, the compound of formula (I) and its salts or solvates include these geometric isomers, with the (E) form (trans form) being preferred.

[0059] 5. Application to Pharmaceutical Uses, Such as Pharmaceutical Compositions and Treatment Methods The compound of formula (I) or its salt or solvate has the activity of inducing the degradation of BRD4 and can be used for the prevention or treatment of diseases involving BRD4. Diseases involving BRD4 include allergic diseases and cancer, and the compound of formula (I) or its salt or solvate, or a pharmaceutical composition containing the same, can be used as an antiallergic agent or anticancer agent. Examples of allergic diseases include atopic dermatitis, allergic bronchial asthma, and allergic rhinitis, and the compound is preferably used as a therapeutic agent for atopic dermatitis. Examples of cancers include leukemia, lung cancer, colon cancer, central nervous system cancer, prostate cancer, skin cancer, ovarian cancer, breast cancer, and kidney cancer, and the compound is preferably used as a therapeutic agent for these cancers. The association of BRD4 with these cancers is described in detail in Fei Jiang et al., Bioorganic & Medicinal Chemistry Volume 28, Issue 1, 1 January 2020, 115181, the contents of which are incorporated herein by reference.

[0060] The compound of formula (I) or a salt or solvate thereof may be used as an antiallergic agent or anticancer agent as it is, but is usually used as a pharmaceutical composition containing various pharmaceutically acceptable carriers (e.g., isotonicity agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, solubilizing agents, thickeners, etc.).

[0061] Examples of isotonic agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, and sorbitol, polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol, and inorganic salts such as sodium chloride, potassium chloride, and calcium chloride. Examples of chelating agents include edetate salts such as disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or a salt thereof, sodium hexametaphosphate, and citric acid.

[0062] The stabilizer may, for example, be sodium hydrogen sulfite.

[0063] Examples of pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, as well as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol.

[0064] Examples of preservatives include sorbic acid, potassium sorbate, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, quaternary ammonium salts such as chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine.

[0065] Antioxidants include, for example, sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the like.

[0066] Examples of solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc. Examples of thickening agents include polyethylene glycol, methylcellulose, ethylcellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. Furthermore, the pharmaceutical composition may further contain, in addition to compound (I) or a salt thereof, a compound known to have antiallergic or anticancer activity.

[0067] In an embodiment of the pharmaceutical composition, the content of the compound of formula (I) or a salt or solvate thereof in the composition is not particularly limited and can be appropriately set based on conditions such as, for example, 90% by mass or more, 70% by mass or more, 50% by mass or more, 30% by mass or more, 10% by mass or more, 5% by mass or more, or 1% by mass or more in terms of the content of the compound of formula (I).

[0068] The dosage form is not particularly limited, and examples thereof include various dosage forms such as oral administration preparations such as tablets, pills, capsules, powders, granules, and syrups; and parenteral administration preparations such as injections (intravenous injection, intramuscular injection, local injection, etc.), mouthwashes, infusions, topical preparations (ointments, creams, patches, inhalants), and suppositories. Among the above dosage forms, preferred antiallergic agents include topical preparations (ointments, creams, patches, inhalants), etc. The compound of formula (I) or a salt or solvate thereof targets TSLP produced by epithelial cells, rather than lymphocytes, and is therefore expected to have an antiallergic effect when used as a topical preparation.

[0069] Furthermore, preferred anticancer agents include, for example, oral administration agents and injections. The content of the compound of formula (I) or its salt or hydrate in the formulation varies depending on the route of administration, the patient's age, weight, symptoms, etc., and cannot be generally specified, but it is sufficient to set the amount so that the daily dose is usually about 10 to 5,000 mg, more preferably about 100 to 1,000 mg, in terms of the compound of formula (I). When administered once a day, this amount needs to be contained in one formulation, and when administered three times a day, one third of this amount needs to be contained in one formulation.

[0070] The subjects to which the compounds or pharmaceutical compositions of the present invention are administered are usually mammals, including humans, monkeys, mice, rats, rabbits, cats, dogs, pigs, cows, horses, sheep, etc.

[0071] The present invention will be described in more detail below with reference to examples, but is not limited to these. In the examples, "parts" means parts by mass and "%" means % by mass.

[0072] 1. Synthesis of BET Family Protein Ligand (BETL) Derivatives Compounds 12, 16, 17, 18, 23, and 24, which are BET ligand derivatives, were synthesized according to the reaction scheme described below.

[0073] [Synthesis Example 1] Synthesis of Compound 12 ((E)-N-(4-ethoxy-2-(3-(2-((6-ethynylpyridin-3-yl)methoxy)phenyl)acryloyl)-5-methoxyphenethyl)acetamide) Overall reaction scheme

[0074] <Synthesis of Compound 3 (2-((5-bromopyridin-2-yl)methoxy)benzaldehyde)>

[0075] Phosphorus tribromide (750 μL, 7.90 mmol) was added to a solution of 6-bromo-3-pyridinemethanol (1) (500 mg, 2.66 mmol) in dichloromethane (10 mL) at 0°C, and the mixture was stirred at room temperature for 4 hours. Water (10 mL) was added to the reaction mixture at 0°C to quench the reaction. The resulting mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain compound 2 (457 mg) as a white solid, suitable for use in the next step. To a solution of compound 2 in N,N-dimethylformamide (5.3 mL) were added potassium carbonate (735 mg, 5.32 mmol) and salicylaldehyde (280 μL, 2.66 mmol). After stirring at room temperature for 6 hours, water (20 mL) was added at 0°C to quench the reaction. The resulting mixture was extracted with n-hexane / ethyl acetate (1:4, 3 × 20 mL). The combined organic layers were washed with saturated brine (3 × 50 mL) and then dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (gradient: n-hexane / ethyl acetate 4:1 to n-hexane / ethyl acetate 2:1) to obtain compound 3 (431 mg, two-step yield 56%) as a colorless solid.

[0076]

[0077] <Synthesis of Compound 4 (2-((5-((trimethylsilyl)ethynyl)pyridin-2-yl)methoxy)benzaldehyde)>

[0078] To a solution of compound 3 (300 mg, 1.03 mmol) in tetrahydrofuran (2.7 mL), copper iodide (39.1 mg, 205 μmol), dichlorobis(triphenylphosphine)palladium (36.0 mg, 51.5 μmol), ethynyltrimethylsilane (350 μL, 2.48 mmol), and triethylamine (600 μL, 4.31 mmol) were added and degassed. After stirring at 50 °C for 8 hours, the resulting mixture was filtered through Celite, and the filtrate was extracted with diethyl ether (4 × 100 mL). Water (20 mL) was added at 0 °C to quench the reaction. The filtered solution was concentrated under reduced pressure, and the resulting crude product (10.7 g) was purified by flash column chromatography (normal hexane / ethyl acetate 6:1, gradient to ethyl acetate) to give compound 4 (296 mg, 93%) as a colorless solid.

[0079]

[0080] <Synthesis of Compound 8 (N-(4-ethoxy-3-methoxyphenethyl)acetamide)>

[0081] Ammonium acetate (343 mg, 4.45 mmol) was added to a solution of 4-ethoxy-3-methoxybenzaldehyde (5) (8.02 g, 44.5 mmol) in nitromethane (40 mL), and the mixture was refluxed for 2 hours. After cooling to 0 °C, the resulting yellow solid was collected by filtration and washed with diethyl ether to obtain compound 6 (6.27 g) as a yellow solid, which could be used in the next step. A solution of compound 6 (5.24 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of lithium aluminum hydride (2.66 g, 70.0 mmol) in tetrahydrofuran (90 mL) at 0 °C, and the mixture was refluxed for 5 hours. After cooling the reaction mixture to 0 °C, the reaction was quenched by the dropwise addition of water (3 mL), 10% aqueous sodium hydroxide solution (3 mL), and water (9 mL), successively. The suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure to give compound 7 (4.88 g) as an orange amorphous solid, suitable for use in the next step. To a solution of compound 7 (4.88 g, 25.0 mmol) in dichloromethane (50 mL) was added acetic anhydride (5.0 mL, 53.0 mmol) and triethylamine (11 mL, 78.9 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel 50 g, n-hexane / ethyl acetate 10:1 gradient to ethyl acetate) to give compound 8 (4.21 g, 40% yield for three steps) as a colorless solid.

[0082]

[0083] <Synthesis of Compound 9 (N-(2-acetyl-4-ethoxy-5-methoxyphenethyl)acetamide)>

[0084] Acetyl chloride (900 μL, 4.45 mmol) and aluminum trichloride (1.46 g, 10.9 mmol) were added to a solution of compound 8 (1.00 g, 4.21 mmol) in nitrobenzene (8.4 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water at 0°C to quench the reaction. The resulting mixture was extracted with chloroform (30 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain a crude product (1.89 g). The crude product was purified by flash column chromatography (n-hexane / ethyl acetate 4:1) to obtain a mixture of compound 9 and compound 10 (2.72 g). Potassium carbonate (329 mg, 2.38 mmol) was added to a methanol solution (24 mL) of the mixture of compound 9 and compound 10 at 0°C. After stirring at room temperature for 30 minutes, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL) at 0°C. The resulting mixture was concentrated under reduced pressure to remove methanol. The residue was extracted with dichloromethane (2 × 10 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain a mixture of Compound 9 and Compound 11 (2.19 g). Potassium carbonate (656 mg, 4.76 mmol) and ethyl iodide (400 μL, 4.95 mmol) were added to a solution of the mixture of Compound 9 and Compound 11 in N,N-dimethylformamide (12 mL). After stirring at 50°C for 16 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) at 0°C. The resulting mixture was extracted with n-hexane / ethyl acetate (1:4, 3 × 50 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product (10.7 g). The crude product was purified by flash column chromatography (normal hexane / ethyl acetate 4:1) to give Compound 9 (1.77 g, three-step yield 75%).

[0085]

[0086] <Synthesis of Compound 12 ((E)-N-(4-ethoxy-2-(3-(2-((6-ethynylpyridin-3-yl)methoxy)phenyl)acryloyl)-5-methoxyphenethyl)acetamide)>

[0087] To a solution (1.8 mL) of compound 4 (aldehyde, 297 mg, 960 μmol) and compound 9 (ketone, 297 mg, 960 μmol) in ethanol, 10% aqueous sodium hydroxide (1.8 mL) was added at 20°C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with chloroform (2 × 10 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (gradient: ethyl acetate to ethyl acetate / methanol 20:1) to give compound 12 (332 mg, 69%) as a yellow solid.

[0088]

[0089] [Synthesis Examples 2 to 4] Synthesis reaction schemes of compounds 16, 17, and 18

[0090] Synthesis of Compound 16 ((E)-N-(4-ethoxy-5-methoxy-2-(3-(2-(prop-2-yn-1-yloxy)phenyl)acryloyl)phenethyl)acetamide) To a solution of aldehyde 13 (224 mg, 1.40 mmol) and compound 9 (ketone, 300 mg, 1.07 mmol) in ethanol (4.0 mL) was added 10% aqueous sodium hydroxide solution (4.0 mL) at 20°C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with chloroform (2 × 8 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (gradient: ethyl acetate to ethyl acetate / methanol 20:1) to obtain compound 16 (400 mg, 88%) as a yellow solid.

[0091]

[0092] Synthesis of Compound 17 ((E)-N-(4-ethoxy-5-methoxy-2-(3-(3-(prop-2-yn-1-yloxy)phenyl)acryloyl)phenethyl)acetamide) To a solution of aldehyde 14 (150 mg, 937 μmol) and ketone 9 (200 mg, 716 μmol) in ethanol (4.0 mL) was added 10% aqueous sodium hydroxide (4.0 mL) at 20°C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with chloroform (2 × 8 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (gradient: ethyl acetate to ethyl acetate / methanol 20:1) to give Compound 17 (280 mg, 93%) as a yellow solid.

[0093]

[0094] Synthesis of Compound 18 ((E)-N-(4-ethoxy-5-methoxy-2-(3-(4-(prop-2-yn-1-yloxy)phenyl)acryloyl)phenethyl)acetamide) To a solution of aldehyde 15 (234 mg, 1.46 mmol) and ketone 9 (300 mg, 1.07 mmol) in ethanol (4.0 mL) was added 10% aqueous sodium hydroxide solution (4.0 mL) at 20°C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with chloroform (2 × 8 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (gradient: ethyl acetate to ethyl acetate / methanol 20:1) to give Compound 18 (438 mg, 93%) as a yellow solid.

[0095]

[0096] [Synthesis Example 5] Synthesis of Compound 23 (N-(4-ethoxy-5-methoxy-2-(3-(4-(prop-2-yn-1-yloxy)phenyl)propanoyl)phenethyl)acetamide) Overall reaction scheme

[0097] <Synthesis of Compound 20 ((E)-N-(4-ethoxy-2-(3-(4-(1-ethoxyethoxy)phenyl)acryloyl)-5-methoxyphenethyl)acetamide)>

[0098] To an ethanol solution (8.0 mL) of aldehyde 19 (542 mg, 2.79 mmol) and ketone 9 (600 mg, 2.15 mmol), 10% aqueous sodium hydroxide (8.0 mL) was added at 20 °C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (10 mL) at 0 °C. The resulting mixture was extracted with chloroform (2 × 10 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (ethyl acetate → ethyl acetate / methanol 20:1) to give compound 20 (910 mg, 93%) as a yellow oil.

[0099]

[0100] <Synthesis of Compound 22 (N-(4-ethoxy-2-(3-(4-hydroxyphenyl)propanoyl)-5-methoxyphenethyl)acetamide)>

[0101] To a solution of compound 20 (400 mg, 906 μmol) in ethyl acetate (7.6 mL) was added 5% palladium carbon (77.1 mg). After stirring for 8 hours under a hydrogen atmosphere at room temperature, the resulting mixture was filtered through Celite, and the filtrate was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give compound 21 (438 mg) as a colorless solid. To a solution of compound 21 in ethanol (7.2 mL) was added pyridinium paratoluenesulfonate (22.7 mg, 90.2 μmol). After stirring at 50°C for 1 hour, the reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with saturated brine (100 mL) and then dried over anhydrous sodium sulfate. The cotton plug filtered solution was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (chloroform / methanol gradient from 50:1 to 20:1) to give compound 22 (242 mg, two-step yield 69%) as a colorless solid.

[0102]

[0103] <Synthesis of Compound 23 (N-(4-ethoxy-5-methoxy-2-(3-(4-(prop-2-yn-1-yloxy)phenyl)propanoyl)phenethyl)acetamide)>

[0104] To a solution of compound 22 (75.8 mg, 197 μmol) in N,N-dimethylformamide (400 μL) were added potassium carbonate (32.8 mg, 236 μmol) and propargyl bromide (20 μL, 231 μmol). After stirring at room temperature for 9 hours, the reaction was quenched by adding water (10 mL) at 0°C. The resulting mixture was extracted with n-hexane / ethyl acetate (1:1, 3 × 10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (chloroform / methanol, gradient from 50:1 to 20:1) to obtain compound 23 (63.8 mg, 77%) as a colorless solid.

[0105]

[0106] Comparative Synthesis Example 1 Compound 24 (N-(4-ethoxy-5-methoxy-2-((1R * ,2R * Synthesis of 4-(2-(4-(prop-2-yn-1-yloxy)phenyl)cyclopropane-1-carbonyl)phenethyl)acetamide

[0107] To a solution of compound 18 (40.2 mg, 95.4 μmol) in dimethyl sulfoxide (400 μL) were added sodium hydride (60% suspension in mineral oil, 7.63 mg, 191 μmol) and trimethylsulfonium iodide (42.0 mg, 191 μmol). The mixture was stirred at room temperature for 30 minutes and then at 50°C for an additional 30 minutes. The reaction was quenched by the addition of saturated brine (10 mL) at 0°C, and the resulting mixture was extracted with chloroform (2 × 10 mL). The combined organic layer was washed with saturated brine (3 × 20 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (gradient: chloroform to chloroform / methanol 50:1) to give compound 24 (33.1 mg, 80%) as a colorless solid.

[0108]

[0109] <Synthesis of Compound 45 (4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)benzaldehyde)> To a solution of aryl bromide 44 (950 mg, 3.18 mmol) in tetrahydrofuran (21 mL) was added n-butyllithium (2.10 mL, 3.36 mmol) dropwise at −78°C. After stirring at 78°C for 30 minutes, N,N-dimethylformamide (740 μL, 9.56 mmol) was added dropwise to the reaction mixture. After stirring at room temperature for an additional 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (normal hexane / ethyl acetate 4:1) to give compound 45 (aldehyde, 645 mg, 2.60 mmol, 82% yield) as a colorless oil.

[0110]

[0111] <Synthesis of Compound 46 ((E)-N-(4-ethoxy-2-(3-(4-(3-hydroxypropyl)phenyl)acryloyl)-5-methoxyphenethyl)acetamide)> To a solution (7.5 mL) of compound 45 (aldehyde, 489 mg, 1.97 mmol) and methyl ketone 9 (500 mg, 1.79 mmol) in ethanol (7.5 mL) was added 10% aqueous sodium hydroxide (7.5 mL) at 20 °C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (20 mL) at 0 °C, and the mixture was extracted with chloroform (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product (crude ether, 812 mg) obtained after filtration and concentration under reduced pressure was used without further purification. Pyridinium paratoluenesulfonate (30.3 mg, 159 μmol) was added to a methanol solution (13 mL) of the crude product (crude ether, 812 mg). After stirring at room temperature for 1 hour, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL) at 0 °C, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over sodium sulfate. Filtration and concentration under reduced pressure gave a crude product which was purified by flash column chromatography (chloroform / methanol gradient from 50:1 to 20:1) to give compound 46 (alcohol, 560 mg, 83% yield over two steps) as a yellow solid.

[0112]

[0113] Synthesis of Compound 47 (N-(4-ethoxy-5-methoxy-2-(3-(4-(3-oxopropyl)phenyl)propanoyl)phenethyl)acetamide) To a solution of compound 46 (alcohol, 186 mg, 437 μmol) in methanol / ethyl acetate (1:1, 4.4 mL) was added 5% palladium on carbon (10.0 mg), and the mixture was stirred under hydrogen for 2 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the crude product (202 mg) was used without further purification. To a solution of the crude product (202 mg) in dichloromethane (4.7 mL) was added Dess-Martin periodinane (220 mg, 520 μmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (10 mL), and the reaction was quenched with saturated aqueous sodium bicarbonate / 10% aqueous sodium thiosulfate (1:1, 10 mL). After stirring at room temperature for an additional 30 minutes, the mixture was extracted with dichloromethane (2 × 20 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (chloroform / methanol gradient from 50:1 to 20:1) to give compound 47 (aldehyde, 190 mg, 100% yield over two steps) as a colorless solid.

[0114]

[0115] Synthesis of Compound 48 (N-(2-(3-(4-(buten-3-yn-1-yl)phenyl)propanoyl)-4-ethoxy-5-methoxyphenethyl)acetamide) To a solution of compound 47 (aldehyde, 121 mg, 284 μmol) in methanol (5.0 mL) were added Ohira-Bestmann reagent (63.0 μL, 341 μmol) and potassium carbonate (78.6 mg, 569 μmol) at room temperature. After stirring at room temperature for 5 hours, the reaction was quenched with saturated aqueous ammonium chloride (5 mL) at 0°C, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (chloroform / methanol gradient from 50:1 to 20:1) to give compound 48 (alkyne, 90.2 mg, 214 μmol, 75% yield) as a colorless solid.

[0116] 2. Synthesis of E3 Ligase Ligand Derivatives [Comparative Synthesis Example 2 and Synthesis Examples 6 to 9] Overall Reaction Scheme for the Synthesis of Compounds 30, 31, 32, 33, and 34

[0117] Synthesis of Compound 30 (2-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide) To a solution of pomalidomide (500 mg, 1.83 mmol) in tetrahydrofuran (9.3 mL) was added chloroacetyl chloride (216 μL, 2.74 mmol). After stirring at 40° C. for 24 hours, diethyl ether (20 mL) was added to the mixture at 0° C. The resulting solid was collected by filtration and washed with diethyl ether to obtain Compound 25 (628 mg) as a milky solid, which could be used in the next step. To a solution of Compound 25 in acetone (10 mL) was added sodium azide (350 mg, 5.39 mmol). After stirring at 50° C. for 24 hours, water (20 mL) was added to the mixture at room temperature. The resulting solid was collected by filtration and washed with water to obtain Compound 30 (628 mg, two-step yield 98%) as a milky solid.

[0118]

[0119] Synthesis of Compound 31 (4-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide) To a solution of pomalidomide (508 mg, 1.86 mmol) in tetrahydrofuran (9.3 mL) was added 4-chlorobutanoic acid chloride (320 μL, 2.86 mmol) at 0° C. After stirring at 40° C. for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (20 mL) was added to the residue at 0° C. The resulting solid was collected by filtration and washed with diethyl ether to obtain crude Compound 26 (687 mg) as a milky solid, which could be used in the next step. To a solution of crude Compound 26 in N,N-dimethylformamide (10 mL) was added sodium azide (355 mg, 5.46 mmol). After stirring at 50° C. for 24 hours, water (20 mL) was added to the mixture at room temperature, and the resulting solid was collected by filtration and washed with water to obtain compound 31 (655 mg, two-step yield 91%) as a milky solid.

[0120]

[0121] Synthesis of Compound 32 (6-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) Pomalidomide (477 mg, 1.75 mmol) was added to a tetrahydrofuran solution (12 mL) of 6-bromohexanoic acid chloride (520 mg) at 0°C. After stirring at 40°C for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (10 mL) was added to the residue. The resulting solid was collected by filtration and washed with diethyl ether to obtain crude Compound 27 (774 mg) as a milky solid, which could be used in the next step. Sodium azide (335 mg, 5.16 mmol) was added to a N,N-dimethylformamide solution (10 mL) of crude Compound 27. After stirring at 50°C for 24 hours, water (10 mL) was added to the mixture at room temperature. The resulting solid was collected by filtration and washed with water to obtain Compound 32 (614 mg, two-step yield 85%) as a milky solid.

[0122]

[0123] Synthesis of Compound 33 (8-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)octanamide) Pomalidomide (1.60 g, 5.86 mmol) was added to a tetrahydrofuran solution (30 mL) of 8-bromooctanoic acid chloride (2.79 g) at 0° C. After stirring at 40° C. for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (30 mL) was added to the residue. The resulting solid was collected by filtration and washed with diethyl ether to obtain crude Compound 28 (2.60 g) as a milky solid, which could be used in the next step. Sodium azide (335 mg, 5.16 mmol) was added to a solution of crude Compound 28 in N,N-dimethylformamide (27 mL). After stirring at 50° C. for 24 hours, water (30 mL) was added to the mixture at room temperature. The resulting solid was collected by filtration and washed with water to obtain Compound 33 (2.00 g, two-step yield 77%) as a milky solid.

[0124]

[0125] Synthesis of Compound 34 (11-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide) To a solution of 11-bromoundecanoic acid chloride (2.34 g) in tetrahydrofuran (30 mL) was added pomalidomide (1.60 g, 5.86 mmol) at 0°C. After stirring at 40°C for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (30 mL) was added to the residue. The resulting solid was collected by filtration and washed with diethyl ether to obtain crude Compound 29 (2.60 g) as a milky solid, which could be used in the next step. To a solution of crude Compound 29 in N,N-dimethylformamide (25 mL) was added sodium azide (974 mg, 15.0 mmol). After stirring at 50° C. for 24 hours, water (30 mL) was added to the mixture at room temperature, and the resulting solid was collected by filtration and washed with water to give compound 34 (2.65 g, two-step yield: 94%) as a milky solid.

[0126]

[0127] [Synthesis Example 10] Synthesis reaction scheme of Compound 36 (6-azido-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide)

[0128] N-methylpomalidomide (500 mg, 1.74 mmol) was added to a solution of 6-bromohexanoic acid chloride (672 mg) in tetrahydrofuran (15 mL) at 0°C. After stirring at 40°C for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (20 mL) was added to the residue. The resulting solid was collected by filtration and washed with diethyl ether to obtain crude compound 35 (770 mg) as a milky solid, suitable for use in the next step. Sodium azide (323 mg, 4.98 mmol) was added to a solution of crude compound 35 in N,N-dimethylformamide (8.3 mL). After stirring at 50°C for 24 hours, water (10 mL) was added to the mixture at room temperature. The resulting solid was collected by filtration and washed with water to obtain compound 36 (421 mg, two-step yield: 57%) as a milky solid.

[0129]

[0130] Comparative Synthesis Example 3 Synthesis of Compound 39 ((2S,4R)-1-((S)-2-(6-azidohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)

[0131] To a solution of compound 37 (5.40 g) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 5 hours, the mixture was concentrated under reduced pressure. To a solution of the residue (700 mg) in N,N-dimethylformamide (5.0 mL), compound 38 (148 mg), diisopropylethylamine (0.8 mL, 4.59 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (341 mg, 1.41 mmol) were added. After stirring at room temperature for 16 hours, 1 M hydrochloric acid (5 mL) was added to the mixture. The resulting mixture was extracted with n-hexane / ethyl acetate (1:4, 3 × 10 mL). The combined organic layer was washed with saturated brine (3 × 40 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (ethyl acetate) to give Compound 39 (300 mg, two-step yield 56%) as a colorless solid.

[0132]

[0133] [Synthesis Example 11] Synthesis of Compound 43 (8-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oct-7-ynamide) Overall reaction scheme

[0134]

[0135] <Synthesis of Compound 42 (N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oct-7-ynamide)>

[0136] Pomalidomide (4.00 g, 14.7 mmol) was added to a solution of 7-octynoic acid chloride (3.25 g) in N,N-dimethylformamide (30 mL) at 0°C. After stirring at 40°C for 24 hours, the mixture was concentrated under reduced pressure, and diethyl ether (20 mL) was added to the residue. The resulting solid was collected by filtration and washed with diethyl ether to obtain compound 42 (5.26 g, 91%) as a milky solid.

[0137]

[0138] <Synthesis of Compound 43 (8-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oct-7-ynamide)>

[0139] To a solution of compound 42 (3.00 g, 7.59 mmol) in acetone (400 μL) were added silver nitrate (129 mg, 759 μmol) and N-bromosuccinimide (1.62 g, 9.10 mmol). After stirring at room temperature for 3 hours, the suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure, and the resulting crude product was purified by flash column chromatography (chloroform) to give compound 43 (2.85 g, 79%) as a yellow solid.

[0140]

[0141] Comparative Synthesis Example 4: Compound 40 (14-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecanamide) To a dichloromethane solution (400 μL) of 14-azido-3,6,9,12-tetraoxatetradecanoic acid (0.24 mmol), thionyl chloride (100 μL) and N,N-dimethylformamide solution (2 drops) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (800 μL), and pomalidomide (65.6 mg, 0.24 mmol) was added. After stirring at room temperature for 4 hours, water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered through a cotton plug and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (n-hexane / ethyl acetate 1:1) to obtain compound 40 (47.0 mg, 37%) as a yellow solid.

[0142]

[0143] 3. Synthesis of PROTAC Compounds However, compound 13 (TKP33) was synthesized by a different scheme (described later).

[0144] Example 1 Synthesis of TKP-5 ((E)-6-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-5 was synthesized by the click reaction shown in the following scheme.

[0145] To a tetrahydrofuran solution (1.0 mL) of compound 12 (alkyne 12) and compound 32 (azide 32), copper thiophene-2-carboxylate (6.8 mg, 35.6 μmol) was added. After stirring at room temperature for 5 hours, saturated aqueous ammonium chloride / aqueous ammonia (1:1, 5 mL) was added to the mixture at room temperature, and the resulting mixture was extracted with chloroform (2 × 10 mL). The combined organic layer was dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (chloroform / methanol 9:1) to obtain TKP-5 (51.7 mg, 87%) as a yellow solid.

[0146]

[0147] Comparative Example 1 Synthesis of TKP-1 ((E)-14-(4-(5-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecanamide) TKP-1 was synthesized from compound 12 (alkyne 12) and compound 40 (azide 40) by click reaction in the same manner as in Example 1.

[0148]

[0149] Comparative Example 2 Synthesis of TKP-2 ((4R)-1-((S)-2-(6-(4-(5-((2-((E)-3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazo1-5-yl)benzyl)pyrrolidine-2-carboxamide) TKP-2 was synthesized from compound 12 (alkyne 12) and compound 39 (azide 39) by click reaction in the same manner as in Example 1.

[0150]

[0151] Example 2 Synthesis of TKP-3 ((E)-6-(4-(5-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-3 was synthesized from compound 12 (alkyne 12) and compound 32 (azide 32) by click reaction in the same manner as in Example 1.

[0152]

[0153] Comparative Example 3 Synthesis of TKP-4 ((E)-2-(4-(5-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide) TKP-4 was synthesized from compound 12 (alkyne 12) and compound 30 (azide 30) by click reaction in the same manner as in Example 1.

[0154]

[0155] Example 3 Synthesis of TKP-6 ((E)-6-(4-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-6 was synthesized from compound 16 (alkyne 16) and compound 32 (azide 32) by click reaction in the same manner as in Example 1.

[0156]

[0157] Comparative Example 4 Synthesis of TKP-7 ((E)-2-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide) TKP-7 was synthesized from compound 18 (alkyne 18) and compound 30 (azide 30) by click reaction in the same manner as in Example 1.

[0158]

[0159] Comparative Example 5 Synthesis of TKP-8 ((E)-2-(4-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide) TKP-8 was synthesized from compound 16 (alkyne 16) and compound 30 (azide 30) by click reaction in the same manner as in Example 1.

[0160]

[0161] Example 4 Synthesis of TKP-9 ((E)-4-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide) TKP-9 was synthesized from compound 18 (alkyne 18) and compound 31 (azide 31) by click reaction in the same manner as in Example 1.

[0162]

[0163] Example 5 Synthesis of TKP-10 ((E)-4-(4-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide) TKP-10 was synthesized from compound 16 (alkyne 16) and compound 31 (azide 31) by click reaction in the same manner as in Example 1.

[0164]

[0165] Example 6 Synthesis of TKP-11 ((E)-4-(4-(5-((2-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide) TKP-11 was synthesized from compound 12 (alkyne 12) and compound 31 (azide 31) by click reaction in the same manner as in Example 1.

[0166]

[0167] Example 7 Synthesis of TKP-13 ((E)-6-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-13 was synthesized from compound 18 (alkyne 18) and compound 36 (azide 36) by click reaction in the same manner as in Example 1.

[0168]

[0169] Example 8 Synthesis of TKP-14 ((E)-6-(4-((3-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-14 was synthesized from compound 17 (alkyne 17) and compound 32 (azide 32) by click reaction in the same manner as in Example 1.

[0170]

[0171] Example 9 Synthesis of TKP-16 ((E)-6-(4-((3-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-16 was synthesized from compound 18 (alkyne 18) and compound 33 (azide 33) by click reaction in the same manner as in Example 1.

[0172]

[0173] Example 10 Synthesis of TKP-17 ((E)-11-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undecanamide) TKP-17 was synthesized from compound 18 (alkyne 18) and compound 34 (azide 34) by click reaction in the same manner as in Example 1.

[0174]

[0175] Comparative Example 6 Synthesis of TKP-18 ((E)-6-(4-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxopropyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-18 was synthesized from compound 23 (alkyne 23) and compound 32 (azide 32) by click reaction in the same manner as in Example 1.

[0176]

[0177] Comparative Example 7 Synthesis of TKP-20 (6-(4-((4-((1S,2S)-2-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxybenzoyl)cyclopropyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) TKP-20 was synthesized from compound 24 (alkyne 24) and compound 32 (azide 32) by click reaction in the same manner as in Example 1.

[0178]

[0179] Example 11 Synthesis of TKP-21 ((E)-11-(4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undeca-7,9-diynamide)

[0180] To a solution of bis(dibenzylidene)palladium (6.06 mg, 10.5 μmol) in N,N-dimethylformamide (1.0 mL), copper iodide (1.00 mg, 5.27 μmol) and ligand 41 (4.14 mg, 10.5 μmol) were added and degassed. After stirring for 10 minutes, alkyne 18 (53.3 mg, 126 μmol) and triethylamine (30.0 μL, 215 mmol) were added and degassed. After stirring for an additional 5 minutes, compound 43 (50.0 mg, 105 μmol) was added and degassed. After stirring at room temperature for 10 hours, saturated aqueous ammonium chloride (10 mL) was added. The resulting mixture was extracted with chloroform (2 × 10 mL). The combined organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The cotton plug filtered solution was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (gradient from chloroform to chloroform / methanol 50:1) to give TKP-21 (47.9 mg, 56%) as a yellow solid.

[0181]

[0182] Example 12 Synthesis of TKP-22 ((E)-6-(5-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)thiophen-2-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide)

[0183] Sodium sulfide nonahydrate (8.84 mg, 38.6 μmol) was added to a dimethyl sulfoxide solution (250 μL) of TKP-21 (10.0 mg, 12.3 μmol). After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride (10 mL) was added to quench the reaction. The resulting mixture was extracted with chloroform (3 × 10 mL). The combined organic layer was washed with saturated brine (50 mL) and then dried over anhydrous sodium sulfate. The solution filtered through a cotton plug was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (chloroform → chloroform / methanol 50:1) to give TKP-22 (3.4 mg, 33%) as a yellow solid.

[0184]

[0185] [Example 12-2] Synthesis of TKP-22 ((E)-6-(5-((4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)methyl)thiophen-2-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide) by an improved method A solution of TKP-21 (50.0 mg, 61.4 μmol) in dimethyl sulfoxide (12 ml) was added with sodium sulfide nonahydrate (Na ２ S・9H ２ To the resulting mixture was added TKP-22 (88.4 mg, 368 μmol). After stirring at room temperature for 6 hours, the reaction mixture was diluted with chloroform (20 mL), quenched with half-saturated aqueous ammonium chloride (20 mL), and extracted with chloroform (3 × 30 mL). The combined organic layer was washed with saturated brine (3 × 50 mL) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (gradient from chloroform to chloroform / methanol 50:1) to give TKP-22 (40.0 mg, 47.1 μmol, 77%) as a yellow solid.

[0186] Example 13 Synthesis of TKP-33 ((E)-6-(4-(4-(3-(2-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)phenethyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide)

[0187] <Synthesis of Compound 49 (6-(4-(3-(2-acetamidoethyl)-5-ethoxy-4-methoxyphenyl)-3-oxopropyl)phenethyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)hexanamide)> To a solution of compound 48 (alkyne, 50.0 mg, 119 μmol) in tetrahydrofuran (2.0 mL), copper thiophene-2-carboxylate (11.3 mg, 59.3 μmol) and compound 32 (azide 32, 53.8 mg, 130 μmol) were added. After stirring at room temperature for 5 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride / 28% aqueous ammonia (1:1, 5 mL), and the mixture was extracted with chloroform (2 × 10 mL). The combined organic layer was dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (chloroform / methanol, gradient from 50:1 to 20:1) to give compound 49 (triazole, 85.0 mg, 102 μmol, 86% yield) as a colorless solid.

[0188] <Synthesis of TKP-33> Pd(TFA) ２ (19.5 mg, 58.5 μmol) and 4,5-diazafluoren-9-one (10.7 mg, 58.5 μmol) were added to a dimethyl sulfoxide solution (1.5 mL) of compound 49 (triazole, 40.0 mg, 48.8 μmol), and the reaction mixture was purged with oxygen three times. After stirring at 100°C for 20 hours under an oxygen atmosphere, the reaction was quenched by adding saturated aqueous sodium bicarbonate (5 mL) at 20°C, and the mixture was extracted with chloroform (3 × 10 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration under reduced pressure was purified by flash column chromatography (chloroform / methanol gradient from 50:1 to 20:1) to give TKP-33 (2.80 mg, 3.42 μmol, 7% yield) as a yellow solid.

[0189]

[0190] 4. Evaluation of BET proteolytic activity 4-1. Test compounds The compounds of Example 2 and Comparative Examples 1 and 2 synthesized as described above, as well as the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) were subjected to this test. The structures of each compound are shown below.

[0191]

[0192] 4-2. Test conditions and test procedures KCMH-1 cells, a mouse epidermal keratinocyte cell line, were cultured at 0.5 × 10 ５ KCMH-1 cells were seeded at 1000 cells / well in a 24-well plate. 10% FBS-containing MEM-α medium was used as the cell culture medium. 24 hours after seeding, the medium was replaced with fresh 10% FBS-containing MEM-α medium, and a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1), the compound of Example 2 (TKP-3), the compound of Comparative Example 1 (TKP-1), or the compound of Comparative Example 2 (TKP-2) was added at a concentration of 10 μM. KCMH-1 cells were treated for 24 hours. After 24 hours of treatment, the culture medium was removed, and 50 μL of sample buffer was added to each well to prepare cell treatment solutions for each group. The cells were then heated at 95°C for 5 minutes and used as samples for Western blotting. For Western blotting, an 8% polyacrylamide gel was used as the separating gel, and electrophoresis was performed for 120 minutes with a sample load of 15 μL. Proteins in the separation gel after electrophoresis were transferred to a nitrocellulose membrane at 150 mA / separation gel for 90 minutes. The transferred membrane was blocked with Block Ace for 90 minutes, and various primary antibody solutions against BRD4, BRD2, and GAPDH were added and incubated at 4°C overnight. Subsequently, an HRP-labeled secondary antibody solution against each primary antibody was added and incubated at 4°C for 3 hours. After incubation with the secondary antibody, the membrane was reacted with a substrate solution, and bands for each target protein were detected. In this test, a sample prepared by heating a cell treatment solution containing no test compound was used as a negative control. As a positive control, a sample prepared by heating a cell treatment solution containing a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) was used. GAPDH was used as an internal standard for WB.

[0193] 4-3. Test Results The test results are shown in Figure 1. The compound of Example 2 (TKP-3) produced a weaker BRD4 band than the negative control and the compounds of Comparative Example 1 (TKP-1) and Comparative Example 2 (TKP-2), and is therefore considered to have BRD4 degradation activity.

[0194] 5. Confirmation of the mechanism of BET proteolytic activity 5-1. Test compounds The compound of Example 1 and the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) synthesized as described above were subjected to this test. The structures of each compound are shown below.

[0195] 5-2. Test Conditions and Test Procedures Western blotting samples were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, except that KCMH-1 cells were treated for 2 hours with the compound of Comparative Example 8 (MZ-1), the compound of Example 1 (TKP-5), the proteasome inhibitor MG132, the compound of Comparative Example 8 (MZ-1) and MG132, or the compound of Example 1 (TKP-5) and MG132. Western blotting was then performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a sample prepared by heating a cell treatment solution containing no test compound was used as a negative control. A sample prepared by heating a cell treatment solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) was used as a positive control, and GAPDH was used as an internal standard for WB. In addition, to confirm the degradation mechanism of BRD4, a test was also carried out in which MG132 was added together with each test compound (MZ-1 and TKP-5).

[0196] 5-3. Test Results The test results are shown in Figure 2. With the compound of Example 1 (TKP-5), the BRD4 band almost disappeared, demonstrating significant BRD4 degradation activity. Furthermore, when MG132 was added together with the compound of Example 1 (TKP-5) or the compound of Comparative Example 8 (MZ-1), a BRD4 band similar to that observed in the negative control was observed, confirming that these compounds degrade BRD4 via the proteasome.

[0197] 6. Effect of linker structure on BET proteolytic activity 6-1. Test compounds The compounds of Examples 1 to 6 and Comparative Examples 1 to 5, as well as the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) were subjected to this test. The structure of each compound is shown below.

[0198] 6-2. Test Conditions and Test Procedures Samples for Western blotting were prepared in the same manner as in the test procedure described in "4. Evaluation of BET proteolytic activity" above, except that KCMH-1 cells were treated for 24 hours with a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1), the compound of Comparative Example 2 (TKP-2), the compound of Comparative Example 1 (TKP-1), the compound of Example 2 (TKP-3), the compound of Comparative Example 3 (TKP-4), the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), the compound of Comparative Example 4 (TKP-7), the compound of Comparative Example 5 (TKP-8), the compound of Example 4 (TKP-9), the compound of Example 5 (TKP-10), or the compound of Example 6 (TKP-11) at a concentration of 10 μM. Western blotting was performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a sample prepared by heating a cell treatment solution prepared by adding a dimethyl sulfoxide solution containing no test compound was used as a negative control, and a sample prepared by heating a cell treatment solution prepared by adding a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) was used as a positive control. GAPDH was used as an internal standard for WB.

[0199] 6-3. Test Results The test results are shown in Figure 3. For the compounds of Example 1 (TKP-5), Example 2 (TKP-3), Example 3 (TKP-6), Example 4 (TKP-9), Example 5 (TKP-10), and Example 6 (TKP-11), the BRD4 band was smaller than that of the control, confirming BRD4 degradation activity. In particular, for the compound of Example 1 (TKP-5), the BRD4 band almost disappeared, confirming significant BRD4 degradation activity. Furthermore, it was confirmed that the compounds of Example 1 (TKP-5) and Example 4 (TKP-9), in which the benzene ring is substituted at the para position, exhibited more significant BRD4 degradation activity than the compounds of Example 3 (TKP-6) and Example 5 (TKP-10), which have the same structure except for the benzene ring being substituted at the ortho position. Furthermore, when Example 5 (TKP-10) and Example 6 (TKP-11) were compared, no significant difference in BRD4 degradation activity was observed depending on whether or not there was a pyridine ring. This result is very interesting, since it was understood that the presence of a pyridine ring was essential for the BRD4 degradation activity of the compound described in Patent Document 1.

[0200] 7. Effect of linker length on BET proteolytic activity and TSLP production inhibitory activity 7-1. Test compounds The compounds of Examples 1, 9, and 10 (TKP-5, 16, and 17) and MZ-1 (Comparative Example 8) disclosed in Patent Document 2 were subjected to this test. The linker structure of each compound is shown below.

[0201] 7-2. Test Conditions and Test Procedures WB Samples for Western blotting were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, except that KCMH-1 cells were treated for 24 hours with a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1), the compound of Example 1 (TKP-5), the compound of Example 9 (TKP-16), or the compound of Example 10 (TKP-17). Western blotting was then performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a sample prepared by adding a dimethyl sulfoxide solution containing no test compound to a cell treatment solution and heating the solution was used as a negative control. A sample prepared by adding a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) to a cell treatment solution and heating the solution was used as a positive control. GAPDH was also used as an internal standard for WB.

[0202] TSLP Production Assay KCMH-1 cells, a mouse epidermal keratinocyte cell line, were cultured at 0.5 × 10 ５ KCMH-1 cells were seeded at 1000 cells / well in a 24-well plate. MEM-α medium containing 10% FBS was used as the cell culture medium. 24 hours after seeding, the medium was replaced with fresh MEM-α medium containing 10% FBS, and KCMH-1 cells were treated with dimethyl sulfoxide solutions containing the compound of Comparative Example 8 (MZ-1), the compound of Example 1 (TKP-5), the compound of Example 9 (TKP-16), or the compound of Example 10 (TKP-17) at different concentrations of 0.1, 0.3, and 1.0 μM for each compound. 24 hours after treatment, the culture supernatants were collected, and the TSLP concentration in the supernatants was measured using a mouse TSLP ELISA kit (R&D, DY555). In this test, a dimethyl sulfoxide solution containing no test compound was added as a negative control, and the culture supernatant after 24 hours of incubation was used as a sample. As a positive control, a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) was added at different concentrations of 0.1, 0.3, and 1.0 μM, and the culture supernatant after 24 hours of incubation was used.

[0203] 7-3. Test Results The test results are shown in Figures 4 and 5. For the compounds of Example 1 (TKP-5), Example 9 (TKP-16), and Example 10 (TKP-17), the BRD4 band became smaller at concentrations of 0.1 to 1.0 μM compared to the control, confirming that they exert BRD4 degradation activity. In addition, the minimum number of atoms connecting both ends of the linker was 15 and 17, respectively, and L ２ In the compound of Example 1 (TKP-5) and the compound of Example 9 (TKP-16), in which L is an alkylene having 5 and 7 carbon atoms, respectively, the minimum number of atoms connecting both ends of the linker is 20, and L ２ It was confirmed that the compounds of Example 1 (TKP-5), Example 9 (TKP-16), and Example 10 (TKP-17) exhibited more significant BRD4 degradation activity than the compound of Example 10 (TKP-17) in which L is an alkylene having 10 carbon atoms. Furthermore, it was confirmed that the compounds of Example 1 (TKP-5), Example 9 (TKP-16), and Example 10 (TKP-17) exhibited TSLP production inhibitory activity, reducing TSLP production compared to the negative control at concentrations of 0.1 to 1.0 μM. Furthermore, the minimum number of atoms connecting both ends of the linker was 15 and 17, respectively, and L ２ In the compound of Example 1 (TKP-5) and the compound of Example 9 (TKP-16), in which L is an alkylene having 5 and 7 carbon atoms, respectively, the minimum number of atoms connecting both ends of the linker is 20, and L ２ It was confirmed that this compound exhibited a more significant TSLP production inhibitory activity than the compound of Example 10 (TKP-17), in which is an alkylene having 10 carbon atoms.

[0204] 8. Effect of the Substitution Position on the Benzene Ring on TSLP Production Inhibitory Activity 8-1. Test Compounds The compounds of Examples 1, 3, and 8 (TKP-5, 6, and 14) and the compound of Comparative Example 8 (MZ-1 disclosed in Patent Document 2) were subjected to this test. The structures of each compound are shown below.

[0205] 8-2. Test Conditions and Test Procedures WB Samples for Western blotting were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, except that KCMH-1 cells were treated for 2 hours with a dimethyl sulfoxide solution containing the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), or the compound of Example 8 (TKP-14) at a concentration of 1 μM. Western blotting was then performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a sample prepared by adding a dimethyl sulfoxide solution containing no test compound to a cell treatment solution and heating the solution was used as a negative control. A sample prepared by adding a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) to a cell treatment solution and heating the solution was used as a positive control. GAPDH was also used as an internal standard for WB. TSLP Production Assay KCMH-1 cells were treated and TSLP concentrations were measured in the same manner as in the test procedure described in "7. Effect of Linker Length on BET Proteolytic Activity and TSLP Production Inhibitory Activity," except that a dimethyl sulfoxide solution containing the compound of Example 1 (TKP-5), the compound of Example 3 (TKP-6), or the compound of Example 8 (TKP-14) was used. In this test, a dimethyl sulfoxide solution containing no test compound was added as a negative control, and the culture supernatant after 24 hours of culture was used as a sample. As a positive control, a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1 described in Patent Document 2) was added at different concentrations of 0.1, 0.3, and 1.0 μM, and the culture supernatant after 24 hours of culture was used.

[0206] 8-3. Test Results The test results are shown in Figures 6 and 7. The compounds of Example 1 (TKP-5), Example 3 (TKP-6), and Example 8 (TKP-14) showed smaller BRD4 bands than the control, confirming that they exhibit BRD4 degradation activity. Furthermore, compared to the compound of Example 3 (TKP-6) in which the benzyl ring is substituted at the ortho position, the compounds of Example 1 (TKP-5) and Example 8 (TKP-14) in which the benzyl ring is substituted at the para and meta positions, respectively, showed smaller BRD4 bands and exhibited more pronounced BRD4 degradation activity, and it was confirmed that the compound of Example 1 (TKP-5) in which the benzyl ring is substituted at the para position exhibited the most pronounced BRD4 degradation activity. Furthermore, the compounds of Example 1 (TKP-5), Example 3 (TKP-6), and Example 8 (TKP-14) reduced TSLP production compared to the control, confirming that they exhibit TSLP production inhibitory activity. Furthermore, compared to the compound of Example 3 (TKP-6) in which the substitution position of the benzyl ring is at the ortho position, the compounds of Example 1 (TKP-5) and Example 8 (TKP-14) in which the substitution positions of the benzyl ring are at the para and meta positions, respectively, exhibited more significant TSLP production inhibitory activity, and the compound of Example 1 (TKP-5) in which the benzyl ring is substituted at the para position was confirmed to exhibit the most significant TSLP production inhibitory activity.

[0207] 9. Detailed Comparison of BET Proteolytic Activity with MZ-1 9-1. Test Compounds The compound of Example 1 (TKP-5) and the compound of Comparative Example 8 (MZ-1) were subjected to this test.

[0208] 9-2. Test Conditions and Test Procedures (1) Test for Effect-Related Concentration KCMH-1 cells were treated for 24 hours with a dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1) or the compound of Example 1 (TKP-5) at a concentration of 0.01, 0.03, 0.3, or 1.0 μM. Samples for Western blotting were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, except that Western blotting was performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a cell treatment solution was prepared as a negative control by adding a dimethyl sulfoxide solution containing no test compound, and this solution was heated to prepare a sample. GAPDH was used as an internal standard for WB.

[0209] (2) Test on the time to onset of action A dimethyl sulfoxide solution containing the compound of Comparative Example 8 (MZ-1) or the compound of Example 1 (TKP-5) was added at a concentration of 1 μM, and KCMH-1 cells were treated for 2, 4, 8, 12, or 24 hours. Samples for Western blotting were prepared in the same manner as in the test procedure described above in "4. Evaluation of BET proteolytic activity," and Western blotting was performed in the same manner as in "4. Evaluation of BET proteolytic activity." In this test, a cell treatment solution was prepared by adding a dimethyl sulfoxide solution containing no test compound as a negative control, and this solution was heated to prepare a sample. GAPDH was used as an internal standard for WB.

[0210] (3) Test for duration of action KCMH-1 cells, a mouse epidermal keratinocyte cell line, were cultured at 0.5 × 10 ５KCMH-1 cells were seeded at 1000 cells / well in a 24-well plate. MEM-α medium containing 10% FBS was used as the cell culture medium. 24 hours after seeding, the medium was replaced with fresh MEM-α medium containing 10% FBS, and a dimethyl sulfoxide solution containing the compound of Example 1 (TKP-5) or the compound of Comparative Example 8 (MZ-1) was added at a concentration of 1 μM, and the KCMH-1 cells were treated for 2 hours. After treatment, the medium was replaced with MEM-α medium containing 10% FBS but without the test compound. After 0, 4, 8, 12, and 24 hours, samples for Western blotting were prepared and Western blotting was performed in the same manner as described above in "4. Evaluation of BET proteolytic activity."

[0211] 9-3. Test Results The test results are shown in Figures 8 to 10. The compound of Comparative Example 8 (MZ-1) exhibited BRD4 degradation activity at a concentration of about 0.03 µM, whereas the compound of Example 1 (TKP-5) exhibited BRD4 degradation activity at a concentration of about 0.3 µM. Furthermore, the compounds of Example 1 (TKP-5) and Comparative Example 8 (MZ-1) both exhibited BRD4 degradation activity in about 2 hours. Furthermore, the compounds of Example 1 (TKP-5) and Comparative Example 8 (MZ-1) both exhibited a duration of action of about 24 hours.

[0212] 10. Effect of Linker Structure on BET Proteolytic Activity (2) 10-1. Test Compounds The compound of Example 1 (TEP5), the compound of Example 11 (TKP-21), and the compound of Example 12 (TKP-22) were subjected to this test. The structures of each compound are shown below.

[0213] 10-2. Test Conditions and Test Procedures KCMH-1 cells were treated for 24 hours with a dimethyl sulfoxide solution containing the compound of Example 1 (TEP5), the compound of Example 11 (TKP-21), or the compound of Example 12 (TKP-22) at a concentration of 1.0 μM. Samples for Western blotting were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, and Western blotting was performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, a sample prepared by heating a cell treatment solution prepared by adding a dimethyl sulfoxide solution containing no test compound was used as a negative control.

[0214] 10-3. Test Results The test results are shown in Figure 11. The BRD4 band was smaller in the compound of Example 1 (TEP5), the compound of Example 11 (TKP-21), and the compound of Example 12 (TKP-22) than in the control, confirming the activity of degrading BRD4. In particular, the BRD4 band almost disappeared in the compound of Example 12 (TKP-22), similar to the compound of Example 1 (TKP-5), confirming that the compound exhibited significant activity of degrading BRD4.

[0215] 11. Effect of linker structure on BET proteolytic activity (3) 11-1. Test compound The compound of Example 13 (TEP33) was subjected to this test. Its structure is shown below.

[0216] 11-2. Test Conditions and Test Procedures Samples for Western blotting were prepared in the same manner as in "4. Evaluation of BET proteolytic activity" above, except that KCMH-1 cells were treated for 24 hours with a dimethyl sulfoxide solution containing the compound of Example 13 (TEP33) at different concentrations of 0.1, 0.3, and 1 μM. Western blotting was then performed in the same manner as in "4. Evaluation of BET proteolytic activity" above. In this test, GAPDH was used as an internal standard for WB.

[0217] 11-3. Test Results The test results are shown in Figure 12. With the compound of Example 13 (TEP33), the BRD4 band almost disappeared at a concentration of 1.0 µM, confirming that it exhibits significant BRD4 degradation activity.

Claims

1. A compound having the structure of the following general formula (I): E3LLM-L-BETLM... (I), or a salt or solvate thereof: [In formula (I), BETLM is a group represented by the formula (II): (In formula (II), R １ , R ２ and R ３ each independently represents hydrogen or an alkyl group having 1 to 3 carbon atoms; and E3LLM is a BARD4 ligand module represented by formula (III): (In the formula (III), W is CHR Ｗ１ (R Ｗ１ is hydrogen or an alkyl group having 1 to 10 carbon atoms), C(O), S(O) ２ , and N.R. Ｗ２ (R Ｗ２ is hydrogen or alkyl having 1 to 10 carbon atoms; １ and X ２ are each independently -CHR Ｘ１ (R Ｘ１ is hydrogen or alkyl having 1 to 10 carbon atoms), C(O), C(S), and NR Ｘ２ (R Ｘ２ is hydrogen or alkyl having 1 to 10 carbon atoms; Z is -CHR Ｚ１ (R Ｚ１ is hydrogen or alkyl having 1 to 10 carbon atoms), C(O), C(S), and NR Ｚ２ (R Ｚ２ is selected from the group consisting of hydrogen, alkyl having 1 to 10 carbon atoms, OH, optionally R Ｇ１ 3- to 8-membered heterocyclyl optionally substituted with, and optionally R Ｇ２ R is selected from the group consisting of 5- or 6-membered aryl optionally substituted with Ｇ１ and R Ｇ２ are each independently selected from the group consisting of hydrogen or alkyl having 1 to 10 carbon atoms; R ４ and R ５ are independently hydrogen, alkyl having 1 to 10 carbon atoms, and optionally R ６ 3-8 membered cycloalkyl (R ６ is selected from the group consisting of: (CR Ｌ１ R Ｌ２ ) n (n is an integer from 1 to 20), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer from 1 to 3, and m is an integer from 1 to 10), and (O-(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3, and m is an integer of 1 to 10), Ｌ１ , and R Ｌ２ are each independently hydrogen, halogen, OH, or NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ Alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ Cycloalkyl) ２ , N(C １－８ Cycloalkyl) (C １－８ alkyl), OH, NH ２ , S.H., S(O) ２ C １－８ Alkyl, P(O)(OC １－８ Alkyl) (C １－８ alkyl), P(O)(OC １－８ Alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH=CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ Alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , C.H.F. ２ , C.H. ２ F. NO ２ , S.F. ５ , S(O) ２ N.H.C. １－８ Alkyl, S(O) ２ N (C １－８ Alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ Alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ Alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ Alkyl), N(C １－８ Alkyl)C(O)N(C １－８ Alkyl) ２ ,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ Alkyl) ２ , NHC(O)NH ２ , N(C １－８ Alkyl)S(O) ２ NH (C １－８ Alkyl), N(C １－８ Alkyl)S(O) ２ N (C １－８ Alkyl) ２ , N.H.S. (O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ Alkyl) ２ , or NHS(O) ２ N.H. ２ and the minimum number of atoms connecting both ends is 13 to 20.

2. L is (CR Ｌ１ R Ｌ２ 2. The compound according to claim 1, or a salt or solvate thereof, which exhibits a linker structure comprising:

3. The compound according to claim 1, or a salt or solvate thereof, wherein L represents a linker structure having a minimum number of atoms connecting both ends of 14 to 17.

4. L has the formula: (In the formula, L １ (CR Ｌ１ R Ｌ２ ) n (n is an integer from 2 to 20), ((CR Ｌ１ R Ｌ２ )n-O)m (n is an integer from 1 to 3, and m is an integer from 1 to 10), and (O-(CR Ｌ１ R Ｌ２ ) n) m (n is an integer of 1 to 3, and m is an integer of 1 to 10), and optionally CR Ｌ１ =CR Ｌ２ , C≡C, O, S, C(O), S(O), S(O) ２ , N(R Ｌ３ ), S(O) ２ N.R. Ｌ３ , S(O)N(R Ｌ３ ), C(O)N(R Ｌ３ ), N(R Ｌ３ ) C(O)N(R Ｌ４ ), N(R Ｌ３ ) S (O) ２ N (R Ｌ４ ), C(O), Si(R Ｌ１ ) (R Ｌ２ ), and optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ cycloalkyl, optionally R Ｌ１ and / or R Ｌ２ C optionally substituted with ３－１１ heterocyclyl, optionally R Ｌ１ and / or R Ｌ２ and optionally R Ｌ１ and / or R Ｌ２ and one or a combination of two or more of 5- or 6-membered monocyclic aromatic heterocycles optionally substituted by R Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, or NH ２ , S.H., C. １－８ Alkyl, C １－８ Alkoxy, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ Alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, C １－８ Cycloalkoxy, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ Cycloalkyl) ２ , N(C １－８ Cycloalkyl) (C １－８ alkyl), OH, NH ２ , S.H., S(O) ２ C １－８ Alkyl, P(O)(OC １－８ Alkyl) (C １－８ alkyl), P(O)(OC １－８ Alkyl) ２ , C≡C−C １－８ Alkyl, C≡CH, CH=CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ Alkyl) ２ , C(O)C １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , C.H.F. ２ , C.H. ２ F. NO ２ , S.F. ５ , S(O) ２ N.H.C. １－８ Alkyl, S(O) ２ N (C １－８ Alkyl) ２ , S(O)NHC １－８ Alkyl, S(O)N(C １－８ Alkyl) ２ , C(O)NHC １－８ Alkyl, C(O)N(C １－８ Alkyl) ２ , N(C １－８ alkyl)C(O)NH(C １－８ Alkyl), N(C １－８ Alkyl)C(O)N(C １－８ Alkyl) ２ ,NHC(O)NH(C １－８ alkyl), NHC(O)N(C １－８ Alkyl) ２ , NHC(O)NH ２ , N(C １－８ Alkyl)S(O) ２ NH (C １－８ Alkyl), N(C １－８ Alkyl)S(O) ２ N (C １－８ Alkyl) ２ , N.H.S. (O) ２ NH (C １－８ alkyl), NHS(O) ２ N (C １－８ Alkyl) ２ , or NHS(O) ２ N.H. ２ The compound according to claim 1 , or a salt or solvate thereof, wherein 5. L １ (CR Ｌ１ R Ｌ２ )n, where n is an integer from 3 to 20; (C≡C)n, where n is 1 or 2; and / or optionally R Ｌ１ and / or R Ｌ２ and one or a combination of two or more of 5- or 6-membered monocyclic aromatic heterocycles optionally substituted by (CR Ｌ１ R Ｌ２ ) n (n is an integer from 1 to 3) and R Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ４ are each independently hydrogen, halogen, OH, or NH ２ 5. The compound according to claim 4, or a salt or solvate thereof, wherein R is an alkyl group having 1 to 8 carbon atoms, SH, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms.

6. L １ is represented by the following general formula (VI) or (VII): ２ -L ３ -L ４ ... (VI) L ２ -XL ４ ...(VII) (in the formula, L ２ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as defined in claim 4, and n is an integer from 3 to 10; ３ is (C≡C)n (n is 1 or 2), or C≡C-Het １ -Het ２ X is Ar １ -Ar ２ , Het １ -Ar １ , Ar １ -Het １ , or Het １ -Het ２ and Ar １ is a 5- or 6-membered monocyclic aromatic hydrocarbon; Ar ２ is a bond or a 5- or 6-membered monocyclic aromatic hydrocarbon; Het １ is a 5- or 6-membered monocyclic aromatic heterocycle; Het ２ is a bond or a 5- or 6-membered monocyclic aromatic heterocycle; L ４ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as described in claim 4, n is an integer from 1 to 3, ２ is bonded to C(O) of formula (IV) or formula (IV′), and L ４ is bonded to O of formula (IV) or formula (IV'), or a salt or solvate thereof according to claim 4 .

7. L ２ (CR Ｌ１ R Ｌ２ ) n (wherein, R Ｌ１ and R Ｌ２ is as defined in claim 4, and n is an integer from 3 to 8; ３ is (C≡C)n (n is 1 or 2), and X is Het １ -Het ２ and Het １ is a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen or sulfur atoms as ring-constituting atoms, Het ２ The compound according to claim 6, wherein: is a bond or a 5- or 6-membered monocyclic aromatic heterocycle having one or more nitrogen atoms as ring-constituting atoms, or a salt or solvate thereof.

8. X is Het １ -Het ２ and Het １ is a 5-membered monocyclic aromatic heterocycle having two or more nitrogen atoms as ring-constituting atoms, Het ２ The compound according to claim 7, wherein: is a bond or a 6-membered monocyclic aromatic heterocycle having one nitrogen atom as a ring-constituting atom, or a salt or solvate thereof.

9. X is Het １ and Het １ The compound according to claim 8, wherein: is a 5-membered monocyclic aromatic heterocycle having 2 or 3 nitrogen atoms as ring-constituting atoms, or a salt or solvate thereof.

10. X is Het １ and Het １ The compound according to claim 8, wherein: is a 5-membered monocyclic aromatic heterocycle having one sulfur atom as a ring-constituting atom, or a salt or solvate thereof.

11. L has the formula: The compound according to claim 4, or a salt or solvate thereof, wherein the linker is represented by:

12. L １ is represented by the following general formula (XI) or (XII): The compound according to claim 4, or a salt or solvate thereof, having a structure represented by the following formula: [wherein n is an integer of 3 to 10, m is 0 or 1, 1 is an integer of 0 to 10, and is bonded to C(O) in formula (IV) or (V) at the left end and to O in formula (IV) or (V) at the right end.] 13. L １ is represented by the following general formula (XIII) or (XIV): The compound according to claim 4, or a salt or solvate thereof, having a structure represented by the following formula: [wherein n is an integer of 3 to 10, m is 0 or 1, 1 is an integer of 0 to 10, and is bonded to C(O) in formula (XIII) or (XIV) at the left end and to O in formula (XIII) or (XIV) at the right end.] 14. The compound according to claim 12, or a salt or solvate thereof, wherein l is an integer of 1 or 2.

15. The compound according to claim 13, or a salt or solvate thereof, wherein l is an integer of 1 or 2.

16. Formula: A compound represented by the formula:

17. Formula: A compound represented by the formula:

18. Formula: A compound represented by the formula:

19. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1 to 18.

20. The pharmaceutical composition of claim 19, further comprising a pharma- ceutically acceptable carrier.

21. A compound according to any one of claims 1 to 18, or a salt or solvate thereof, or a pharmaceutical composition according to claim 19, for preventing or treating an allergy.

22. The pharmaceutical composition according to claim 21, wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma and allergic rhinitis.

23. A compound according to any one of claims 1 to 18, or a salt or solvate thereof, or a pharmaceutical composition according to claim 19, for treating cancer.

24. Use of a compound according to any one of claims 1 to 18 or a salt or solvate thereof, or a pharmaceutical composition according to claim 19, for the preparation of a medicament.

25. Use of a compound according to any one of claims 1 to 18 or a salt or solvate thereof, or a pharmaceutical composition according to claim 19, for preparing a medicament for preventing or treating an allergy.

26. The use according to claim 25, wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma and allergic rhinitis.

27. Use of a compound according to any one of claims 1 to 18, or a salt or solvate thereof, or a pharmaceutical composition according to claim 19, for the preparation of a medicament for treating cancer.

28. A method for preventing or treating an allergy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a salt or solvate thereof, or a therapeutically effective amount of the pharmaceutical composition according to claim 19.

29. The method according to claim 28, wherein the allergy is at least one selected from the group consisting of atopic dermatitis, allergic bronchial asthma, and allergic rhinitis.

30. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a salt or solvate thereof, or a therapeutically effective amount of the pharmaceutical composition according to claim 19.

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