Low molecular compounds having cereblon-binding activity and use thereof

Abstract

The novel low-molecular-weight compound according to the present invention has excellent binding affinity to Cereblon, and can act as a novel immunomodulator for the treatment of tumors or cancer diseases.

Description

Technology Field

[0001] The present invention relates to a novel small molecule compound having cereblon binding activity and its use in the treatment of tumors or cancer. Background Technology

[0002] The ubiquitin-proteasome pathway (UPP) is an important pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to various cellular processes, and defects or imbalances in it lead to the development of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases consist of over 500 different proteins and are classified into several classes defined by structural elements of E3 functional activity.

[0003] Cereblon (CRBN) interacts with damaged DNA binding protein 1 (DDB1) and forms the DDB1-CUL4a-Roc1 ubiquitin ligase complex with Cullin 4, and functions as a substrate receptor through which proteins recognized by CRBN are ubiquitinated and can be degraded by the proteasome.

[0004] Cereblon (CRBN) is known as a molecular target of immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide (Lopez-Girona et al.; Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012; 26:2326-2335). Specifically, thalidomide, a drug approved for the treatment of multiple myeloma in the late 1990s, binds to Cereblon and CRL4 CRBN It regulates the substrate specificity of the ubiquitin ligase complex, and this mechanism forms the basis of the pleiotropic effect of thalidomide on immune cells and cancer cells. However, with the reports of side effects of thalidomide, various studies have been conducted to develop analogs with higher efficacy and fewer side effects to utilize it as a cancer treatment. Consequently, cereblon modulators such as lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106 were developed, and their clinical applicability in hematological malignancies, such as multiple myeloma, myelodysplastic syndrome lymphoma, and leukemia, has been demonstrated (Le Roy A et al.: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977).

[0005] The antitumor activity of cereblon modulators is mediated by the following:

[0006] 1) Inhibition of cancer cell proliferation and induction of apoptosis,

[0007] 2) Discontinuation of nutritional support from the tumor stroma,

[0008] 3) Proliferation of T cells, production of cytokines, and activation of NK (natural killer) cells following stimulation of immune cells.

[0009] Accordingly, the inventors of the present invention have made efforts to develop a novel small molecule compound capable of effectively killing tumor cells while possessing substrate specificity for cereblon, and have completed the present invention by developing a novel small molecule compound that acts as a cereblon ligand useful for the treatment of tumors or cancer. Prior art literature

[0010] Lopez-Girona et al.; Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012; 26:2326-2335Le Roy A et al.: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9:977 The problem to be solved

[0011] The present invention aims to provide a novel compound having binding activity to cereblon and its uses. means of solving the problem

[0012] To achieve the above objective, the present invention provides a compound represented by the following formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0013] Chemical formula (I)

[0014]

[0015] In chemical formula (I),

[0016] (i) R is independently hydrogen (H), halogen (X), hydroxy (OH), amino (NH2), alkyl, alkylamine, aminocarbonylalkyl, aminocarbonylaryl, aminosulfonylalkyl, aminocarbonyl alcohol, aminosulfonylaryl, aminosulfonylalkyl, aminoalkylaryl, aminocarbonylaminoaryl, alkylaminocarbonylalkoxy, aminosulfonylaminocarbonylaminoaryl, aminoarylalkylcarboxylkyl, aminoarylalkylcarbonylaminoaryl, aminoarylalkylaminocarboxylkyl, aminoarylalkylaminocarboxylkyl, aminoarylalkylaminocarbonylaminoaryl, aminosulfonylarylaminocarbonylarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoarylalkylcarboxylkoxy, aminoarylalkylcarbonylaminoalkylcarboxyalkyl, aminoarylalkylcarbonylaminoalkylcarboxylic acid, aminoarylaminocarbonylalkylcarbonylaminoaryl, Aminoarylaminocarbonylaryl, or aminosulfonylarylaminocarbonylaryl, or

[0017] (ii) R is a heterocycloalkyl containing CONH, wherein the heterocycloalkyl forms a two-ring fused ring with the benzene ring, the hydrogen (H) bonded to the nitrogen (N) of the CONH is unsubstituted or substituted, and the carbon (C) of the heterocycloalkyl is unsubstituted or substituted with oxygen (O).

[0018] Any benzene ring present in chemical formula (I) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0019] In the present invention, the above chemical formula (I) may be characterized as being represented by the following chemical formula (II).

[0020] Chemical formula (II)

[0021]

[0022] In chemical formula (II),

[0023] R1 is absent, or is CH2, CO, or SO2, and

[0024] R2 is absent or C6H4NHCO, and

[0025] Any benzene ring present in chemical formula (II) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0026] In the present invention, the compound represented by the chemical formula (II) may be characterized as being represented by any one chemical formula selected from the group consisting of the following chemical formulas (II-1) to (II-5).

[0027] Chemical formula (II-1)

[0028]

[0029] Any benzene ring present in the chemical formula (II-1) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted;

[0030] Chemical formula (II-2)

[0031]

[0032] Any benzene ring present in chemical formula (II-2) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted;

[0033] Chemical formula (II-3)

[0034]

[0035] Any benzene ring present in the chemical formula (II-3) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted;

[0036] Chemical formula (II-4)

[0037]

[0038] Any benzene ring present in the chemical formula (II-4) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted;

[0039] Chemical formula (II-5)

[0040]

[0041] Any benzene ring present in the chemical formula (II-5) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0042] In the present invention, any benzene ring present in the formula (I) comprises any one or more hydrogen atoms within the benzene ring, each independently alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, urea, sulfonyl, hydroxy, aldehyde, carboxyl, alkyl halogenated, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heterocycloalkylalkylamino; imino; imido; Amidino; Guanidino; Enamino; Acylamino; Sulfonylamino; Urea, Nitrorea; Oxime; Hydroxylamino; Alkoxyamino; Ar-alkoxyamino; Hydrazino; Hydrazido; Hydrazono; Azido; Nitro; Thio(-SH), Alkylthio; =S; Sulfinyl; Sulfonyl; Aminosulfonyl; Phosphonate; Phospinyl; Acyl; Formyl; Carboxy; Ester; Carbamate; Amido; Cyano; Isocyanato; Isothiocyanato; Cyanato; Thiocyanato; Hydroxyl; Alkoxy; Alkoxyalkyl; Amino; Alkylamino; Carboxy; Nitro; Cyano; Thiol; Thioether; Imine; Imide; Amidine; Guanidine; Enamine; Aminocarbonyl; Acylamino; Phosphonate; Phosphine; Thiocarbonyl; Sulfinyl; It may be characterized by being substituted with sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0043] In the present invention, any benzene ring present in any one of the formulas (II-1) to (II-5) has any one or more hydrogens within the benzene ring independently, -F, -Cl, -Br, -I, (C1-C 10 ) Alkyl group, amino group (-NH2), nitro group (-NO2), -CF3, -CF2H, -CFH2, -CCl2, -CCl2H, -CClH2, -(CH2) n Cl, (C1-C 10 ) alkoxy group, hydroxyl group (-OH), (C1-C 10 ) alkoxyaryl group and C6-C 30 It can be characterized by being substituted with any one selected from the group composed of aryl groups.

[0044] In the present invention, any benzene ring present within the above chemical formula (II-4) has any one or more hydrogens within the benzene ring independently, halogen, C 1-10 Alkyl, C 1-10 It can be characterized by being substituted with an alkyl halide.

[0045] In the present invention, the compound may be characterized by being represented by the following chemical formula (III).

[0046] Chemical formula (III)

[0047]

[0048] In chemical formula (III),

[0049] R 1 Silver, Halogen(X), C 1-10 Alkyl, C 1-10 It is an alkyl halide.

[0050] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt may be characterized by having cereblon binding power.

[0051] The present invention also provides any one of the compounds listed in Table 1, its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts.

[0052] The present invention also aims to provide a pharmaceutical composition for the prevention or treatment of benign tumors or cancer, comprising the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient.

[0053] In the present invention, the cancer may be characterized as being a blood cancer or a solid tumor.

[0054] In the present invention, the blood cancer may be characterized as being selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0055] In the present invention, the solid tumor may be characterized as being selected from the group consisting of melanoma, myoma, multiple myeloma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer.

[0056] The present invention also provides a composition for inhibiting cereblon activity comprising the said compound, its optical isomer, its racemic mixture, its hydrate, or its solvate.

[0057] The present invention also provides a method for the prevention or treatment of diseases associated with cereblon activity, e.g., benign tumors or cancer, comprising the step of administering the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt to a patient in need thereof.

[0058] The present invention also provides the use of said compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of diseases associated with cereblon activity, e.g., benign tumors or cancer.

[0059] The present invention also provides the use of said compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt in the manufacture of a drug for the prevention or treatment of diseases associated with cereblon activity, e.g., benign tumors or cancer. Effects of the invention

[0060] The compound according to the present invention has excellent binding affinity to Cereblon, and can act as a novel immunomodulator for the treatment of tumors or cancer diseases. Specific details for implementing the invention

[0062] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled expert in the art to which this invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

[0064] In the present invention, compounds having excellent binding affinity to Cereblon were selected, and their tumor cell death effects were confirmed.

[0066] Accordingly, in one aspect, the present invention relates to a compound represented by the following formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0067] Chemical formula (I)

[0068]

[0069] In chemical formula (I), R is independently hydrogen (H), halogen (X), hydroxy (OH), amino (NH2), alkyl, alkylamine, aminocarbonylalkyl, aminocarbonylaryl, aminosulfonylalkyl, aminocarbonyl alcohol, aminosulfonylaryl, aminosulfonylalkyl, aminoalkylaryl, aminocarbonylaminoaryl, alkylaminocarbonylalkoxy, aminosulfonylaminocarbonylaminoaryl, aminoarylalkylcarboxylkyl, aminoarylalkylcarbonylaminoaryl, aminoarylalkylaminocarboxylkyl, aminoarylalkylaminocarbonylaminoaryl, aminosulfonylarylaminocarbonylarylalkoxy, aminoarylalkylcarbonylaminoalkylalkoxy, aminoarylalkylcarbonylaminoalkylcarboxylkoxy, aminoarylalkylcarbonylaminoalkylcarboxylic acid, It may be aminoarylaminocarbonylalkylcarbonylaminoaryl, aminoarylaminocarbonylaryl, or aminosulfonylarylaminocarbonylaryl, but is not limited thereto.

[0070] In one embodiment, R is independently hydrogen (H), halogen (X), hydroxyl (OH), NHCOC 1-6 Alkyl, NHCOaryl, Amino(NH2), C 4-8 Cycloalkyl, NH-C 4-8 Heterocycloalkyl, NHCOC 3-7 Heterocycloalkyl, NHCOC2OC2 heterocycloalkyl, NHSO2C 3-7 Heterocycloalkyl, NHSO2C6H5, NHSO2C 10 H6, or it may be NHCOC2H4OH, but is not limited thereto.

[0071] In some embodiments, in the above formula (I), R may independently be aminosulfonylphenyl (NHSO2C6H5) aminoalkylphenyl (NHCH2C6H5), aminophenylaminocarbonylphenyl (NHC6H4NHCOC6H5), aminosulfonylphenylaminocarbonylphenyl (NHSO2C6H4NHCOC6H5) or aminocarbonylphenyl (NHCOC6H5), but is not limited thereto.

[0072] In another embodiment, in the above formula (I), R may be a heterocycloalkyl containing C(O)NH and may form a fused ring of two rings with a benzene ring.

[0073] For example, in the above chemical formula (I), the benzene ring may be an aralkyl fused with a heterocycloalkyl.

[0074] In another embodiment, in the above formula (I), R may be a heterocycloalkyl containing C(O)NH, and the heterocycloalkyl may be a compound in which one carbon of the heterocycloalkyl is substituted with oxygen, forming a fused ring of two rings with a benzene ring. For example, the compound of the above formula (I) may have a structure including the following fused ring of two rings,

[0075] , , , , , or .

[0076] In the present invention, the compound of formula (I) may be AEV40032, AEV40040, AEV40041, AEVAEV40062, AEV40078, or AEV40079.

[0077] In the above two-ring fused ring, the heterocycloalkyl containing CONH may have the hydrogen of CONH unsubstituted or substituted.

[0078] In the above-mentioned fused ring of two rings, the heterocycloalkyl containing CONH has hydrogens of CONH that are alkyl (e.g., CH3), alkoxy, aryl (e.g., C6H5), alkylalkoxy (e.g., C2H4OCH3), alkylaryl (e.g., CH2C6H5), C2H4C6H5), arylamines (C6H4NH2), SO2C6H4Cl, SO2CH3, alkylarylalkoxy (e.g., CH3C6H4OCH3), C6H4NHCO(C 3-7 (Cycloalkyl)CH3, C6H4NHCOC5H9O, C6H4NHCO(C6H4)C 1-7 Alkyl, or C6H4NHCO(C 3-7 Cycloalkyl)CONHC6H4X, C6H4NHCOC6H3X2 can be substituted.

[0079] In the present invention, the compound of formula (I) may be AEV40036, AEV40042, AEV40049, AEV40050, AEV40059, AEV40077, AEV40085, AEV40086, AEV40206, AEV40212, AEV40213, AEV40214, AEV40215, AEV40216, or AEV40217.

[0080] In another embodiment, in the chemical formula (I), R is a heterocyclopentyl in which the carbons in the cyclopentyl are each substituted with nitrogen (N) and oxygen (O), said heterocyclopentyl forms a 2-ring fused ring with a benzene ring, said heterocyclopentyl forms a double bond between the nitrogen (N) and the carbon in the heterocyclopentyl, said heterocyclopentyl forms a double bond, and the hydrogen (H) bonded to the carbon (C) between the nitrogen (N) and the oxygen (O) may be unsubstituted or substituted with a heterocyclohexyl in which one carbon is substituted with nitrogen (N), or a heterocyclohexyl in which one carbon is substituted with nitrogen (N) and the other carbon is substituted with oxygen (O).

[0081] For example, the compound of the above chemical formula (I) may have a structure including the following two-ring fused ring.

[0082] , or

[0083] In the present invention, the compound of formula (I) may be AEV40203, AEV40207, or AEV40208.

[0084] In one embodiment, R of the above chemical formula (I) may be any one selected from the following group.

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] In the present invention, the above chemical formula (I) may be characterized as being represented by the following chemical formula (II), but is not limited thereto.

[0101] Chemical formula (II)

[0102]

[0103] In chemical formula (II),

[0104] R1 is absent, or is CH2, CO, or SO2, and

[0105] R2 is absent or C6H4NHCO, and

[0106] Any benzene ring present in chemical formula (II) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted;

[0107] In the present invention, the compound represented by the chemical formula (II) may be characterized as being represented by any one chemical formula selected from the group consisting of the following chemical formulas (II-1) to (II-5), but is not limited thereto.

[0108] Chemical formula (II-1)

[0109]

[0110] Any benzene ring present in chemical formula (II-1) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0111] In some embodiments, any benzene ring present in formula (II-1) may have one hydrogen atom within the benzene ring that is a halogen (e.g., F, Cl, Br, or I), (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), CF3, NO2, NH2, NHCO(cycloalkyl)alkyl (e.g., NHCOC6H 10It may be substituted with CH3, NHCOC3H4CH3, NHCOC5H9O, or a carboxyl group (e.g., COOCH3), and in another embodiment, one or two benzene rings present in formula (II-1) may have a total of two or more hydrogens independently substituted with a halogen, alkyl CF3, NO2, or NH2. For example, in one benzene ring or in two benzene rings present in formula (II-1), two hydrogens may be substituted with a halogen and a halogen, a halogen and an alkyl, CF3 and NO2, an alkyl and NO2, CF3 and NH2, or an alkyl and NH2.

[0112] In the present invention, the compound of formula (II-1) is AEV40025, AEV40037, AEV40038, AEV40043, AEV40044, AEV40045, AEV40046, AEV40047, AEV40052, AEV40053, AEV40054, AEV40055, AEV40056, AEV40057, AEV40058, AEV40060, AEV40061, AEV40063, AEV40069, AEV40070, AEV40073, AEV40074, AEV40075, AEV40099, AEV40100, AEV40101, AEV40224, AEV40225, in Table 1 It could be AEV40226 or AEV40227.

[0113] Chemical formula (II-2)

[0114]

[0115] Any benzene ring present in chemical formula (II-2) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0116] In some embodiments, any benzene ring present in formula (II-2) may have one hydrogen in the benzene ring substituted with a halogen (e.g., F, Cl, Br or I), (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), hydroxy(OH), alkoxy (e.g., methoxy, ethoxy or phenoxy), CX3, CX2H, CXH2, or aryl, and in other embodiments, one benzene ring or two benzene rings present in formula (II-2) may have a total of two or more hydrogens independently substituted with a halogen, alkyl, hydroxy, alkoxy, CX3, CX2H, CXH2, or aryl. For example, in one benzene ring or two benzene rings present in formula (II-2), two hydrogens can be substituted with halogen and halogen, halogen and alkyl, alkyl and alkyl, halogen and alkoxy, halogen and hydroxy, or alkyl and alkoxy, and three hydrogens in one benzene ring or two benzene rings present in formula (II-2) can be substituted with three halogens.

[0117] In the present invention, the compound of formula (II-2) may be AEV40087, AEV40090, AEV40094, AEV40095, AEV40096, AEV40097, AEV40098, AEV40102, AEV40103, AEV40104, AEV40105, AEV40106, AEV40107, AEV40108, AEV40109, AEV40110, AEV40121, AEV40122 in Table 1.

[0118] Chemical formula (II-3)

[0119]

[0120] Any benzene ring present in the chemical formula (II-3) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0121] In some embodiments, any benzene ring present in formula (II-3) may have one hydrogen within the benzene ring substituted with a halogen (e.g., F, Cl, Br, or I) or an alkyl (branched or unbranched) (methyl, ethyl, propyl, butyl, or pentyl); in other embodiments, one benzene ring or two benzene rings present in formula (II-3) may have a total of two or more hydrogens independently substituted with a halogen (e.g., F, Cl, Br, or I) or an alkyl (branched or unbranched) (methyl, ethyl, propyl, butyl, or pentyl). For example, in the one benzene ring or two benzene rings present in formula (II-3), two hydrogens may be substituted with a halogen and a halogen.

[0122] In the present invention, the compound of formula (II-3) may be AEV40220 or AEV40221 in Table 1.

[0123] Chemical formula (II-4)

[0124]

[0125] Any benzene ring present in the chemical formula (II-4) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0126] In some embodiments, any benzene ring present in formula (II-4) may have one hydrogen atom in the benzene ring that is a halogen (e.g., F, Cl, Br, or I), (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nanyl, or decyl), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), or alkyl halide (CH2X, C2H4X, C3H6X, C4H8X, C5H 10 X, C6H 12 X, C7H 14 X, C8H16X, C9H 18 X or C 10 H 20X), CX3, CX2H, or CXH2 may be substituted, and in another embodiment, one or two benzene rings present in formula (II-4) may have a total of two or more hydrogens independently substituted with halogens, (branched or unbranched) alkyls, or CX3. For example, within the one benzene ring or two benzene rings present in formula (II-4), two hydrogens may be substituted with halogens and halogens, or halogens and CX3, and within the one benzene ring or two benzene rings present in formula (II-4), three hydrogens may be substituted with three halogens.

[0127] In the present invention, the compound of formula (II-4) is AEV40135, AEV40136, AEV40142, AEV40143, AEV40149, AEV40150, AEV40151, AEV40152, AEV40153, AEV40154, AEV40155, AEV40156, AEV40157, AEV40158, AEV40159, AEV40193, AEV40204, AEV40264, AEV41001, AEV41002, AEV41003, AEV41004, AEV41005, AEV41009, AEV41010, AEV41011, AEV41013, AEV41083, in Table 1 It could be AEV41047 or AEV41048.

[0128] Chemical formula (II-5)

[0129]

[0130] Any benzene ring present in the chemical formula (II-5) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted.

[0131] In some embodiments, any benzene ring present in formula (II-5) may have one hydrogen in the benzene ring substituted with a halogen (e.g., F, Cl, Br, or I), (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), CX3, CX2H, CXH2, or aryl (e.g., phenyl); and in other embodiments, one benzene ring or two benzene rings present in formula (II-5) may have a total of two or more hydrogens independently substituted with a halogen (e.g., F, Cl, Br, or I), (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), CX3, CX2H, CXH2, or It can be substituted with an aryl (e.g., phenyl). For example, in one benzene ring or in two benzene rings present in formula (II-5), two hydrogens can be substituted with a halogen and a halogen, a halogen and an alkyl, a halogen and an alkoxy, an alkyl and an alkyl, or a halogen and an aryl, and three hydrogens in one benzene ring or in two benzene rings present in formula (II-5) can be substituted with three halogens.

[0132] In the present invention, the compound of formula (II-5) may be AEV40076, AEV40088, AEV40134, AEV40137, AEV40138, AEV40139, AEV40140, AEV40141, AEV40144, AEV40145, AEV40146, AEV40147, AEV40148, AEV40162, AEV40164, AEV40165, AEV40166, AEV176, AEV40178, AEV40179, AEV40180, AEV40218, AEV40222, or AEV40223 in Table 1.

[0133] In the present invention, any benzene ring present in the formula (I) comprises any one or more hydrogen atoms within the benzene ring, each independently alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, urea, sulfonyl, hydroxy, aldehyde, carboxyl, alkyl halogenated, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heterocycloalkylalkylamino; imino; imido; Amidino; Guanidino; Enamino; Acylamino; Sulfonylamino; Urea, Nitrorea; Oxime; Hydroxylamino; Alkoxyamino; Ar-alkoxyamino; Hydrazino; Hydrazido; Hydrazono; Azido; Nitro; Thio(-SH), Alkylthio; =S; Sulfinyl; Sulfonyl; Aminosulfonyl; Phosphonate; Phospinyl; Acyl; Formyl; Carboxy; Ester; Carbamate; Amido; Cyano; Isocyanato; Isothiocyanato; Cyanato; Thiocyanato; Hydroxyl; Alkoxy; Alkoxyalkyl; Amino; Alkylamino; Carboxy; Nitro; Cyano; Thiol; Thioether; Imine; Imide; Amidine; Guanidine; Enamine; Aminocarbonyl; Acylamino; Phosphonate; Phosphine; Thiocarbonyl; Sulfinyl; Sulfon; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; may be characterized by being substituted with B(OH)2, or O(alkyl)aminocarbonyl, but is not limited thereto.

[0134] In the present invention, any benzene ring present in any one of the formulas (II-1) to (II-5) has any one or more hydrogens within the benzene ring independently, -F, -Cl, -Br, -I, (C1-C 10 ) Alkyl group, amino group (-NH2), nitro group (-NO2), -CF3, -CF2H, -CFH2, -CCl2, -CCl2H, -CClH2, -(CH2) n Cl, (C1-C 10 ) alkoxy group, hydroxyl group (-OH), (C1-C 10 ) alkoxyaryl group and C6-C 30 It may be characterized by being substituted with any one selected from the group composed of aryl groups, but is not limited thereto.

[0135] In the present invention, the compound may be characterized as being any one of the compounds listed in Table 1, but is not limited thereto.

[0136] In the present invention, any benzene ring present within the above chemical formula (II-4) has any one or more hydrogens within the benzene ring independently, halogen, C 1-10 Alkyl, C 1-10 It may be characterized by being substituted with alkyl halides, but is not limited thereto.

[0137] In the present invention, the compound may be characterized by being represented by the following chemical formula (III), but is not limited thereto.

[0138] (Chemical Formula III)

[0139]

[0140] In chemical formula (III),

[0141] R 1 Silver, halogen, C 1-10 Alkyl, C 1-10 It is an alkyl halide.

[0143] As a specific embodiment, the compound may be characterized as being any one selected from the group consisting of the following chemical formulas.

[0144] Chemical formula (i)

[0145]

[0146] Chemical formula (ii)

[0147]

[0148] Chemical formula (iii)

[0149]

[0150] Chemical formula (iv)

[0151]

[0152] Chemical formula (v)

[0153]

[0154] Chemical formula (vi)

[0155]

[0156] Chemical formula (vii)

[0157]

[0158] Chemical formula (viii)

[0159]

[0160] Chemical formula (ix)

[0161]

[0162] Chemical formula (x)

[0163]

[0164] Chemical formula (xi)

[0165]

[0166] Chemical formula (xii)

[0167]

[0168] Chemical formula (xiii)

[0169]

[0170] Chemical formula (xiv)

[0171]

[0172] Chemical formula (xv)

[0173]

[0174] Chemical formula (xvi)

[0175]

[0177] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt may be characterized by having cereblon binding power.

[0179] In the present invention, the "alkyl" group is a saturated, partially saturated, or unsaturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; meanwhile, saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, the alkyl group is an unsaturated alkyl group, which is also referred to as an alkenyl or alkynyl group. The "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. The "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡C-, and -CH2C≡. The alkyl group may be substituted or unsubstituted.Where the alkyl group described herein is described as "substituted," these include any substituent or substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocycliloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclilalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclilamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclilalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; It may be substituted with azido; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, where the alkyl group described herein is described as "substituted," these include any substituent or substitutes such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; It can be substituted with B(OH)2 or O(alkyl)aminocarbonyl.

[0180] The “cycloalkyl” group is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms having a single cyclic ring or a plurality of condensed or cross-linked rings that may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, for example, a single ring structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or a plurality of or cross-linked ring structures, such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0181] The “aryl” group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains 6 to 14 carbons within the ring portion of the group, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms. Specific aryls include phenyl, biphenyl, naphthyl, etc. The hydrogens of the aryl group may be substituted or unsubstituted. The phrase “aryl group” also includes a group containing a fused ring, such as a fused aromatic-aliphatic ring system (e.g., indanyl, tetrahydronaphthyl, etc.). Other functional groups may be attached to one or both ends of the aryl group.

[0182] "Heterocyclile" is a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, the heterocyclile group comprises 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclile may also be bonded to another group at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). The heterocycloalkyl group may be substituted or unsubstituted. The heterocyclile group comprises unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The term heterocyclil includes fused ring species comprising fused aromatic and non-aromatic groups, such as 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxolyl, and benzo[1,3]dioxolyl. This term also includes cross-linked polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclideyl.Representative examples of heterocyclil groups include aziridinyl, azetidinyl, azephanyl, oxetanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolill, imidazolidinyl, pyrazolill, pyrazolidinyl, triazolillyl, tetrazollyl, oxazolillyl, isooxazolillyl, benzisooxazolillyl (e.g., benzo[d]isooxazolillyl), thiazolillyl, thiazolidinyl, isothiazollyl, thiadiazolillyl, oxadiazolillyl, piperidyl, and piperazinyl (e.g., piperazine-2-onyl). Morfollinil, thiomophorinil, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranill, oxatianil, dioxyl, dithianil, pyranil, pyridyl, pyrimidyl, pyridazinil, pyrazinil, triazinil, dihydropyridyl, dihydrodithiinil, dihydrodithionyl, 1,4-dioxaspiro[4.5] Decanyl, homopiperazinyl, quinucridyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazolyl-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzoditinyl, benzoxatininyl, benzothiazinyl, benzoxazolyl (i.e., Benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isooxazolopyridyl, furinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naftiridinyl, pteridinyl, Tianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidine-2(1H)-one, and tetrahydroquinolinyl groups are included but not limited thereto. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups.Examples of non-aromatic heterocyclil groups include aziridinyl, azetidinyl, azephanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranill, oxatianil, dithianil, 1,4-dioxaspiro[4.5]decanil, homopiperazinyl, quinuclideyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclil groups may be unsubstituted or substituted more than once, and include pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents such as those listed below, for example, but not limited to.

[0183] The "cycloalkylalkyl" group has the chemical formula -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. The substituted cycloalkylalkyl group may be substituted at the alkyl portion, the cycloalkyl portion, or both the alkyl portion and the cycloalkyl portion of this group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, etc.

[0184] The “aralkyl” group has the chemical formula -alkyl-aryl, where alkyl and aryl are defined above. The substituted aralkyl group may be substituted in the alkyl portion, the aryl portion, or both the alkyl portion and the aryl portion of this group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which an aryl group is fused to a cycloalkyl group, such as indan-4-yl ethyl.

[0185] The "heterocyclylalkyl" group has the chemical formula -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. The "heterocycloalkylalkyl" group has the chemical formula -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. The substituted heterocyclylalkyl group may be substituted at the alkyl portion, the heterocyclyl portion, or both the alkyl portion and the heterocyclyl portion of this group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-yl ethyl, morpholine-4-yl propyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indole-2-yl propyl.

[0186] "Halogen(X)" is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0187] "Alkyl halide" is one in which some hydrogens of an alkyl group are substituted with a halogen, for example, it may be an alkyl fluoride, an alkyl chloride, an alkyl bromide, or an alkyl iodide, and in some embodiments, the alkyl halide is a saturated alkyl halide (C n H 2n It may be X), preferably an alkyl halide having 1 to 10 carbon atoms (CH2X, C2H4X, C3H6X, C4H8X, C5H 10 X, C6H 12 X, C7H 14 X, C8H 16 X, C9H 18 X, C 10 H 20 X) It could be.

[0188] The "hydroxyalkyl" group is an alkyl group substituted with one or more hydroxyl groups. It can also be represented as an alcohol, and other functional groups may be attached to one or both ends.

[0189] The "alkoxy" group is -O-(alkyl), where alkyl is defined above. Other functional groups may be attached to one or both ends of the alkoxy group.

[0190] The "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0191] The "amino" or "amine" group has the chemical formula -NH2 or -NH-, and other functional groups may be attached to one or both ends.

[0192] In one embodiment, the "amino" group is a chemical formula -NH2, -NH- or -NH-alkyl, where each alkyl is independently defined above.

[0193] The “sulfonyl” group has the chemical formula -SO2-, and other functional groups may be attached to one or both ends.

[0194] The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heterocycloalkylamino," etc., reflect the above description of "alkylamino," wherein the term "alkyl" is replaced here with "cycloalkyl," "aryl," "heterocyclyl," "heterocycloalkyl," etc., respectively.

[0195] The "carboxy(carboxyl)" group or carboxylic acid has the chemical formula -C(O)OH or -C(O)O-, and other functional groups may be attached to one or both ends.

[0196] The "hydroxy" group has the chemical formula -OH.

[0197] The "aldehyde" group has the chemical formula -CHO.

[0198] As used herein and unless otherwise specified, the “acyl” group is the formula -C(O)(R) or -C(O)H, where R is defined above. The “formyl” group is the formula -C(O)H.

[0199] As used herein and unless otherwise specified, the “carbonyl” group is -C(O)-, and other functional groups may be attached to one or both ends.

[0200] As used in this specification and unless otherwise specified, the “amido” group is the chemical formula -C(O)-NH2, -C(O)-NH(R), -C(O)-N(R)2, -NH-C(O)H, -NH-C(O)-(R), -N(R)-C(O)H, or -N(R)-C(O)-(R), where each R is independently defined above.

[0201] In one embodiment, the "amido" group is an "aminocarbonyl" group with the chemical formula -C(O)-NH2, -C(O)-NH(R), -C(O)-N(R)2, where each R is independently defined above.

[0202] In one embodiment, the "amido" group is an "acylamino" group with the chemical formula -NH-C(O)H, -NH-C(O)-(R), -N(R)-C(O)H, or -N(R)-C(O)-(R), where each R is independently defined above.

[0203] The "sulfonylamino" group has the chemical formula -NHSO2(R) or -N(alkyl)SO2(R), where each alkyl and R is defined above.

[0204] The "urea" group has the chemical formula -N(alkyl)C(O)N(R)2, -N(alkyl)C(O)NH(R), -N(alkyl)C(O)NH2, -NHC(O)N(R)2, -NHC(O)NH(R), or -NH(CO)NH2, where each alkyl and R are independently defined as above.

[0205] The “alkylamine” group is formed by the combination of an alkyl group and an amine group, and other functional groups may be attached to one or both ends.

[0206] The “aminocarbonylalkyl” group is formed by sequentially bonding an amino group, a carbonyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0207] The “aminocarbonylaryl” group is formed by sequentially combining an amino group, a carbonyl group, and an aryl group, and other functional groups may be attached to one or both ends.

[0208] The “aminosulfonylalkyl” group is formed by sequentially bonding an amino group, a sulfonyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0209] The “aminocarbonylhydroxyalkyl” group is formed by sequentially bonding an amino group, a carbonyl group, and a hydroxyalkyl group, and other functional groups may be bonded to one or both ends.

[0210] The “aminosulfonylaryl” group is formed by sequentially combining an amino group, a sulfonyl group, and an aryl group, and other functional groups may be attached to one or both ends.

[0211] The “aminosulfonylalkyl” group is formed by sequentially bonding an amino group, a sulfonyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0212] The “aminocarbonylaminoaryl” group is formed by sequentially combining an amino group, a carbonyl group, an amino group, and an aryl group, and other functional groups may be attached to one or both ends.

[0213] The “alkylaminocarbonylalkoxy” group is formed by sequentially bonding an alkyl group, an amino group, a carbonyl group, and an alkoxy group, and other functional groups may be bonded to one or both ends.

[0214] The “aminosulfonylaminocarbonylaminoaryl” group is formed by sequentially bonding an amino group, a sulfonyl group, an amino group, a carbonyl group, an amino group, and an aryl group, and other functional groups may be bonded to one or both ends.

[0215] The “aminoarylkylcarboxylkyl” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, a carboxyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0216] The “aminoarylalkylcarbonylaminoaryl” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, and an aryl group, and other functional groups may be bonded to one or both ends.

[0217] The “aminoarylalkylaminocarboxylkyl” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, an amino group, a carboxyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0218] The “aminoarylalkylaminocarbonylaminoaryl” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, an amino group, a carbonyl group, an amino group, and an aryl group, and other functional groups may be bonded to one or both ends.

[0219] The “aminosulfonylarylaminocarbonylarylalkoxy” group is formed by sequentially combining an amino group, a sulfonyl group, an aryl group, an amino group, a carbonyl group, an aryl group, and an alkoxy group, and other functional groups may be attached to one or both ends.

[0220] The “aminoarylalkylcarbonylaminoarylalkoxy” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, an aryl group, and an alkoxy group, and other functional groups may be bonded to one or both ends.

[0221] The “aminoarylalkylcarbonylaminoalkylcarboxyalkyl” group is formed by sequentially bonding an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, an alkyl group, a carboxyl group, and an alkyl group, and other functional groups may be bonded to one or both ends.

[0222] The “aminoarylalkylcarbonylaminoalkylcarboxylic acid” group is formed by sequentially combining an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, an alkyl group, and a carboxylic acid, and other functional groups may be attached to one or both ends.

[0223] The “aminoarylaminocarbonylalkylcarbonylaminoaryl” group is formed by sequentially bonding an amino group, an aryl group, an amino group, a carbonyl group, an alkyl group, a carbonyl group, an amino group, and an aryl group, and other functional groups may be bonded to one or both ends.

[0224] The “aminoarylaminocarbonylaryl” group is formed by sequentially combining an amino group, an aryl group, an amino group, a carbonyl group, and an aryl group, and other functional groups may be attached to one or both ends.

[0225] The “aminosulfonylarylaminocarbonylaryl” group is formed by sequentially bonding an amino group, a sulfonyl group, an aryl group, an amino group, a carbonyl group, and an aryl group, and other functional groups may be bonded to one or both ends.

[0226] Where groups described herein excluding alkyl groups are described as "substituted," they may be substituted with any suitable substituents. Exemplary examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; Cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl (which may be monocyclic or fused or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl)), or heterocyclic (which may be monocyclic or fused or unfused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl)); monocyclic or fused or unfused polycyclic aryl (e.g., phenyl, naphthyl) aryloxy; aralkyloxy; heterocyclicoxy; and heterocyclic alkoxy.

[0228] Since the compound according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, the above-mentioned prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. Furthermore, the compound has a chiral carbon, so stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0229] The term "prodrug" refers to a substance that is modified into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be able to achieve bioavailability by oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, the prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to expose the active site of the peptide.

[0230] The term "hydrate" means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0231] The term "solvate" means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0232] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or stereochemically. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0233] The term "pharmaceuticalally acceptable salt" refers to a form of salt of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc.; organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound according to the present invention can be converted into its salt by conventional methods.

[0235] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of benign tumors or cancer comprising, as an active ingredient, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt.

[0236] In the present invention, the cancer may be characterized as being a blood cancer or a solid tumor.

[0237] In the present invention, the blood cancer may be characterized as being selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma, but is not limited thereto.

[0238] In the present invention, the solid tumor may be selected from the group consisting of melanoma, myoma, multiple myeloma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer, but is not limited thereto.

[0240] In the present invention, the terms “pharmaceutical composition” or “pharmaceutical formulation” refer to a mixture comprising a novel compound of the present invention and a pharmaceutically acceptable excipient, such as a diluent or carrier, which makes the novel compound particularly suitable for in vivo or in vitro diagnostic or therapeutic use. According to some embodiments, a pharmaceutical composition comprising a composition of the present invention may be provided by a method of administering a therapeutically effective amount to a subject as needed. In some embodiments, a composition of the present invention may be administered to a human.

[0241] As used in the present invention, "effective amount" or "therapeutically-effective amount" refers to an amount of a compound or composition (e.g., a compound or composition of the present invention) sufficient to achieve a beneficial or desired result. The effective amount may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific formulation or route of administration.

[0242] The pharmaceutical composition provided in the present invention relates, in principle, to a pharmaceutical composition intended for administration to humans; however, a person skilled in the art will understand that such composition is generally suitable for administration to all kinds of animals. That is, the pharmaceutical composition according to the present invention may also be administered to other mammals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). A skilled veterinary pharmacologist who has a good understanding of variations of the pharmaceutical composition for administration to various animals can design and / or perform such variations simply through routine experimentation if necessary.

[0243] The pharmaceutical compositions described in the present invention may be prepared by any method known in the pharmacological field or described below. Generally, such methods for tablets include the step of associating an active ingredient with an excipient and / or one or more other auxiliary ingredients, and then, if necessary or desired, forming and / or packaging the product into desired single- or multiple-dose units.

[0244] The pharmaceutical composition of the present invention may be manufactured, packaged, and / or sold unpackaged as a single unit dose and / or multiple single unit doses. As used herein, a “unit dose” is an individual amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient administered to a subject and / or a convenient fraction of such dose, e.g., 1 / 2 or 1 / 3 of the dose.

[0245] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical composition of the present invention will vary depending on the identity, size, and / or disorder of the patient being treated and the route of administration of the composition. For example, the composition may contain 0.001% to 100% (w / w) of the active ingredient.

[0246] As used in the present invention, pharmaceutically acceptable excipients include any solvent, dispersion medium, diluent, or other liquid vehicle, dispersion or suspension aid, surfactant, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, etc. suitable for a specific dosage form. The literature of Remington [The Science and Practice of Pharmacy, 21st Edition, AR Gennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006)] discloses various excipients used in the preparation of pharmaceutical compositions and known techniques for their preparation. Except where any conventional carrier medium cannot coexist with the substance or its derivatives by, for example, providing any undesirable biological effect or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition, its use is considered to be within the scope of the present invention. Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.

[0247] The excipients are approved for human and veterinary use. In some embodiments, the excipients are approved by the U.S. Food and Drug Administration. In some embodiments, the excipients are pharmaceutical grade. In some embodiments, the excipients meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia (EP).

[0248] In some embodiments, the excipients are approved for human and veterinary use. In some embodiments, the excipients are approved by the U.S. Food and Drug Administration. In some embodiments, the excipients are pharmaceutical grade. In some embodiments, the excipients meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia (EP).

[0249] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils.

[0250] These excipients may optionally be included in the formulation of the present invention. Excipients such as cocoa butter and suppository wax, coloring agents, coating agents, sweeteners, flavoring agents, and perfumes may be present in the composition at the discretion of the pharmacist.

[0251] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dical calcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugars, and combinations thereof.

[0252] Exemplary granulators and / or dispersants include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginate, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pre-gelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (bi gum), sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof.

[0253] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and bee gum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, and cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethyl Cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Twin 20], polyoxyethylene sorbitan [Twin 60], polyoxyethylene sorbitan monooleate [Twin 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Mirz 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., cremophor), polyoxyethylene Ether, (e.g., polyoxyethylene lauryl ether [Breeze 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laureate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, sodium docusate, and / or combinations thereof, including but not limited to these.

[0254] Exemplary binders include, but are not limited to, starch (e.g., corn starch and starch paste); gelatin; sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, Panwer gum, Shaty gum, Isapol husks mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (V-gum), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silica; polymethacrylates; waxes; water; alcohols; and combinations thereof.

[0255] Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimid, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexatidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acid preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, fenonib, methylparaben, Germol 115, Germaben II, neolon, carton, and euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0256] Exemplary buffers include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentacarbonate, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof, but not limited to these.

[0257] Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0258] Exemplary oils include almond, apricot kernel, avocado, babassu, bergamot, black currant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, pumpkin, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, cucui nut, lavandin, lavender, lemon, Lythea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange lapis lazuli, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sazquana, savory, sea buckthorn, sesame, and shea. Butter, silicone, soybean, sunflower, tea tree, milk thistle, tsubaki, vetiver, walnut, and wheat germ oils are included, but not limited thereto. Exemplary oils include butyl stearate, caprylic acid triglyceride, capric acid triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof, but are not limited thereto.

[0259] Liquid formulations for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid formulation may include inert diluents commonly used in the art, such as, for example, water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (particularly cottonseed, peanut, corn, sprout, olive, castor, and sesame oils); polyethylene glycol and fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, and sorbitan; and mixtures thereof. In addition to the inert diluent, the oral composition may include ajuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and perfumes. In a specific embodiment for parenteral administration, the novel compound of the present invention is mixed with a solubilizing agent such as cremophor, alcohol, oil, denatured oil, glycol, polysorbate, cyclodextrin, polymer, and combinations thereof.

[0260] Injectable formulations, e.g., sterile injectable aqueous or oily suspensions, may be prepared according to the known art using dispersants or wetting agents and suspending agents. Sterile injectable formulations may be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, e.g., solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solutions may be adopted. Additionally, sterile fixing oils are typically adopted as solvents or suspension media. For this purpose, any non-irritating fixing oil containing synthetic mono- or diglycerides may be adopted. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

[0261] Injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by including a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0262] To prolong the effect of a drug, it is often desirable to slow down its absorption from subcutaneous or intramuscular injections. This is achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on the solubility, which can ultimately be influenced by crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drugs is achieved by dissolving or suspending the drug in an oil vehicle.

[0263] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient comprises one or more inert pharmaceutically acceptable excipients or carriers, such as sodium citrate or dical phosphate and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, It is mixed with solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.

[0264] In the case of capsules, tablets, and pills, the dosage forms may include a buffer. Similar types of solid compositions may also be adopted as fillers in soft and hard-filled gelatin capsules using lactose or lacsose, as well as high molecular weight polyethylene glycol, etc., as such excipients. Solid dosage forms of tablets, coated tablets, capsules, pills, and granules may be manufactured with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. These may optionally include an opacifying agent and may be compositions that release only the active ingredient, or preferentially, to a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric materials and waxes. Similar types of solid compositions may also be adopted as fillers in soft and hard-filled gelatin capsules using lactose or lacsose, as well as high molecular weight polyethylene glycol, etc., as such excipients.

[0265] The active ingredient may be in a micro-encapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, coated tablets, capsules, pills, and granules may be manufactured with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In these solid dosage forms, the active ingredient may be mixed with one or more inert diluents, such as sucrose, lactose, or starch. These dosage forms may include additional substances other than inert diluents as in ordinary practice, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may include buffers. They may optionally include opacifiers and may be compositions that release only the active ingredient, or preferentially, to a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric materials and waxes.

[0266] Dosage forms for topical and / or transdermal administration of the novel compounds of the present invention or pharmaceutical compositions containing them may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffers that may be required under sterile conditions. Additionally, the present invention considers the use of transdermal patches, which have the additional advantage of providing controlled delivery of the active ingredient to a body. Such dosage forms may be prepared, for example, by melting and / or dispersing the active ingredient in a suitable medium. Alternatively, or additionally, the ratio may be controlled by providing a ratio-controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0267] Formulations for topical administration include, but are not limited to, liquid and / or semi-liquid formulations such as ointments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments / or pastes, and / or solutions and / or suspensions. Although the concentration of the active ingredient may be as high as the limit of the solubility of the active ingredient in the solvent, the topically administered formulation may contain, for example, about 1% to about 10% (w / w) of the active ingredient. The formulation for topical administration may additionally contain one or more additional ingredients as described herein.

[0268] The novel compounds of the present invention or pharmaceutical compositions containing them described herein are typically prepared in the form of dosage units for easy and uniform administration. However, it will be understood that the total daily dosage of the compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject will depend on various factors including disease, disorder, or the disorder and severity of the disorder being treated; the activity of the specific active ingredient adopted; the specific composition adopted; the subject's age, weight, overall health, gender, and diet; the time of administration, route of administration, and elimination rate of the specific active ingredient adopted; the duration of treatment; drugs used in combination with or simultaneously with the specific active ingredient adopted; and factors well known in the medical field, etc.

[0269] The novel compounds of the present invention, their salts, or their pharmaceutical compositions may be administered by any route. In some embodiments, the novel compounds, their salts, or their pharmaceutical compositions are administered by various routes including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or droplet), mucosal, nasal, oral, enteral, sublingual; tracheal drip infusion, bronchial drip infusion, and / or inhalation; and / or oral sprays, nasal sprays, and / or aerosols. Routes specifically considered are invasive intravenous injection, local administration via blood and / or lymphatic supply, and / or direct administration to the affected area. In general, the most suitable route of administration will depend on various factors, including the characteristics of the agent (e.g., stability in the gastrointestinal environment) and the subject's impairment (e.g., whether the subject can tolerate oral administration).

[0270] In certain embodiments, the novel compound of the present invention, its salt, or its pharmaceutical composition may be administered at a dosage level sufficient to deliver about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 25 mg / kg of the subject's body weight at least once a day to achieve the desired therapeutic effect. The target dosage may be delivered three times a day, twice a day, every day, every two days, every three days, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the target dose may be delivered through multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0271] It will be understood that the dosage ranges described in the present invention provide guidance for the administration of pharmaceutical compositions provided to adults. For example, the amount administered to children or adolescents may be determined by a specialist or a person skilled in the art and may be less or equal to that administered to adults. The exact amount of peptide according to the present invention required to achieve an effective dose will vary from subject to subject, for example, depending on the subject's species, age, and overall disorder, side effects or severity of disorder, identity of the characteristic compound, mode of administration, etc.

[0272] It will be understood that the novel compounds and pharmaceutical compositions of the present invention may be used in combination therapy. A specific combination of treatments (therapeutics or procedures) to be used in combination therapy will be chosen considering the intended therapeutic effect to be achieved and the suitability of the intended therapeutic agents and / or procedures.

[0273] The pharmaceutical composition of the present invention may be administered alone or in combination with one or more therapeutic agents. In the case of "combination," while the following delivery methods fall within the scope of the present invention, it is not intended to imply that the agents must be administered at the same time and / or formulated to be delivered together. The composition may be administered simultaneously with, before, or after one or more other therapeutic agents or medical procedures. Generally, each agent will be administered at a prescribed dosage and / or time schedule for that agent. Additionally, the present invention encompasses delivering the pharmaceutical composition of the present invention in combination with an agent capable of improving its bioavailability within the body, reducing and / or modifying its metabolism, inhibiting its secretion, and / or modifying its distribution. It will be further understood that the novel compounds and therapeutic agents of the present invention used in this combination may be administered together as a single composition or separately as different compositions.

[0274] The specific combination used in combination therapy will take into account the intended therapeutic effect to be achieved and / or the suitability of the procedure and / or therapeutic agent comprising the peptide of the present invention. It will be understood that the combination used may achieve the intended effect for the same disorder (e.g., the novel compound of the present invention may be administered in combination with another therapeutic agent used to treat the same disorder (e.g., a second therapeutic agent)), and / or these may achieve different effects (e.g., control of any side effects).

[0275] As used herein, “therapeutic agent” refers to any substance used as a medicine to treat, prevent, delay, reduce, or improve a disorder, and refers to a substance used for treatment, including preventive and curative treatments.

[0276] In some embodiments, other therapeutic agents for concomitant administration are intended to treat multiple myeloma. In some embodiments, said other therapeutic agents may be proteasome inhibitors and / or immune-modifying drugs. In the present invention, said other therapeutic agents may be selected from the group consisting of dexamethasone, bortezomib, carfilzomib, melphalan, doxorubicin, and cyclophosphamide, but are not limited thereto.

[0277] In some embodiments, the pharmaceutical composition of the present invention may be administered in combination with any therapeutic agent or procedure (e.g., surgery, radiation therapy) useful for treating, alleviating, improving, or mitigating one or more symptoms or features, delaying their onset, inhibiting their progression, reducing their severity, and / or reducing their incidence.

[0279] In one embodiment, the present invention may be provided as a kit for treating a tumor or cancer disease in a subject suffering from said disease.

[0280] In some embodiments, the kit comprises i) instructions for administering the novel compound or pharmaceutical composition according to the present invention to a subject suffering from the said disease, and ii) the novel compound or pharmaceutical composition according to the present invention. In some embodiments, the kit may comprise one or more unit dosage forms containing the novel compound or pharmaceutical composition in a dose as described in the present invention that is effective in treating the said disease in a subject. In some embodiments, the subject is a human patient.

[0281] In some embodiments, the kit further comprises one or more selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.

[0282] The term "about" as used in the present invention may be interpreted as meaning approximately, roughly, or to a certain degree. When the term "about" is used in conjunction with a numerical range, it is interpreted as modifying the range by extending the boundaries above and below the specified numerical value. Generally, the term "about" is used in the present invention to modify numerical values ​​above and below the value specified by a 10% variance.

[0283] "Individual," "patient," and "subject" are used interchangeably and include any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates including humans.

[0284] In the present invention, "treatment" means reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of a disease or illness to which the term applies, or said disease or illness, unless otherwise stated; and as used herein, the term "treatment" refers to the act of treating when "treating" is defined as above. Accordingly, "treatment" or "therapeutic regimen" of a disease in mammals may include one or more of the following:

[0285] (1) Preventing the development of the disease,

[0286] (2) Preventing the spread of disease,

[0287] (3) Relieves disease,

[0288] (4) Preventing the recurrence of the disease and

[0289] (5) Palliating the symptoms of the disease

[0290] In the present invention, "prevention" means any act of suppressing the disease or delaying its onset by administering a pharmaceutical composition according to the present invention, unless otherwise stated.

[0292] In another aspect, the present invention provides a method for the prevention or treatment of a disease associated with cereblon activity, e.g., a benign tumor or cancer, comprising the step of administering the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt to a patient in need thereof.

[0293] The present invention also provides the use of said compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of diseases associated with cereblon activity, e.g., benign tumors or cancer.

[0294] The present invention also provides the use of said compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt in the manufacture of a drug for the prevention or treatment of diseases associated with cereblon activity, e.g., benign tumors or cancer.

[0296] In addition, the present invention provides a method for preparing the compounds of Table 1. The following describes a synthesis method for some of the compounds among the methods for preparing the compounds of Table 1 according to the present invention, and the synthesis methods of Preparation Examples 1 to 15 below do not limit the method for preparing the compounds according to the present invention. The said synthesis method is merely an example and it is obvious that it can be easily modified by a person skilled in the art depending on specific substituents.

[0298] Manufacturing method

[0300] Preparation of Intermediate B(3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide)

[0302] Intermediate B used to prepare the compound of the present invention can be prepared by the following reaction:

[0303] (a') A step of preparing 3-(2,6-bis(benzyloxy)pyridin-3-yl)aniline by reacting 2,6-bis(benzyloxy)-3-bromopyridine with 3-aminophenylboronic acid;

[0304] (b') A step of reacting 3-(2,6-bis(benzyloxy)pyridine-3-yl)aniline with hydrogen to produce 3-(3-aminophenyl)piperidine-2,6-dione;

[0305] (c') a step of reacting 3-(3-aminophenyl)piperidin-2,6-dione with 3-nitrobenzenesulfonyl chloride to produce N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide; and

[0306] (d') A step of reacting N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide with hydrogen to produce 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0307] In the above method, step (a') may involve adding PD(dppf)Cl2 and potassium carbonate to a mixture of 1,4-dioxane and water, and further adding and reacting 2,6-bis(benzyloxy)-3-bromopyridin and 3-aminophenylboronic acid.

[0308] In the above method, step (a') may be carried out at about 80 to 100°C, for example, about 85 to 95°C, and the reaction time may be about 8 to 16 hours, for example, about 9 to 15 hours, preferably about 10 to 14 hours, but is not limited thereto.

[0309] In the above method, step (b') may involve adding 3-(2,6-bis(benzyloxy)pyridine-3-yl)aniline and palladium on carbon to a mixture of tetrahydrofuran (THF) and methanol and reacting it with hydrogen.

[0310] In the above method, step (b') may be carried out at room temperature, and the reaction time may be about 2 to 6 hours, preferably about 3 to 5 hours, but is not limited thereto.

[0311] In the present invention, room temperature refers to a general indoor temperature of about 15 to 30°C, preferably about 20 to 28°C, but is not limited thereto.

[0312] In the above method, step (c') may involve reacting a mixture of dichloromethane and pyridine with 3-(3-aminophenyl)piperidine-2,6-dione and 3-nitrobenzenesulfonyl chloride.

[0313] In the above method, the above step (c') may be carried out at room temperature, and the reaction time may be about 8 to 16 hours, e.g., about 9 to 15 hours, preferably about 10 to 14 hours, but is not limited thereto.

[0314] In the above method, step (d') may involve adding N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide and palladium on carbon to methanol and reacting them with hydrogen.

[0315] In the above method, step (d') may be carried out at room temperature, and the reaction time may be about 2 to 6 hours, preferably about 3 to 5 hours, but is not limited thereto.

[0317] Method for preparing compounds of formulas (i) to (vii)

[0318] The method for preparing the above chemical formulas (2) to (8) may include the step of reacting C6H5-(CH2)nC(O)Cl (where n is 0 to 6) with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide).

[0319] In the above method, step (a) may involve dissolving potassium carbonate in N,N-dimethylacetamide and then reacting it with C6H5-(CH2)nC(O)Cl (where n is an integer from 0 to 6) and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0320] In the above method, step (a) may be carried out at room temperature and may be carried out by stirring for less than 1 hour, for example, about 1 to 20 minutes, e.g., about 2 to 10 minutes, preferably about 4 to 8 minutes, but is not limited thereto.

[0322] As one embodiment, a method for preparing a compound represented by the chemical formula (2) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-methylbenzamide) may include the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with benzoyl chloride:

[0323] Chemical formula (i)

[0324] .

[0326] As one embodiment, a method for preparing a compound represented by the chemical formula (3) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-ethylbenzamide) may include the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 2-phenylacetyl chloride:

[0327] Chemical formula (ii)

[0328] .

[0330] As one embodiment, a method for preparing a compound represented by the chemical formula (4) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-propylbenzamide) may include the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 3-phenylpropanoyl chloride:

[0331] Chemical formula (iii)

[0332] .

[0334] As one embodiment, a method for preparing a compound represented by the formula (iv) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-butylbenzamide) may comprise the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 4-phenylbutanoyl chloride:

[0335] Chemical formula (iv)

[0336] .

[0338] As one embodiment, a method for preparing a compound represented by the chemical formula (v) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-pentylbenzamide) may include the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 5-phenylpentanoyl chloride:

[0339] Chemical formula (v)

[0340] .

[0342] As one embodiment, a method for preparing a compound represented by the formula (vi) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-hexylbenzamide) may include the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 6-phenylhexanoyl chloride:

[0343] Chemical formula (vi)

[0344] .

[0346] As one embodiment, a method for preparing a compound represented by the formula (vii) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide) may comprise the step of (a) reacting 7-phenylheptanoyl chloride with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide;

[0347] Chemical formula (vii)

[0348] .

[0350] The above 7-phenylheptanoyl chloride can be prepared by reacting 7-phenylheptanoic acid with thionyl chloride, and the reaction may be carried out at about 60 to 80°C.

[0352] Method for preparing the compound of formula (ix) or formula (x).

[0353] The method for preparing the above chemical formula (ix) or chemical formula (x) may include the step of (a) reacting 4-chlorobenzoyl chloride or 4-(chloromethyl)benzoyl chloride with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide).

[0354] In the above method, step (a) may involve dissolving potassium carbonate in N,N-dimethylacetamide and then reacting it with 4-chlorobenzoyl chloride or 4-(chloromethyl)benzoyl chloride and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0355] In the above method, step (a) may be carried out at room temperature and may be carried out by stirring for less than 1 hour, for example, about 1 to 20 minutes, e.g., about 2 to 10 minutes, preferably about 4 to 8 minutes, but is not limited thereto.

[0357] As one embodiment, a method for preparing a compound represented by the chemical formula (ix) (4-chloro-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may comprise the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide) with 4-chlorobenzoyl chloride:

[0358] Chemical formula (ix)

[0359] .

[0361] As one embodiment, a method for preparing a compound represented by the chemical formula (x) (4-(chloromethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may comprise the step of reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 4-(chloromethyl)benzoyl chloride:

[0362] Chemical formula (x)

[0363] .

[0365] Method for preparing compounds of formulas (xi) to (xv)

[0366] The method for preparing the above chemical formulas (xi) to (xv) may include the step of reacting Cl-(CH2)n-C6H4-COOH (where n is an integer from 2 to 6) with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide).

[0367] In the above method, step (a) may involve dissolving potassium carbonate in N,N-dimethylacetamide and then reacting it with Cl-(CH2)n-C6H4-COOH (where n is an integer from 2 to 6) and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0368] In the above method, step (a) may be carried out at room temperature and may be carried out by stirring for less than 1 hour, for example, about 1 to 20 minutes, for example, about 2 to 10 minutes, preferably about 4 to 8 minutes, but is not limited thereto.

[0369] In the above method, Cl-(CH2)n-C6H4-COOH (where n is an integer from 2 to 6) can be prepared by adding lithium hydroxide to Cl-(CH2)n-C6H4-COOCH3 (where n is an integer from 2 to 6) to demethylate it, and the demethylation reaction may be carried out at room temperature and may be carried out by stirring for about 2 to 20 hours, e.g., about 4 to 12 hours, preferably about 6 to 10 hours, but is not limited thereto. In this case, Cl-(CH2)n-C6H4-COOCH3 (where n is an integer from 2 to 6) may be dissolved in a mixture of methanol and water to undergo the demethylation reaction.

[0370] The above Cl-(CH2)n-C6H4-COOCH3 (where n is an integer from 2 to 6) can be prepared by reacting OH-(CH2)n-C6H4-COOCH3 (where n is an integer from 2 to 6) with thionyl chloride to halogenate it, and the halogenation reaction may be carried out at about 40 to 80°C, e.g., about 50 to 70°C, preferably about 60°C, and may be carried out by stirring for about 2 to 20 hours, e.g., about 4 to 12 hours, preferably about 6 to 10 hours, but is not limited thereto. In this case, OH-(CH2)n-C6H4-COOCH3 (where n is an integer from 2 to 6) may be dissolved in toluene to undergo the halogenation reaction.

[0372] In one embodiment, a method for preparing a compound represented by the chemical formula (xi) (4-(2-chloroethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting 4-(2-chloroethyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide;

[0373] Chemical formula (xi)

[0374] .

[0375] In a preferred embodiment, a compound represented by the chemical formula (xi) can be prepared by a manufacturing method comprising the following steps:

[0376] Chemical formula (xi)

[0377]

[0378] (a) a step of preparing methyl 4-(2-chloroethyl)benzoate by reacting methyl 4-(2-oxopropyl)benzoate with thionyl chloride;

[0379] (b) a step of preparing 4-(2-chloroethyl)benzoic acid by adding lithium hydroxide to methyl 4-(2-chloroethyl)benzoate to demethylate it; and

[0380] (c) A step of preparing a compound represented by the chemical formula (11) by reacting 4-(2-chloroethyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0382] In one embodiment, a method for preparing a compound represented by the chemical formula (xii) (4-(3-chloropropyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting 4-(3-chloropropyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide:

[0383] Chemical formula (xii)

[0384] .

[0385] In a preferred embodiment, the compound represented by the formula (xii) can be prepared by a manufacturing method comprising the following steps:

[0386] Chemical formula (xii)

[0387]

[0388] (a) a step of preparing methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate by reacting methyl 4-iodobenzoate with prop-2-yn-1-ol;

[0389] (b) a step of preparing methyl 4-(3-hydroxypropyl)benzoate by reacting methyl 4-(3-hydroxyprop-1-in-1-yl)benzoate with hydrogen;

[0390] (c) a step of preparing methyl 4-(3-chloropropyl)benzoate by reacting methyl 4-(3-hydroxypropyl)benzoate with thionyl chloride to halogenate it;

[0391] (d) a step of preparing 4-(3-chloropropyl)benzoic acid by adding lithium hydroxide to methyl 4-(3-chloropropyl)benzoate to demethylate it; and

[0392] (e) a step of preparing a compound represented by the chemical formula (xii) by reacting 4-(3-chloropropyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0394] In one embodiment, a method for preparing a compound represented by the chemical formula (xiii) (4-(4-chlorobutyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting 4-(4-chlorobutyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide:

[0395] Chemical formula (xiii)

[0396] .

[0397] In a preferred embodiment, the compound represented by the formula (13) can be prepared by a manufacturing method comprising the following steps:

[0398] Chemical formula (xiii)

[0399]

[0400] (a) a step of preparing methyl 4-(4-chlorobutyl)benzoate by reacting methyl 4-(4-hydroxybutyl)benzoate with thionyl chloride to halogenate it;

[0401] (b) a step of preparing 4-(4-chlorobutyl)benzoic acid (4-(4-chlorobutyl)benzoic acid) by adding lithium hydroxide to methyl 4-(4-chlorobutyl)benzoate to demethylate it; and

[0402] (c) A step of preparing a compound represented by the chemical formula (xiii) by reacting 4-(4-chlorobutyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0404] In one embodiment, a method for preparing a compound represented by the chemical formula (xiv) (4-(5-chloropentyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting 4-(5-chloropentyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide;

[0405] Chemical formula (xiv)

[0406] .

[0407] In a preferred embodiment, the compound represented by the formula (xiv) can be prepared by a manufacturing method comprising the following steps:

[0408] Chemical formula (xiv)

[0409]

[0410] (a) a step of preparing methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate by reacting methyl 4-iodobenzoate with pent-4-yn-1-ol;

[0411] (b) a step of preparing methyl 4-(5-hydroxypentyl)benzoate by reacting methyl 4-(5-hydroxypentyl)benzoate with hydrogen;

[0412] (c) a step of preparing methyl 4-(5-chloropentyl)benzoate by reacting methyl 4-(5-hydroxypentyl)benzoate with thionyl chloride to halogenate it;

[0413] (d) a step of preparing 4-(5-chloropentyl)benzoic acid by demethylating methyl 4-(5-chloropentyl)benzoate with the addition of lithium hydroxide; and

[0414] (e) a step of reacting 4-(5-chloropentyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide) to prepare a compound represented by the chemical formula (xiv).

[0416] In one embodiment, a method for preparing a compound represented by the chemical formula (xv) (4-(6-chlorohexyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting 4-(6-chlorohexyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide:

[0417] Chemical formula (xv)

[0418] .

[0420] In a preferred embodiment, a compound represented by the formula (xv) can be prepared by a manufacturing method comprising the following steps:

[0421] Chemical formula (xv)

[0422]

[0423] (a) a step of preparing methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate by reacting methyl 4-iodobenzoate with hex-5-yn-1-ol;

[0424] (b) a step of preparing methyl 4-(6-hydroxyhexyl)benzoate by reacting methyl 4-(6-hydroxyhexyl)benzoate with hydrogen;

[0425] (c) a step of preparing methyl 4-(6-chlorohexyl)benzoate by reacting methyl 4-(6-hydroxyhexyl)benzoate with thionyl chloride to halogenate it;

[0426] (d) a step of preparing 4-(6-chlorohexyl)benzoic acid by demethylating methyl 4-(6-chlorohexyl)benzoate with the addition of lithium hydroxide; and

[0427] (e) a step of reacting 4-(6-chlorohexyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide) to prepare a compound represented by the chemical formula (xv).

[0429] In another aspect, the present invention relates to a cereblon activity inhibitor or a composition for inhibiting cereblon activity comprising the said compound, its optical isomer, its racemic mixture, its hydrate, or its solvate.

[0430] In one embodiment, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its salt may be provided as an experimental reagent used to inhibit Cereblon activity in vitro.

[0432] The present invention will be explained in more detail below through manufacturing examples and embodiments. However, the following manufacturing examples and embodiments are intended to illustrate the present invention and do not limit the scope of the present invention.

[0434] Preparation Example

[0436] Manufacturing of Intermediate B

[0437]

[0439] Compound 2 preparation

[0440] After adding PD(dppf)Cl2 ([1,1′CAS: 72287-26-4) and potassium carbonate (CAS: 584-08-7) to a 5:1 mixture of 1,4-dioxane (CAS: 123-91-1) and water (H2O), Compound 1 (2,6-Bis(benzyloxy)-3-bromopyridine, CAS: 16727-47-2) and 3-aminophenylboronic acid (CAS: 206658-89-1) were added, and stirred at 90°C for 12 hours. Compound 2 (3-(2,6-bis(benzyloxy)pyridin-3-yl)aniline) was obtained.

[0442] Intermediate A manufacturing

[0443] In a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and methanol (Methanol, CAS: 67-56-1) Compound 2 Palladium on carbon (CAS: 7440-05-3) was added, hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 4 hours. Intermediate A (3-(3-aminophenyl)piperidine-2,6-dione) was obtained.

[0445] Preparation of Compound 3

[0446] In a mixture of methylene chloride (Dichloromethane, CAS: 75-09-2) and pyridine (Pyridine, CAS: 110-86-1) Intermediate A (3-(3-aminophenyl)piperidine-2,6-dione) and 3-Nitrobenzenesulfonyl chloride (CAS: 121-51-7) were added and stirred at room temperature for 12 hours. Compound 3 (N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide) was obtained.

[0448] Intermediate B manufacturing

[0449] In methanol (CAS: 67-56-1) Compound 3 (N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide) and Palladium on carbon (CAS: 7440-05-3) were added, hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 4 hours. Intermediate B (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide) was obtained.

[0451] Preparation Example 1. Preparation of compound of formula (i) (AEV41009)

[0452] Chemical formula (i)

[0453]

[0454] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and benzoyl chloride (CAS: 98-88-4) were added and stirred at room temperature for 6 minutes to form compound of formula (i). AEV41009 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-methylbenzamide) was obtained.

[0455]

[0457] Preparation Example 2. Preparation of compound (ii) (AEV41010)

[0458] Chemical formula (ii)

[0459]

[0460] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B Add 2-phenylacetyl chloride (CAS: 103-80-0) and stir at room temperature for 6 minutes to form compound of formula (ii). AEV41010 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-ethylbenzamide) was obtained.

[0461]

[0463] Preparation Example 3. Preparation of compound of formula (iii) (AEV41011)

[0464] Chemical formula (iii)

[0465]

[0466] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B Add 3-phenylpropanoyl chloride (CAS: 645-45-4) and stir at room temperature for 6 minutes to form compound of formula (iii). AEV41011 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-propylbenzamide) was obtained.

[0467]

[0469] Preparation Example 4. Preparation of compound of formula (iv) (AEV41012 or AEV40154)

[0470] Chemical formula (iv)

[0471]

[0472] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and 4-phenylbutanoyl chloride (CAS: 18496-54-3) were added and stirred at room temperature for 6 minutes to form compound of formula (iv). AEV41012 (4-butyl-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0473]

[0475] Preparation Example 5. Preparation of compound of formula (v) (AEV41013)

[0476] Chemical formula (v)

[0477]

[0478] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B Add 5-phenylpentanoyl chloride (CAS: 20371-41-9) and stir at room temperature for 6 minutes to form compound of formula (v). AEV41013 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-pentylbenzamide) was obtained.

[0479]

[0481] Preparation Example 6. Preparation of compound of formula (vi) (AEV41083)

[0482] Chemical formula (vi)

[0483]

[0484] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and 6-phenylhexanoyl chloride (CAS: 21389-46-8)) were added and stirred at room temperature for 6 minutes to form the compound of formula (vi). AEV41083 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-hexylbenzamide) was obtained.

[0485]

[0487] Preparation Example 7. Preparation of compound of formula (vii) (AEV40204)

[0488] Chemical formula (vii)

[0489]

[0490] Compound 204-1( 7-phenylheptanoic acid (CAS: 40228-90-8) and thionyl chloride (CAS: 7719-09-7) were added and stirred at 70 ℃. Compound 204-2 (7-phenylheptanoyl chloride) was obtained.

[0491]

[0492] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and anger Compound 204-2 Add (6-phenylhexanoyl chloride) and stir at room temperature for 6 minutes to form the compound of formula (vii). AEV40204 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide) was obtained.

[0493]

[0495] Preparation Example 8. Preparation of compound of formula (viii) (AEV40264)

[0496] Chemical formula (viii)

[0497]

[0498] Intermediate B, 4-octylbenzoic acid (CAS: 3575-31-3), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, CAS: 148893-10-1), N-dimethylacetamide (CAS: 127-19-5), and triethylamine (CAS: 121-44-8) were stirred at 30 °C for 12 hours to produce compound of formula (viii). AEV40264 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide) was obtained.

[0499]

[0501] Preparation Example 9. Preparation of compound of formula (ix) (AEV41001)

[0502] Chemical formula (ix)

[0503]

[0504] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B Add 4-chlorobenzoyl chloride (CAS: 104-83-6) and stir at room temperature for 6 minutes to form compound of formula (ix). AEV41001(4-chloro-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0505]

[0507] Preparation Example 10. Preparation of compound of formula (x) (AEV41002)

[0508] Chemical formula (x)

[0509]

[0510] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and 4-(chloromethyl)benzoyl chloride (CAS: 63024-77-1) were added and stirred at room temperature for 6 minutes to form the compound of formula (x). AEV41002 (4-(chloromethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0511]

[0513] Preparation Example 11. Preparation of compound of formula (xi) (AEV41003)

[0514] Chemical formula (xi)

[0515]

[0516] Methyl 4-(2-oxopropyl)benzoate (CAS: 46190-45-8), pyridine (CAS: 110-86-1), and thionyl chloride (CAS: 7719-09-7) were added to toluene (CAS: 108-88-3) and stirred at 60°C for 8 hours, Compound 3-2(methyl 4-(2-chloroethyl)benzoate) was obtained. In a mixture of methanol (CAS: 67-56-1) and water Compound 3-2 Add (methyl 4-(2-chloroethyl)benzoate) and lithium hydroxide (CAS: 1310-65-2) and stir at room temperature for 8 hours. Compound 3-3 (4-(2-chloroethyl)benzoic acid) was obtained.

[0517]

[0518] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and Compound 3-3 Add (4-(2-chloroethyl)benzoic acid) and stir at room temperature for 6 minutes to form the compound of chemical formula (xi). AEV41003 (4-(2-chloroethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0519]

[0521] Preparation Example 12. Preparation of compound of formula (xii) (AEV41004)

[0522] Chemical formula (xii)

[0523]

[0524] In acetonitrile (CAS: 75-05-8), PD(dppf)Cl2([1,1′(diphenylphosphino)ferrocene] dichloropalladium(II), CAS: 72287-26-4), copper iodide (Copper(I) iodide, CAS: 7681-65-4), Compound 4-1After adding (methyl 4-iodobenzoate, CAS: 619-44-3) and triethylamine (CAS: 121-44-8), prop-2-yn-1-ol (CAS: 107-19-7) was added and stirred at 60°C for 12 hours. Compound 4-2 (methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate, CAS: 61266-36-2) was obtained.

[0525] In methanol (CAS: 67-56-1) Compound 4-2 After adding methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate (CAS: 61266-36-2) and palladium on carbon (CAS: 7440-05-3) and injecting hydrogen gas (H2, 15 Psi), and stirring at room temperature for 12 hours, Compound 4-3 (methyl 4-(3-hydroxypropyl)benzoate, CAS: 15403-22-2) was obtained.

[0526]

[0527] In toluene (CAS: 108-88-3) Compound 4-3 (methyl 4-(3-hydroxypropyl)benzoate, CAS: 15403-22-2) and thionyl chloride (CAS: 7719-09-7) were added and stirred at 60 ℃ for 8 hours, Compound 4-4 (methyl 4-(3-chloropropyl)benzoate) was obtained.

[0528] In a mixture of methanol (CAS: 67-56-1) and water Compound 4-4 Add (methyl 4-(3-chloropropyl)benzoate) and lithium hydroxide (CAS: 1310-65-2) and stir at room temperature for 5 hours. Compound 4-5(4-(3-chloropropyl)benzoic acid, CAS: 90919-20-3) was obtained.

[0529]

[0530] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and Compound 4-5 Add (4-(3-chloropropyl)benzoic acid, CAS: 90919-20-3) and stir at room temperature for 6 minutes to form compound of formula (xii). AEV41004 (4-(3-chloropropyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0531]

[0533] Preparation Example 13. Preparation of compound of formula (xiii) (AEV41005)

[0534] Chemical formula (xiii)

[0535]

[0536] In toluene (CAS: 108-88-3) Compound 5-1 (methyl 4-(4-hydroxybutyl)benzoate, CAS: 123910-88-3), pyridine, CAS: 110-86-1, and thionyl chloride, CAS: 7719-09-7) were added and stirred at 60 ℃ for 8 hours, Compound 5-2 (methyl 4-(4-chlorobutyl)benzoate) was obtained. In a mixture of methanol (CAS: 67-56-1) and water Compound 5-2Add methyl 4-(4-chlorobutyl)benzoate and lithium hydroxide (CAS: 1310-65-2) and stir at room temperature for 8 hours. Compound 5-3 (4-(4-chlorobutyl)benzoic acid) was obtained.

[0537]

[0538] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and Compound 5-3 Add (4-(4-chlorobutyl)benzoic acid) and stir at room temperature for 6 minutes to form compound of chemical formula (xiii). AEV41005 (4-(4-chlorobutyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0539]

[0541] Preparation Example 14. Preparation of compound of formula (xiv) (AEV41047)

[0542] Chemical formula (xiv)

[0543]

[0544] In acetonitrile (CAS: 75-05-8), PD(dppf)Cl2([1,1′(diphenylphosphino)ferrocene] dichloropalladium(II), CAS: 72287-26-4), copper iodide (Copper(I) iodide, CAS: 7681-65-4), Compound 47-1After adding (methyl 4-iodobenzoate, CAS: 619-44-3) and triethylamine (CAS: 121-44-8), pent-4-yn-1-ol (CAS: 619-44-3) was added and stirred at 60 ℃ for 12 hours. Compound 47-2 (methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate) was obtained.

[0545] In methanol (CAS: 67-56-1) Compound 47-2 (methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate) and Palladium on carbon (CAS: 7440-05-3) were added, hydrogen gas (H2, 15 Psi) was injected, and after stirring at room temperature for 12 hours, Compound 47-3 (methyl 4-(5-hydroxypentyl)benzoate) was obtained.

[0546]

[0547] Pyridine (CAS: 110-86-1) and thionyl chloride (CAS: 7719-09-7) were added to toluene (CAS: 108-88-3), Compound 47-3 (methyl 4-(5-hydroxypentyl)benzoate) was added and stirred at 60 ℃ for 8 hours, Compound 47-4 (methyl 4-(5-chloropentyl)benzoate) was obtained.

[0548] In a mixture of methanol (CAS: 67-56-1) and water Compound 47-4 Add methyl 4-(5-chloropentyl)benzoate and lithium hydroxide (CAS: 1310-65-2) and stir at room temperature for 5 hours. Compound 47-5 (4-(5-chloropentyl)benzoic acid) was obtained.

[0549]

[0550] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and Compound 47-5 Add (4-(5-chloropentyl)benzoic acid) and stir at room temperature for 6 minutes to form compound of formula (xiv). AEV41047 (4-(5-chloropentyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0551]

[0553] Preparation Example 15. Preparation of compound of formula (xv) (AEV41048)

[0554] Chemical formula (xv)

[0555]

[0556] In acetonitrile (CAS: 75-05-8), PD(dppf)Cl2([1,1′(diphenylphosphino)ferrocene] dichloropalladium(II), CAS: 72287-26-4), copper iodide (Copper(I) iodide, CAS: 7681-65-4), Compound 48-1 After adding (methyl 4-iodobenzoate, CAS: 619-44-3) and triethylamine (CAS: 121-44-8), hex-5-yn-1-ol (CAS: 28916-38-3) was added and stirred at 60 ℃ for 12 hours. Compound 48-2 (methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate) was obtained.

[0557] In methanol (CAS: 67-56-1) Compound 48-2(methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate) and Palladium on carbon (CAS: 7440-05-3) were added, hydrogen gas (H2, 15 Psi) was injected, and after stirring at room temperature for 12 hours, Compound 48-3 (methyl 4-(6-hydroxyhexyl)benzoate) was obtained.

[0558]

[0559] Thionyl chloride (CAS: 7719-09-7) and pyridine (CAS: 110-86-1) were added to toluene (CAS: 108-88-3), Compound 48-3 Add (methyl 4-(6-hydroxyhexyl)benzoate) and stir at 60 ℃ for 8 hours. Compound 48-4 (methyl 4-(6-chlorohexyl)benzoate) was obtained.

[0560] In a mixture of methanol (CAS: 67-56-1) and water Compound 48-4 Add methyl 4-(6-chlorohexyl)benzoate and lithium hydroxide (CAS: 1310-65-2) and stir at room temperature for 5 hours. Compound 48-5 (4-(6-chlorohexyl)benzoic acid) was obtained.

[0561]

[0562] Potassium carbonate (CAS: 584-08-7) is dissolved in N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5), and Intermediate B and Compound 48-5 Add (4-(6-chlorohexyl)benzoic acid) and stir at room temperature for 6 minutes to form the compound of chemical formula (xv). AEV41048(4-(6-chlorohexyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) was obtained.

[0563]

[0565] Examples 1. In vitro CRBN binding assay

[0567] Thalidomide-based compounds are known to regulate immune cell function and exert various pharmacological effects by binding to the E3 ligase Celeblon (CRBN) and degrading the transcription factors Aiolos and Ikaros as substrates. Accordingly, the binding affinity of various compounds to Celeblon was compared in vitro.

[0569] The binding affinity to Cereblon was measured using the Fluorescence Resonance Energy Transfer (FRET)-based 'AlphaScreen' method. This test was conducted using the PROTAC Optimization kit for BET Bromodomain-Cereblon binding kit (#79770, BPS Bioscience, CA USA) in accordance with the 'Competitive Inhibition of the PROTAC assay' indicated in the kit's manual. All reagents included in the kit were used, with the exception of the candidate substance, DMSO, and Flag / Glutathione beads (#6765300, PerkinElmer, USA).

[0571] As a result, compounds having cereblon binding activity as shown in Table 1 were identified.

[0573] [Table 1]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0596] Example 2. Tumor cell death effect

[0597] We intended to verify whether the compound having CRBN binding activity according to the present invention exerts a tumor cell death effect using human multiple myeloma cell lines (MM.1S, MM.1R-LR), human breast cancer cell lines (MDA-MB-231), human lung cancer cell lines (A549), human rhabdomyosarcoma cell lines (RD), and human lymphoma cell lines (Jeko-1).

[0599] MM.1S, MM.1R-LR, MDA-MB-231, A549, RD, and Jeko-1 cell lines were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured for 24 hours in a 5% CO2 incubator at 37°C using RPMI1640 medium (Corning, MD, USA) or DMEM (Corning, MD, USA) supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U / ml penicillin (Corning, MD, USA), and 100 μg / ml streptomycin (Corning, MD, USA). Cells were cultured at a volume of 1 × 10⁶ 4 Cells were seeded into a 96-well plate at a cell / well and cultured for 24 hours. Then, a compound dissolved in dimethyl sulfoxide (Cas no.: 67-68-5) was serially diluted to a concentration of 10 μM and treated. After additional culture for 2 to 5 days, analysis was performed using a CCK-8 analysis kit (Dojindo, Japan) according to the manufacturer's instructions.

[0601] [Table 2]

[0602]

[0604] As a result, as shown in Table 3, the tumor cell line killing effect of the compound exhibiting CRBN binding activity was confirmed.

[0606] [Table 3]

[0607]

Claims

Claim 1 delete Claim 2 A compound represented by the following chemical formula (II), its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts, chemical formula (II) In formula (II), R1 is absent, CH2, CO, or SO2, R2 is absent, or C6H4NHCO₃, and any benzene ring present in formula (II) is an unsubstituted benzene ring or any one or more hydrogens within the benzene ring are each independently -F, -Cl, -Br, -I, (C1-C 10 ) Alkyl group, amino group (-NH2), nitro group (-NO2), -CF3, -CF2H, -CFH2, -CCl2, -CCl2H, -CClH2, -(CH2) n Cl(n is an integer from 1 to 10), (C1-C 10 ) alkoxy group, hydroxyl group (-OH), (C1-C 10 ) alkoxyaryl group and C6-C 30 A compound substituted with any one selected from the group consisting of aryl groups, its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts. Claim 3 In paragraph 2, the compound represented by the formula (II) is a compound represented by any one of the formulas selected from the group consisting of the following formulas (II-1) to (II-5), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein any benzene ring present in any one of the formulas selected from the group consisting of the following formulas (II-1) to (II-5) is an unsubstituted benzene ring or any one or more hydrogens within the benzene ring are each independently -F, -Cl, -Br, -I, (C1-C 10 ) Alkyl group, amino group (-NH2), nitro group (-NO2), -CF3, -CF2H, -CFH2, -CCl2, -CCl2H, -CClH2, -(CH2) n Cl(n is an integer from 1 to 10), (C1-C 10 ) alkoxy group, hydroxyl group (-OH), (C1-C 10 ) alkoxyaryl group and C6-C 30 Compound, optical isomer thereof, racemic mixture thereof, hydrate thereof, solvate thereof, or pharmaceutically acceptable salt thereof, characterized by being substituted with any one selected from the group consisting of aryl groups: Chemical Formula (II-1) ;Chemical formula (II-2) ;Chemical formula (II-3) ;Chemical formula (II-4) ;Chemical formula (II-5) . Claim 4 delete Claim 5 delete Claim 6 In paragraph 3, any benzene ring present in the above chemical formula (II-4) has any one or more hydrogens within the benzene ring independently, halogen, C 1-10 Alkyl, C 1-10 A compound, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with an alkyl halide. Claim 7 In paragraph 2, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt is characterized by being represented by the following chemical formula (III). (Chemical Formula III) In chemical formula (III), R 1 Silver, Halogen(X), C 1-10 Alkyl, C 1-10 It is an alkyl halide. Claim 8 In paragraph 2, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt is characterized by having a Cereblon binding force. Claim 9 A compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt, characterized as being any one of the compounds listed in Table 1 below: [Table 1] Claim 10 A pharmaceutical composition for the prevention or treatment of benign tumors or cancer comprising, as an active ingredient, a compound of any one of claims 2, 3, 6 through 9, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. Claim 11 A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in claim 10, the cancer is a blood cancer or a solid tumor. Claim 12 A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in claim 11, the blood cancer is selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma. Claim 13 A pharmaceutical composition for the prevention or treatment of benign tumors or cancers according to claim 11, wherein the solid tumor is selected from the group consisting of melanoma, myoma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer. Claim 14 An in vitro reagent composition for inhibiting cereblon activity comprising a compound of any one of claims 2, 3, 6 to 9, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, or a solvate thereof.

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