Small molecule compounds with cereblon-binding activity and their applications

Abstract

The novel low-molecular-weight compounds according to the present invention exhibit excellent binding affinity to cereblon and can act as novel immunomodulators for the treatment of tumors or cancerous diseases.

Description

[Technical Field]

[0001] This invention relates to a novel low-molecular-weight compound having cereblon-binding activity and its therapeutic application for tumors or cancer. [Background technology]

[0002] The ubiquitin-proteasome pathway (UPP) is a crucial pathway that controls major regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to numerous cellular processes, and defects or imbalances in it can 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 distinct proteins and are classified into several classes based on the structural elements of their E3 functional activity.

[0003] Cereblon (CRBN) interacts with damaged DNA-binding protein 1 (DDB1) and, together with Cullin4, forms the DDB1-CUL4a-Roc1 ubiquitin ligase complex. This complex functions as a substrate receptor that allows proteins recognized by CRBN to be ubiquitinated and degraded by the proteasome.

[0004] Cereblon (CRBN) is known as a molecular target for 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 in the late 1990s for the treatment of multiple myeloma, binds to cereblon and CRL4 CRBN By regulating the substrate specificity of ubiquitin ligase complexes, this mechanism underlies the pleiotropic effects of thalidomide on immune and cancer cells. However, following reports of thalidomide's side effects, various studies have been conducted to develop analogues with higher efficacy and fewer side effects as a way to utilize it as a cancer treatment. As a result, cereblon modulators such as lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106 have been developed, and their potential for clinical application has been demonstrated in hematological malignancies, such as multiple myeloma, myelodysplastic syndrome, lymphoma, and leukemia (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 regulators is mediated by the following: 1) Suppression of cancer cell proliferation and induction of apoptosis, 2) Interruption of nutritional support from the tumor stroma, 3) Proliferation of T cells, production of cytokines, and activation of NK (natural killer) cells in response to stimulation of immune cells.

[0006] Therefore, the inventors worked to develop a novel small molecule compound that has substrate specificity for cereblon and can effectively kill tumor cells. As a result, they 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. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present invention aims to provide novel compounds having binding activity to cereblon and their applications. [Means for solving the problem]

[0008] To achieve the above objective, the present invention provides compounds represented by the following formula (I), their optical isomers, their racemic mixtures, their hydrates, their solvates, or pharmaceutically acceptable salts thereof: [ka] In formula (I), (i) Each R is independently hydrogen (H), halogen (X), hydroxy (OH), amino (NH2), alkyl, alkylamine, aminocarbonylalkyl, aminocarbonylaryl, aminosulfonylalkyl, aminocarbonylalcohol, aminosulfonylaryl, aminosulfonylalkyl, aminoalkylaryl, aminocarbonylaminoaryl, alkylaminocarbonylalkoxy, aminosulfonylaminocarbonylaminoaryl, aminoarylalkylcarboxyalkyl, aminoarylalkylcarbonylaminoaryl, aminoarylalkylaminocarboxyalkyl, aminoarylalkylaminocarbonylaminoaryl, aminosulfonylarylaminocarbonylarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoalkylcarboxyalkyl, aminoarylalkylcarbonylaminoalkylcarboxylic acid, aminoarylaminocarbonylalkylcarbonylaminoaryl, aminoarylaminocarbonylaryl, or aminosulfonylarylaminocarbonylaryl, or

[0009] (ii) R is heterocycloalkyl containing CONH, wherein the heterocycloalkyl forms a fused ring of two rings 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),

[0010] Any benzene ring present in formula (I) is an unsubstituted benzene ring or a benzene ring in which one or more hydrogens in the benzene ring are substituted.

[0011] In the present invention, the formula (I) can be characterized by being represented by the following formula (II).

Chemical formula

[0012] In the present invention, the compound represented by formula (II) can be characterized by being represented by any formula selected from the group consisting of the following formulas (II-1) to (II-5). [ka] Any benzene ring present in formula (II-1) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted; [ka] Any benzene ring present in formula (II-2) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted; [ka] Any benzene ring present in formula (II-3) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted; [ka] Any benzene ring present in formula (II-4) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted; [ka] Any benzene ring present in formula (II-5) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0013] In the present invention, any benzene ring present in formula (I) is defined as any one or more hydrogen atoms in the benzene ring independently being alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amide, urea, sulfonyl, hydroxy, aldehyde, carboxy, halogenated alkyl, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heterocycloalkylalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; o Xim; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imi It may be characterized by being substituted with n;imide;amidine;guanidine;enamine;aminocarbonyl;acylamino;phosphonate;phosphine;thiocarbonyl;sulfinyl;sulfone;sulfonamide;ketone;aldehyde;ester;urea;urethane;oxime;hydroxylamine;alkoxyamine;aralkoxiamine;N-oxide;hydrazine;hydrazide;hydrazone;azide;isocyanate;isothiocyanate;cyanate;thiocyanate;B(OH)2, or O(alkyl)aminocarbonyl.

[0014] In the present invention, any benzene ring present in any of the formulas (II-1) to (II-5) is such that any one or more hydrogens in 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, (C1-C 10 ) alkoxy group, hydroxy group (-OH), (C1-C 10 ) alkoxyaryl group, and C6-C 30 aryl group, and may be characterized as being substituted with any one selected from the group consisting of.

[0015] In the present invention, any benzene ring present in the formula (II-4) is such that any one or more hydrogens in the benzene ring are each independently halogen, C 1-10 alkyl, C 1-10 halogenated alkyl, and may be characterized as being substituted.

[0016] In the present invention, the compound may be characterized as being represented by the following formula (III).

Chemical formula

[0017] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate or its pharmaceutically acceptable salt may be characterized as having a binding force to cerebron.

[0018] The present invention also provides any compound shown in Table 1, its optical isomer, its racemic mixture, its hydrate, its solvate or its pharmaceutically acceptable salt.

[0019] The present invention also aims to provide a pharmaceutical composition for the prevention or treatment of positive tumors or cancer, comprising the aforementioned compound, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] In the present invention, the cancer may be characterized by being a blood cancer or a solid tumor.

[0021] In the present invention, the hematological cancer may be selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0022] In the present invention, the solid tumor can be characterized by being selected from the group consisting of melanoma, sarcoma, multiple myeloma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, esophagogastric 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.

[0023] The present invention also provides a cereblon activity inhibitory composition comprising the compound, its optical isomers, its racemic mixtures, its hydrates, or its solvates.

[0024] The present invention also provides a method for preventing or treating a disease associated with cereblon activity, such as a positive tumor or cancer, comprising the step of administering the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof to a patient in need.

[0025] The present invention also provides applications for the prevention or treatment of diseases associated with the cerebron activity of the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof, such as positive tumors or cancer.

[0026] The present invention also provides uses for the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof in the manufacture of drugs for the prevention or treatment of diseases associated with cereblon activity, such as positive tumors or cancer. [Effects of the Invention]

[0027] The compounds according to the present invention exhibit excellent binding affinity to cereblon and can act as novel immunomodulators for treating tumors or cancerous diseases. [Modes for carrying out the invention]

[0028] Unless otherwise specified, all technical and scientific terms used herein have the meanings that are ordinarily understood by experts skilled in the art to which this invention pertains. Generally, the nomenclature and experimental methods used herein and described below are widely known and commonly used in the art.

[0029] In this invention, compounds exhibiting excellent binding affinity to cereblon were selected, and the apoptosis effect on these tumor cells was confirmed.

[0030] Therefore, in one aspect, the present invention relates to a compound represented by the following formula (I), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof: [ka] In formula (I), R may independently be hydrogen (H), halogen (X), hydroxy (OH), amino (NH2), alkyl, alkylamine, aminocarbonylalkyl, aminocarbonylaryl, aminosulfonylalkyl, aminocarbonyl alcohol, aminosulfonylaryl, aminosulfonylalkyl, aminoalkylaryl, aminocarbonylaminoaryl, alkylaminocarbonylalkoxy, aminosulfonylaminocarbonylaminoaryl, aminoarylalkylcarboxyalkyl, aminoarylalkylcarbonylaminoaryl, aminoarylalkylaminocarboxyalkyl, aminoarylalkylaminocarbonylaminoaryl, aminosulfonylarylaminocarbonylarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoarylcarboxyalkyl, aminoarylalkylcarbonylaminoalkylcarboxylic acid, aminoarylaminocarbonylalkylcarbonylaminoaryl, aminoarylaminocarbonylaryl, or aminosulfonylarylaminocarbonylaryl.

[0031] In one embodiment, R can independently be hydrogen (H), halogen (X), hydroxyl (OH), or 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 It may also be H6 or NHCOC2H4OH, but is not limited to these.

[0032] In some embodiments, R in formula (I) may independently be aminosulfonylphenyl (NHSO2C6H5)aminoalkylphenyl (NHCH2C6H5), aminophenylaminocarbonylphenyl (NHC6H4NHCOC6H5), aminosulfonylphenylaminocarbonylphenyl (NHSO2C6H4NHCOC6H5), or aminocarbonylphenyl (NHCOC6H5), but is not limited thereto.

[0033] In another embodiment, in formula (I), R may be a heterocycloalkyl group containing C(O)NH, which can form a fused ring of a benzene ring and two other rings.

[0034] For example, in formula (I), the benzene ring may be an aralkyl group fused with a heterocycloalkyl group.

[0035] In another embodiment, in formula (I), R may be a heterocycloalkyl group containing C(O)NH, and the heterocycloalkyl group may be a compound in which a benzene ring and a fusion ring of two rings are formed, and one of the carbon atoms of the heterocycloalkyl group is substituted with oxygen. For example, the compound of formula (I) may have a structure that includes a fusion ring of the following two rings, [ka] In the present invention, the compound of formula (I) may be AEV40032, AEV40040, AEV40041, AEVAEV40062, AEV40078, or AEV40079.

[0036] In the fusion ring of the two rings, the heterocycloalkyl group containing CONH may have unsubstituted or substituted hydrogen atoms.

[0037] In the fusion ring of the two rings mentioned above, the heterocycloalkyl group containing CONH has hydrogen atoms of alkyl (e.g., CH3), alkoxy, aryl (e.g., C6H5), alkylalkoxy (e.g., C2H4OCH3), alkylaryl (e.g., CH2C6H5, C2H4C6H5), arylamine (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 It may be substituted with cycloalkyl)CONHC6H4X or C6H4NHCOC6H3X2.

[0038] 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.

[0039] In another embodiment, in formula (I), R is a heterocyclopentyl in which the carbon atoms in the cyclopentyl are substituted with nitrogen (N) and oxygen (O), respectively, wherein the heterocyclopentyl forms a fused ring with the benzene ring, and in the heterocyclopentyl, the nitrogen (N) and carbon atoms form a double bond, and the hydrogen (H) bonded to the carbon (C) between the nitrogen (N) and oxygen (O) atoms may be unsubstituted, or may be a heterocyclohexyl in which one carbon atom is substituted with nitrogen (N), or a heterocyclohexyl in which one carbon atom is substituted with nitrogen (N) and the other carbon atom is substituted with oxygen (O).

[0040] For example, the compound of formula (I) may have a structure that includes a fusion ring of the following two rings. [ka]

[0041] In the present invention, the compound of formula (I) may be AEV40203, AEV40207, or AEV40208.

[0042] In one embodiment, R in formula (I) may be selected from the following group. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] In the present invention, formula (I) can be characterized by being represented by the following formula (II), but is not limited thereto. [ka] In formula (II), R1 is either null, or CH2, CO, or SO2. R2 is either null or C6H4NHCO. Any benzene ring in formula (II) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted;

[0043] In the present invention, the compound represented by formula (II) may be characterized by being represented by any formula selected from the group consisting of formulas (II-1) to (II-5) below, but is not limited thereto. [ka] Any benzene ring present in formula (II-1) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0044] In some embodiments, any benzene ring present in formula (II-1) may have one hydrogen atom within the benzene ring be a halogen (e.g., F, Cl, Br, or I), an alkyl (methyl, ethyl, propyl, butyl, or pentyl) (branched or unbranched), CF3, NO2, NH2, NHCO(cycloalkyl)alkyl (e.g., NHCOC6H) 10The atoms may be substituted with CH3, NHCOC3H4CH3, NHCOC5H9O, or carboxyl (e.g., COOCH3), and in another embodiment, one or two benzene rings in formula (II-1) may have a total of two or more hydrogens independently substituted with halogens, alkylCF3, NO2, or NH2. For example, within one or two benzene rings in formula (II-1), two hydrogens may be substituted with halogen and halogen, halogen and alkyl, CF3 and NO2, alkyl and NO2, CF3 and NH2, or alkyl and NH2.

[0045] In the present invention, the compound of formula (II-1) is AEV40025, AEV40037, AEV40038, AEV40043, AEV40044, AEV40045, AEV40046, AEV40047, AEV40052, AEV40053, AEV40054, AEV40055, AEV40056, AEV400 57, AEV40058, AEV40060, AEV40061, AEV40063, AEV40069, AEV40070, AEV40073, AEV40074, AEV40075, AEV40099, AEV40100, AEV40101, AEV40224, AEV40225, AEV40226, and AEV40227 may also be used. [ka] Any benzene ring present in formula (II-2) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0046] In some embodiments, any benzene ring in formula (II-2) may have one hydrogen atom substituted with a halogen (e.g., F, Cl, Br, or I), a (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), a hydroxy(OH), an alkoxy (e.g., methoxy, ethoxy, or phenoxy), a CX3, a CX2H, a CXH2, or an aryl; in other embodiments, one or two benzene rings in formula (II-2) may have a total of two or more hydrogen atoms independently substituted with a halogen, an alkyl, a hydroxyl, an alkoxy, a CX3, a CX2H, a CXH2, or an aryl. For example, within one or two benzene rings in formula (II-2), two hydrogen atoms may be substituted with halogen and halogen, halogen and alkyl, alkyl and alkyl, halogen and alkoxy, halogen and hydroxyl, or alkyl and alkoxy; or within one or two benzene rings in formula (II-2), three hydrogen atoms may be substituted with three halogens.

[0047] 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, or AEV40122 as shown in Table 1. [ka] Any benzene ring present in formula (II-3) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0048] In some embodiments, any benzene ring in formula (II-3) may have one hydrogen atom substituted with a halogen (e.g., F, Cl, Br, or I) or an alkyl (methyl, ethyl, propyl, butyl, or pentyl) (branched or unbranched). In other embodiments, one or two benzene rings in formula (II-3) may have a total of two or more hydrogen atoms independently substituted with halogens (e.g., F, Cl, Br, or I) or an alkyl (methyl, ethyl, propyl, butyl, or pentyl) (branched or unbranched). For example, within one or two benzene rings in formula (II-3), two hydrogen atoms may be substituted with a halogen and a halogen.

[0049] In the present invention, the compound of formula (II-3) may be AEV40220 or AEV40221 in Table 1. [ka] Any benzene ring present in formula (II-4) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0050] In some embodiments, any benzene ring present in formula (II-4) may have one hydrogen atom in the benzene ring be a halogen (e.g., F, Cl, Br, or I), an alkyl (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl), an alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), or an alkyl halide (CH2X, C2H4X, C3H6X, C4H8X, C5H 10 X, C6H 12 X, C7H 14 X, C8H16X, C9H 18 X or C 10 H 20X) may be substituted with CX3, CX2H, or CXH2, and in another embodiment, one or two benzene rings 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 one or two benzene rings in formula (II-4), two hydrogens may be substituted with halogen and halogen, halogen and CX3, and within one or two benzene rings in formula (II-4), three hydrogens may be substituted with three halogens.

[0051] In the present invention, the compounds of formula (II-4) are, in Table 1, AEV40135, AEV40136, AEV40142, AEV40143, AEV40149, AEV40150, AEV40151, AEV40152, AEV40153, AEV40154, AEV40155, AEV40156, AEV40157, AEV4015 8. AEV40159, AEV40193, AEV40204, AEV40264, AEV41001, AEV41002, AEV41003, AEV41004, AEV41005, AEV41009, AEV41010, AEV41011, AEV41013, AEV41083, AEV41047, or AEV41048 may also be used. [ka] Any benzene ring present in formula (II-5) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

[0052] In some embodiments, any benzene ring in formula (II-5) may have one hydrogen atom within the benzene ring substituted with a halogen (e.g., F, Cl, Br, or I), a (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), an alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), CX3, CX2H, CXH2, or an aryl (e.g., phenyl). In other embodiments, one or two benzene rings in formula (II-5) may have a total of two or more hydrogen atoms independently substituted with halogens (e.g., F, Cl, Br, or I), a (branched or unbranched) alkyl (methyl, ethyl, propyl, butyl, or pentyl), an alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, or pentyloxy), CX3, CX2H, CXH2, or an aryl (e.g., phenyl). For example, in one or two benzene rings present in formula (II-5), two hydrogens may be substituted with halogen and halogen, halogen and alkyl, halogen and alkoxy, alkyl and alkyl, or halogen and aryl, and in one or two benzene rings present in formula (II-5), three hydrogens may be substituted with three halogens.

[0053] 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 as shown in Table 1.

[0054] In the present invention, any benzene ring present in formula (I) is defined as having any one or more hydrogen atoms in the benzene ring independently of alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amide, urea, sulfonyl, hydroxy, aldehyde, carboxy, halogenated alkyl, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heterocycloalkylalkylamino; imino; imide; amidino; guanidino; eneamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydr Roxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amide The compounds may be characterized by being substituted with n; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxiamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl, but are not limited thereto.

[0055] In the present invention, any benzene ring present in any of the formulas (II-1) to (II-5) is such that any one or more hydrogen atoms within the benzene ring are 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 The material may be characterized by being substituted with any of the groups selected from the group consisting of aryl groups, but is not limited thereto.

[0056] In the present invention, the compound may be any of the compounds shown in Table 1, but is not limited thereto.

[0057] In the present invention, any benzene ring present in formula (II-4) is such that any one or more hydrogen atoms within the benzene ring are independently a halogen, C 1-10 Alkyl, C 1-10 It can be characterized by being substituted with an alkyl halide, but is not limited to this.

[0058] In the present invention, the compound may be characterized by being represented by the following formula (III), but is not limited thereto. [ka] In formula (III), R 1 is halogen, C 1-10 Alkyl, C 1-10 It is an alkyl halogen.

[0059] In a specific embodiment, the compound may be characterized by being selected from the group composed of the following formulas.

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[0060] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvide, or its pharmaceutically acceptable salt may be characterized by having cerebron-binding affinity.

[0061] In the present invention, the "alkyl" group is a saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, 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. Typical saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; on the other hand, saturated branched alkyl groups 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 called 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 an alkyl group described herein is referred to as "substituted," these include not only any substituted or substituted compounds as found in the exemplary compounds and embodiments disclosed herein, but also halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkyl Amino, heterocyclylalkylamino, heterocycloalkylalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or may be substituted with -B(OH)2.In specific embodiments, where alkyl groups described herein are said to be "substituted," they may be substituted not only with any substituted or substituted compounds, such as those found in the exemplary compounds and embodiments disclosed herein, but also with 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; B(OH)2, or O(alkyl)aminocarbonyl.

[0062] The "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a monocyclic ring or a plurality of fused or bridged rings that can be selectively 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. Examples of such saturated cycloalkyl groups include monocyclic structures, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or plurality of or bridged ring structures, e.g., 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc. In another embodiment, 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. Examples of substituted cycloalkyl groups include cyclohexanol.

[0063] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms. Certain aryls include phenyl, biphenyl, naphthyl, etc. The hydrogen atoms of the aryl group may be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, e.g., fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Other active groups may be bonded to one or both ends of the aryl group.

[0064] A "heterocyclyl" is a non-aromatic cycloalkyl group 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 heterocyclyl group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl may also be bonded to other groups at any ring atom (i.e., at any carbon or heteroatom of the heterocyclic group). The heterocycloalkyl group may be substituted or unsubstituted. The heterocyclyl group includes unsaturated, partially saturated, and saturated ring systems, such as the imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The term "heterocyclyl" includes fused ring species containing fused aromatic and non-aromatic groups, such as 1- and 2-aminotetralines, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl. This term also includes bridged polycyclic systems containing heteroatoms, such as quinuclidyl, indefinitely. Representative examples of heterocyclyl groups include azilidinyl, azetidinyl, azepanil, oxetanyl, pyrrolidyl, and imidazolidinyl (e.g., imidazolidinyl-4-onyl or imidazolidinyl-2).4-Dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-onyl , morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyridazinyl, triazinyl, dihydropyridyl, dihydrodithinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoi Indoryl, isoindolinyl, azaindoryl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolidinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzoxazinyl, benzodithinyl, benzoxathinyl, benzo Azinyl, 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, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,This includes, but is not limited to, the 4-dihydroisoquinoline-1(2H)-onyl, quinolidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, phthalazinyl, naphthylidinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidine-2(1H)-one, and tetrahydroquinolinyl groups. Typical non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or once hypersubstituted, and these include, without restriction, a variety of substituted pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted, as listed below.

[0065] A "cycloalkylalkyl" group is defined as -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. A substituted cycloalkylalkyl group may be substituted in the alkyl portion, the cycloalkyl portion, or both the alkyl and cycloalkyl portions of the group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, and cyclohexylpropyl.

[0066] An "aralkyl" group is defined as an alkyl-aryl group, where alkyl and aryl are as defined above. A substituted aralkyl group may be substituted in the alkyl portion, the aryl portion, or both the alkyl and aryl portions. Typical 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-ylethyl.

[0067] A "heterocyclylalkyl" group is defined as -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. A "heterocycloalkylalkyl" group is defined as -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are as defined above. A substituted heterocyclylalkyl group may be substituted in the alkyl portion, the heterocyclyl portion, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-ylethyl, morpholine-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0068] "Halogen (X)" is fluoro(F), chlorine (Cl), bromo(Br), or iodine (I).

[0069] "Alkyl halogens" are alkyl groups in which some of the hydrogen atoms are replaced with halogens. For example, they may be alkyl fluorinated, alkyl chloride, alkyl bromide, or alkyl iodide. In some concrete examples, the alkyl halogen is a saturated alkyl halogen (C n H 2n X) may be, 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) is fine.

[0070] A "hydroxyalkyl" group is one in which an alkyl group is replaced by one or more hydroxyl groups. This can also be represented as an alcohol, and may have other active groups attached to one or both ends.

[0071] An "alkoxy" group is -O-(alkyl), where alkyl is defined above. Another active group may be bonded to one or both ends of the alkoxy group.

[0072] The "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0073] An "amino" or "amine" group is defined as -NH2 or -NH-, and may have other active groups attached to one or both ends.

[0074] In one embodiment, the "amino" group is an alkyl group of the formula -NH2, -NH-, or -NH-, where each alkyl group is independently defined as described above.

[0075] The "sulfonyl" group has the formula -SO2- and may have other active groups attached to one or both ends.

[0076] The terms "cycloalkylamino," "arylamino," "heterocyclylamino," and "heterocycloalkylamino" reflect the above explanation for "alkylamino," and here, the term "alkyl" is replaced with "cycloalkyl," "aryl," "heterocyclyl," and "heterocycloalkyl," respectively.

[0077] A "carboxyl" group or carboxylic acid has the formula -C(O)OH or -C(O)O-, and may have other active groups attached to one or both ends.

[0078] The "hydroxy" group is represented by the formula -OH.

[0079] The "aldehyde" group is represented by the formula -CHO.

[0080] As used herein and unless otherwise specified, an "acyl" group is defined as -C(O)(R) or -C(O)H, where R is as defined above. A "formyl" group is defined as -C(O)H.

[0081] As used herein and unless otherwise specified, a "carbonyl" group is -C(O)- which may have other active groups attached to one or both ends.

[0082] As used herein and unless otherwise specified, the “amide” group is of the 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 R is independently defined above.

[0083] In one embodiment, the "amide" group is an "aminocarbonyl" group of the formula -C(O)-NH2, -C(O)-NH(R), or -C(O)-N(R)2, where each R is independently defined as described above.

[0084] In one embodiment, the "amide" group is an "acylamino" group of the 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.

[0085] The "sulfonylamino" group is of the formula -NHSO2(R) or -N(alkyl)SO2(R), where alkyl and R are defined above.

[0086] The "urea" group is defined by the formulas -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 is independently defined as described above.

[0087] An "alkylamine" group is a group in which an alkyl group and an amine group are bonded, and other active groups may be bonded to one or both ends.

[0088] An "aminocarbonylalkyl" group is one in which an amino group, a carbonyl group, and an alkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0089] An "aminocarbonylaryl" group is one in which an amino group, a carbonyl group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0090] An "aminosulfonylalkyl" group is one in which an amino group, a sulfonyl group, and an alkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0091] An "aminocarbonylhydroxyalkyl" group is one in which an amino group, a carbonyl group, and a hydroxyalkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0092] An "aminosulfonylaryl" group is one in which an amino group, a sulfonyl group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0093] An "aminosulfonylalkyl" group is one in which an amino group, a sulfonyl group, and an alkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0094] An "aminocarbonylaminoaryl" group is one in which an amino group, a carbonyl group, an amino group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0095] An "alkylaminocarbonylalkoxy" group is one in which an alkyl group, an amino group, a carbonyl group, and an alkoxy group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0096] The "aminosulfonylaminocarbonylaminoaryl" group is a group in which an amino group, a sulfonyl group, an amino group, a carbonyl group, an amino group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0097] An "aminoarylalkylcarboxyalkyl" group is one in which an amino group, an aryl group, an alkyl group, a carboxyl group, and an alkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0098] The "aminoarylalkylcarbonylaminoaryl" group is a group in which an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0099] The "aminoarylalkylaminocarboxyalkyl" group is a group in which an amino group, an aryl group, an alkyl group, an amino group, a carboxyl group, and an alkyl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0100] The "aminoarylalkylaminocarbonylaminoaryl" group is a group in which an amino group, an aryl group, an alkyl group, an amino group, a carbonyl group, an amino group, and an aryl group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0101] The "aminosulfonylarylaminocarbonylarylalkoxy" group is a group in which an amino group, a sulfonyl group, an aryl group, an amino group, a carbonyl group, an aryl group, and an alkoxy group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0102] The "aminoarylalkylcarbonylaminoarylalkoxy" group is a group in which an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, an aryl group, and an alkoxy group are sequentially bonded, and other active groups may be bonded to one or both ends.

[0103] The "aminoarylalkylcarbonylaminoalkylcarboxyalkyl" group is a group in which 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 are sequentially bonded, and other active groups may be bonded to one or both ends.

[0104] The "aminoarylalkylcarbonylaminoalkylcarboxylic acid" group is a group in which an amino group, an aryl group, an alkyl group, a carbonyl group, an amino group, an alkyl group, and a carboxylic acid are sequentially bonded, and other active groups may be bonded to one or both ends.

[0105] The "aminoarylaminocarbonylalkylcarbonylaminoaryl" group is a group in which 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 are sequentially bonded, and other active groups may be bonded to one or both ends.

[0106] The "aminoarylaminocarbonylaryl" group is a group in which an amino group, an aryl group, an amino group, a carbonyl group, and an aryl group are sequentially bonded, and one or both ends may have other active groups bonded to them.

[0107] The "aminosulfonylarylaminocarbonylaryl" group is a group in which an amino group, a sulfonyl group, an aryl group, an amino group, a carbonyl group, and an aryl group are sequentially bonded, and one or both ends may have other active groups bonded to them.

[0108] Where groups described herein, excluding alkyl groups, are described as "substituted," they may be substituted with any suitable substituted or equivalent. Examples of substituted groups include, but are not limited to, those found in the exemplary compounds and embodiments disclosed herein, 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; Examples include isocyanates; isothiocyanates; cyanates; thiocyanates; 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 heterocyclyl (which may be monocyclic or fused or unfused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiadinyl)); monocyclic or fused or unfused polycyclic aryls (e.g., phenyl, naphthyl)aryloxys; aralkyloxys; heterocyclyloxys; and heterocyclylalkoxys.

[0109] Since the compounds according to the present invention can be prepared and used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts to enhance bioavailability or increase solubility, the aforementioned prodrugs, hydrates, solvates, and pharmaceutically acceptable salts also fall within the scope of the present invention. Furthermore, the compounds have chiral carbon atoms and stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0110] The term "prodrug" refers to a substance that is converted into a parent drug in the body. Prodrugs are often used because, in some cases, they are easier to administer than parent drugs. For example, they may achieve physiological activity through oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than parent drugs. For example, a prodrug may be a biohydrolyzable 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) to which an acid group is converted by metabolism so that the peptide exposes its active site.

[0111] The term "hydrate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0112] The term "solvate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Preferred solvents relating thereto are volatile, non-toxic, and / or suitable for administration to humans.

[0113] The term "isomer" refers to a compound or salt of the present invention that has the same chemical or molecular formula but is structurally or sterically different from other compounds of the present invention. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with chiral carbon centers, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0114] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not impair the biological activity and physical properties of the compound without inducing serious irritation to the organism to which the compound is administered. The pharmaceutically acceptable salt includes acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., which form pharmaceutically acceptable, non-toxic acid addition salts containing negative ions; organic carboxylic acids such as 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 such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compounds according to the present invention can be converted to their salts by conventional methods.

[0115] In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of positive tumors or cancer, comprising the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof as an active ingredient.

[0116] In the present invention, the cancer may be characterized by being a blood cancer or a solid tumor.

[0117] In the present invention, the hematological cancer may be selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma, but is not limited thereto.

[0118] In the present invention, the solid tumor is characterized by being selected from the group consisting of melanoma, sarcoma, multiple myeloma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, esophagogastric 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.

[0119] In the present invention, the terms "pharmaceutical composition" or "pharmaceutical formulation" mean a mixture of the novel compounds of the present invention containing pharmaceutically acceptable excipients, such as diluents or carriers, to make them particularly suitable for in vivo or in vitro diagnostic or therapeutic applications. According to some examples, a pharmaceutical composition containing the composition of the present invention may be provided in a manner that allows it to be administered to a target body in a therapeutically effective amount as needed. In some examples, the composition of the present invention can be administered to humans.

[0120] As used in this invention, "effective amount" or "therapeutic-effective amount" refers to the amount of compound or composition (e.g., the compound or composition of this 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.

[0121] The pharmaceutical compositions provided in this invention primarily relate to pharmaceutical compositions for administration to humans, but ordinary technicians should understand that such compositions are generally suitable for administration to all types of animals. That is, the pharmaceutical compositions according to the present invention can also be administered to animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.), and other mammals such as laboratory animals (e.g., rats, mice, guinea pigs, etc.). With a good understanding of variations of pharmaceutical compositions for administration to various animals, a skilled veterinary pharmacologist can design and / or implement such variations by simple, conventional experiments if necessary.

[0122] The pharmaceutical compositions described in this invention may also be produced by any method known in the field of pharmacology or developed as described below. Generally, such purification methods include the step of associating the active ingredient with excipients and / or one or more other auxiliary components, and then, if necessary or desired, the step of shaping and / or packaging the product in desired single- or multi-dose units.

[0123] The pharmaceutical compositions of the present invention may be manufactured, packaged, and / or sold unpackaged as single unit doses and / or multiple single unit doses. As used herein, “unit dose” refers to an individual amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally the same as the dose of the active ingredient administered to a subject and / or a convenient fraction of said dose, for example, 1 / 2 or 1 / 3 of the dose.

[0124] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical composition of the present invention may vary depending on the identity, size, and / or disorder of the target organism, and the route through which the composition is administered. For example, the composition may contain 0.001% to 100% (w / w) of the active ingredient.

[0125] As used in the present invention, pharmaceutically acceptable excipients include all solvents, dispersion media, diluents, or other liquid vehicles, dispersions or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the purpose of a particular dosage form. Remington's literature [The Science and Practice of Pharmacy, 21st Edition, ARGennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006)] discloses a variety of excipients used in the preparation of pharmaceutical compositions and known techniques for their manufacture. Consideration is given to excipients whose use falls within the scope of the present invention, excluding any common carrier medium that exhibits, for example, any undesirable biological effects or that cannot coexist with the substance or its derivatives due to adverse interactions with any other component of the pharmaceutical composition. Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.

[0126] The excipients are approved for human and veterinary use. In some examples, the excipients are approved by the U.S. Food and Drug Administration. In some examples, the excipients are pharmaceutical grade. In some examples, the excipients meet the standards of the United States Pharmacopeia (USP), European Pharmacopeia (EP), British Pharmacopeia, and / or International Pharmacopoeia (EP).

[0127] In some examples, the excipients are approved for human and veterinary use. In some examples, the excipients are approved by the U.S. Food and Drug Administration. In some examples, the excipients are pharmaceutical grade. In some examples, the excipients meet the standards of the United States Pharmacopeia (USP), European Pharmacopeia (EP), British Pharmacopeia, and / or International Pharmacopoeia (EP).

[0128] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inactive diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils.

[0129] Such excipients may optionally be included in the formulation of the present invention. Excipients, such as cocoa butter and suppository wax, colorants, coatings, sweeteners, flavorings, and fragrances, may be present in the composition at the discretion of the compounder.

[0130] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydroxide phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugars, and combinations thereof.

[0131] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, positive ion exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pre-gelatinized starch (starch 1500), microcrystalline starch, insoluble starch, calcium carboxymethylcellulose, aluminum magnesium silicate (bee gum), sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof.

[0132] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, tallow, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and beegum [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), and caraggi. Nan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 [Mills 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, andThis includes, but is not limited to, solutol, sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremofor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or combinations thereof.

[0133] Exemplary binders include, but are not limited to, starches (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, panwar gum, gatchigum, isagol husk mucus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), aluminum magnesium silicate (bee gum), and larch arabinogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylate; waxes; water; alcohols; and combinations thereof.

[0134] Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic 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), citrate monohydrate, disodium edetate, dipotassium edetate, edetate, 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, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, 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 acidic 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, deteroxymemesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium bisulfite, potassium metabisulfite, glidantoplus, phenonip, methylparaben, gelmar 115, gelmarben II, neolon, caisson, and euxyl. In certain examples, the preservative is an antioxidant. In other examples, the preservative is a chelating agent.

[0135] Exemplary buffers include, but are not limited to, citrate buffer, acetate buffer, phosphate buffer, 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, pentanoic acid, dicalcium phosphate, phosphate, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dicalocotium phosphate, monopotassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dicalocotium phosphate, monosodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof.

[0136] Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0137] Examples of oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seeds, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seeds, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, and Litsea cubeba. Contains, but is not limited to, oils from cubeba, macadamia nuts, mallow, mango seeds, meadowfoam seeds, mink, nutmeg, olives, oranges, orange roughy, palm, palm kernels, peach kernels, peanuts, poppy seeds, pumpkin seeds, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soy, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oils, and combinations thereof.

[0138] Liquid dosage forms 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, liquid dosage forms may include inert diluents commonly used in the art, so-called, for example, water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. Beyond inert diluents, oral compositions may include adjuvants, for example, wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. In specific examples for parenteral administration, the novel compounds of the present invention are mixed with solubilizers, such as cremophor, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and combinations thereof.

[0139] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be prepared by known art using dispersants or wetting agents and suspending agents. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions as solutions in non-toxic, parenterally acceptable diluents or solvents, such as 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Sterile, fixative oils are also typically used as solvents or suspension media. Any non-irritating fixative oil, including synthetic mono- or diglycerides, may be used for this purpose. Fatty acids, such as oleic acid, are also used in the manufacture of injectable formulations.

[0140] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent, which is in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable culture medium before use.

[0141] To prolong the effects of a drug, it is generally preferable to delay drug absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having low water solubility. In this case, the absorption rate of the drug ultimately depends on the crystal size and crystalline form, and is subject to solubility. Alternatively, the delay in absorption of parenterally administered drugs can be achieved by dissolving or suspending the drug in an oil vehicle.

[0142] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is one or more inactive pharmaceutically acceptable excipients or carriers, e.g., sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, so-called, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents. It is mixed with, 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, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.

[0143] In the case of capsules, tablets and pills, the dosage forms may include buffers. Similar types of solid compositions can be adopted as fillers in soft and rigid gelatin capsules, using not only lactose or lactose but also high molecular weight polyethylene glycol and the like as excipients. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be manufactured with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical preparation. These may optionally contain opacifying agents and may be compositions that release only the active ingredient, or preferentially in a specific part of the intestinal tract, in an optionally delayed manner. Examples of embedding compositions used include polymeric substances and waxes. Similar types of solid compositions can be adopted as fillers in soft and rigid gelatin capsules, using not only lactose or lactose but also high molecular weight polyethylene glycol and the like as excipients.

[0144] The active ingredient may be in a microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be manufactured with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical preparation. In such solid dosage forms, the active ingredient may also be mixed with one or more inert diluents, such as sucrose, lactose, or starch. Such dosage forms may typically include additional substances that are not inert diluents, such as tablet lubricants and other tablet adjuvants, such as magnesium stearate and microcrystalline cellulose, as shown in the examples. In the case of capsules, dosage forms such as tablets and pills may also include buffers. These may optionally include opacifiers and may be compositions that release only the active ingredient, or primarily to a specific part of the intestinal tract, optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0145] Dosage forms for topical and / or transdermal administration of the novel compounds of the present invention or pharmaceutically active compositions containing the same may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffers, which may also be required. Furthermore, the present invention generally considers the use of transdermal patches, which have the additional advantage of providing controlled delivery of the active ingredient into the body. Such dosage forms can be manufactured, for example, by melting and / or dispersing the active ingredient in a suitable culture medium. Alternatively or additionally, the release rate may also be controlled by providing / providing a rate-limiting membrane or by dispersing the active ingredient in a polymer matrix and / or gel.

[0146] Formulations for topical administration include, but are not limited to, liquid and / or semi-liquid formulations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments / or pastes, and / or solutions and / or suspensions. The concentration of the active ingredient can be as high as the limit of the solubility of the active ingredient in the solvent, but a topically administered formulation may contain, for example, about 1% to about 10% (w / w) of the active ingredient. Formulations for topical administration may further contain one or more additional ingredients described herein.

[0147] The novel compounds of the present invention described herein, or pharmaceutical compositions containing them, are typically manufactured in dose units for ease of administration and uniformity of administration. However, it should be understood that the total daily dosage of the compositions of the present invention is to be determined by the attending physician within reasonable medical judgment. A specific therapeutically effective dose level for any particular subject depends on a variety of factors, including the disease, disorder, or disorder and its severity during treatment; the activity of the specific active ingredient adopted; the specific composition adopted; the subject's age, weight, overall health, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient adopted; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient adopted; and other factors well known in the medical field.

[0148] The novel compounds of the present invention, their salts, or their pharmaceutically acceptable compositions can also be administered by any route. In some examples, the novel compounds, their salts, or their pharmaceutically acceptable compositions can be administered by a variety of routes, including oral, intravenous, intramuscular, intraarterial, intramedullary, intraspinal, subcutaneous, intraventricular, percutaneous, intradermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or droplet), mucous membrane, nasal cavity, oral cavity, enteral, sublingual; intratracheal infusion, bronchial infusion, and / or inhalation; and / or oral spray, nasal spray, and / or aerosol. Routes specifically considered include osmotic intravenous injection, topical administration via blood and / or lymph supply, and / or direct administration to the affected site. Generally, the most suitable route of administration depends on a variety of factors, including the properties of the agonist (e.g., stability in the gastrointestinal environment) and the subject's tolerance (e.g., whether the subject can tolerate oral administration).

[0149] In certain embodiments, the novel compounds of the present invention, their salts, or their pharmaceutically active compositions may also be administered at dose levels sufficient to deliver approximately 0.001 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 50 mg / kg, approximately 0.1 mg / kg to approximately 40 mg / kg, approximately 0.5 mg / kg to approximately 30 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, or approximately 1 mg / kg to approximately 25 mg / kg of the subject's body weight once or more daily to obtain the desired therapeutic effect. The desired dose may also be delivered three times a day, twice a day, every other day, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose can also be delivered via multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more doses).

[0150] It will be understood that the dose range described in the present invention provides a guide for the administration of the pharmaceutical composition provided to adults. For example, the amount administered to children or adolescents may be determined by a specialist or an expert in the art and may be less than or the same as 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 type of subject, age, and the severity of the general disorder, side effects or disorders, the identity of the characteristic compound, the method of administration, etc.

[0151] It will be understood that the novel compounds and pharmaceutical compositions of the present invention can be used as combination therapies. Specific combinations of therapies (therapeutic agents or procedures) for use in combination therapy can be determined by considering the desired therapeutic effect to be achieved and the suitability of the desired therapeutic agents and / or procedures.

[0152] The pharmaceutical compositions of the present invention can be administered alone or in combination with one or more therapeutic activators. In the case of “combination,” the following delivery methods are within the scope of the invention, but are not intended to suggest that the activators must necessarily be administered at the same time or be formulated to be delivered simultaneously. The compositions may be administered simultaneously with, before, or after, one or more other therapeutic agents or medical procedures. Generally, each activator is administered according to a prescribed dosage and / or time schedule for that activator. Furthermore, the invention encompasses the delivery of the pharmaceutical compositions of the present invention in combination with activators that can improve their bioavailability in the body, reduce and / or modify their metabolism, suppress their secretion, and / or modify their distribution. It will be understood that the novel compounds and therapeutic activators of the present invention used in this combination may be administered simultaneously in a single composition or separately in different compositions.

[0153] The specific combinations used in combination therapy take into account the desired therapeutic effect to be achieved and / or the suitability of the procedure and / or therapeutic activator containing the peptide of the present invention. It will be understood that the combinations used can achieve the desired effect for the same disorder (for example, the novel compounds of the present invention may be administered in combination with other therapeutic activators (e.g., a second therapeutic agent) used to treat the same disorder), and / or achieve different effects (e.g., control of any side effects).

[0154] As used in this application, "therapeutic activator" refers to any substance used as a pharmacopoeia to treat, prevent, delay, reduce or improve a disorder, and includes substances used in treatment, including prophylactic and curative treatments.

[0155] In some embodiments, the other therapeutic activator for concomitant administration is for the treatment of multiple myeloma. In some embodiments, the other therapeutic activator may be a proteasome inhibitor and / or an immunomodulating drug. In the present invention, the other therapeutic activator may be selected from, but is not limited to, the group consisting of dexamethasone, bortezomib, carfilzomib, melphalan, doxorubicin, and cyclophosphamide.

[0156] In some embodiments, the pharmaceutical compositions of the present invention may be administered in combination with any therapeutic activator or procedure (e.g., surgery, radiotherapy) that is useful in treating, reducing, improving, alleviating, delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or characteristics.

[0157] In one embodiment, the present invention can be provided as a kit for treating a tumor or cancerous disease in a subject suffering from said disease.

[0158] In some embodiments, the kit includes i) instructions for administering the novel compound or pharmaceutical composition according to the present invention to a subject suffering from the disease, and ii) the novel compound or pharmaceutical composition according to the present invention. In some embodiments, the kit may include one or more unit dosage forms containing the novel compound or pharmaceutical composition as described in the present invention in a dose effective for treating the disease in the subject. In some embodiments, the subject is a human patient.

[0159] In some embodiments, the kit further includes one or more selected from the group including sterile syringes, sterile needles, sterile IV bags, infusion pumps, or any combination thereof.

[0160] As used in this invention, the term "about" can be interpreted as roughly, approximately, or to a certain extent. When the term "about" is used with a range of numbers, it is interpreted as modifying the range by extending the boundary above and below the specified numerical value. Generally, the term "about" is used in this application to modify the numerical values ​​above and below the value specified by the 10% variance.

[0161] The terms "individual," "patient," and "subject" are interchangeable and include any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, including humans.

[0162] In the present invention, unless otherwise specified, “treatment” means reversing, alleviating, inhibiting the progression of, or preventing a disease or illness to which the above terms apply, or one or more symptoms of such disease or illness, and the term “treatment” as used in the present invention means the act of treating as defined above. Accordingly, a “treatment” or “treatment” for a disease in mammals may include one or more of the following: (1) To prevent the onset of disease, (2) To prevent the spread of disease, (3) To alleviate the disease, (4) To prevent recurrence of the disease and (5) To alleviate the symptoms of a disease (palliating)

[0163] In the present invention, "prevention" means any action that suppresses or delays the onset of the disease by administering the pharmaceutical composition according to the present invention, unless otherwise specified.

[0164] In another aspect, the present invention provides a method for preventing or treating a disease associated with cereblon activity, such as positive tumors or cancer, comprising the step of administering the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof to a patient in need.

[0165] The present invention also provides applications for the prevention or treatment of diseases associated with the cerebron activity of the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof, such as positive tumors or cancer.

[0166] The present invention also provides uses for the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof in the manufacture of drugs for the prevention or treatment of diseases associated with cereblon activity, such as positive tumors or cancer.

[0167] Furthermore, the present invention provides a method for producing the compounds listed in Table 1. Below, some of the methods for producing the compounds in Table 1 according to the present invention are illustrated by examples of synthesis methods, and the synthesis methods in Production Examples 1 to 15 below are not limited to the methods for producing the compounds according to the present invention. These synthesis methods are merely illustrative and can be easily modified by an ordinary person depending on the specific substituted compound.

[0168] Manufacturing method Preparation of intermediate B (3-amino-N-(3-(2,6-dioxopiperidine-3-yl)phenyl)benzenesulfonamide) Intermediate B used to produce the compound of the present invention can be produced by the following reaction: (a') A step of reacting 2,6-bis(benzyloxy)-3-bromopyridine with 3-aminophenylboronic acid to produce 3-(2,6-bis(benzyloxy)pyridin-3-yl)aniline; (b') The step of reacting 3-(2,6-bis(benzyloxy)pyridine-3-yl)aniline with hydrogen to produce 3-(3-aminophenyl)piperidine-2,6-dione; (c') The step of reacting 3-(3-aminophenyl)piperidine-2,6-dione with 3-nitrobenzenesulfonyl chloride to produce N-(3-(2,6-dioxopiperidine-3-yl)phenyl)-3-nitrobenzenesulfonamide; and (d')N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide is reacted with hydrogen to produce 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0169] 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 then further adding and reacting 2,6-bis(benzyloxy)-3-bromopyridin and 3-aminophenylboronic acid.

[0170] In the above method, step (a') may be carried out at a temperature of 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.

[0171] 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.

[0172] 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.

[0173] In the present invention, room temperature may be a typical indoor temperature of about 15 to 30°C, preferably about 20 to 28°C, but is not limited to this.

[0174] In the above method, step (c') may involve adding 3-(3-aminophenyl)piperidine-2,6-dione and 3-nitrobenzenesulfonyl chloride to a mixture of dichloromethane and pyridine and reacting the mixture.

[0175] In the above method, step (c') may be carried out at room temperature, 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.

[0176] In the above method, step (d') may involve adding N-(3-(2,6-dioxopiperidine-3-yl)phenyl)-3-nitrobenzenesulfonamide and palladium on carbon to methanol and reacting it with hydrogen.

[0177] 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.

[0178] Methods for producing compounds of formulas (i) to (vii) The production methods for 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.

[0179] In the above method, step (a) may involve dissolving potassium carbonate in N,N-dimethylacetamide, and then adding C6H5-(CH2)nC(O)Cl (where n is a positive number from 0 to 6) and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide and reacting them.

[0180] In the above method, step (a) may be carried out at room temperature, and may be stirred and reacted for no more than 1 hour, for example, for about 1 to 20 minutes, for example, for about 2 to 10 minutes, preferably for about 4 to 8 minutes, but is not limited thereto.

[0181] As one example, a method for producing the compound represented by formula (2) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-methylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with benzoyl chloride; [ka]

[0182] As an example, a method for producing the compound represented by formula (3) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-ethylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 2-phenylacetyl chloride; [ka]

[0183] As an example, a method for producing the compound represented by formula (4) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-propylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 3-phenylpropanoyl chloride; [ka]

[0184] As an example, a method for producing the compound represented by formula (iv) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-butylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 4-phenylbutanoyl chloride; [ka]

[0185] As an example, a method for producing the compound represented by formula (v)(N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-pentylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 5-phenylpentanoyl chloride; [ka]

[0186] As an example, a method for producing the compound represented by formula (vi) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-hexylbenzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 6-phenylhexanoyl chloride; [ka]

[0187] As an embodiment, a method for producing a compound represented by formula (vii) (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide) can include: (a) reacting 7-phenylheptanoyl chloride with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide;

Chemical formula

[0188] Method for producing a compound of formula (ix) or formula (x) The method for producing the compound of formula (ix) or formula (x) can include: (a) reacting 4-chlorobenzoyl chloride or 4-(chloromethyl)benzoyl chloride with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide;

[0189] In the above method, in step (a), potassium carbonate may be dissolved in N,N-dimethylacetamide, and then 4-chlorobenzoyl chloride or 4-(chloromethyl)benzoyl chloride and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide may be added and reacted.

[0190] In the above method, step (a) may be carried out at room temperature and stirred and reacted for within 1 hour, for example, about 1 to 20 minutes, for example, about 2 to 10 minutes, preferably about 4 to 8 minutes, but not limited thereto.

[0191] As an embodiment, the method for producing the compound represented by the above formula (ix) (4-chloro-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include: (a) reacting 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 4-chlorobenzoyl chloride. [Chemical formula]

[0192] As one example, a method for producing the compound represented by formula (x)(4-(chloromethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) may include the step of reacting (a) 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide with 4-(chloromethyl)benzoyl chloride; [ka]

[0193] Methods for producing compounds of formulas (xi) to (xv) The method for producing formulas (xi) to (xv) may include the step of reacting (a) Cl-(CH2)n-C6H4-COOH (where n is a positive number from 2 to 6) with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide.

[0194] In the above method, step (a) may involve dissolving potassium carbonate in N,N-dimethylacetamide, and then adding Cl-(CH2)n-C6H4-COOH (where n is a positive number from 2 to 6) and 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide and reacting them.

[0195] In the above method, step (a) may be carried out at room temperature, and may be stirred and reacted for no more than 1 hour, for example, about 1 to 20 minutes, for example, about 2 to 10 minutes, preferably about 4 to 8 minutes.

[0196] In the above method, Cl-(CH2)n-C6H4-COOH (where n is a positive number from 2 to 6) can be produced by adding lithium hydroxide to Cl-(CH2)n-C6H4-COOCH3 (where n is a positive number from 2 to 6) and demethylating it. The demethylation reaction may be carried out at room temperature and may be carried out with stirring for about 2 to 20 hours, for example, 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 a positive number from 2 to 6) may be dissolved in a methanol-water mixture and undergo demethylation.

[0197] The aforementioned Cl-(CH2)n-C6H4-COOCH3 (where n is a positive number from 2 to 6) can be produced by halogenating OH-(CH2)n-C6H4-COOCH3 (where n is a positive number from 2 to 6) with thionyl chloride. The halogenation reaction may be carried out at approximately 40 to 80°C, for example, approximately 50 to 70°C, preferably approximately 60°C, and may be stirred and reacted for approximately 2 to 20 hours, for example, approximately 4 to 12 hours, preferably approximately 6 to 10 hours, but is not limited thereto. In this case, OH-(CH2)n-C6H4-COOCH3 (where n is a positive number from 2 to 6) may be dissolved in toluene and undergo the halogenation reaction.

[0198] In one embodiment, a method for producing the compound represented by 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; [ka]

[0199] As a preferred embodiment, the compound represented by formula (xi) can be produced by a manufacturing method comprising the following steps: [ka] (a) The step of reacting methyl 4-(2-oxopropyl)benzoate with thionyl chloride to produce methyl 4-(2-chloroethyl)benzoate; (b) The step of adding lithium hydroxide to methyl 4-(2-chloroethyl)benzoate to demethylate it and producing 4-(2-chloroethyl)benzoic acid; and (c) A step of reacting 4-(2-chloroethyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide to produce a compound represented by formula (11).

[0200] In one embodiment, the method for producing a compound represented by formula (xii) (4-(3-chloropropyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide) can include the step of reacting 4-(3-chloropropyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide: [Chemical formula]

[0201] In a preferred embodiment, the compound represented by formula (xii) can be produced by a production method including the following steps: [Chemical formula] (a) Reacting methyl 4-iodobenzoate with prop-2yn-1-ol to produce methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate; (b) Reacting methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate with hydrogen to produce methyl 4-(3-hydroxypropyl)benzoate; (c) Reacting methyl 4-(3-hydroxypropyl)benzoate with thionyl chloride for halogenation to produce methyl 4-(3-chloropropyl)benzoate; (d) The step of adding lithium hydroxide to methyl 4-(3-chloropropyl)benzoate to demethylate it and produce 4-(3-chloropropyl)benzoic acid; and (e) A step of reacting 4-(3-chloropropyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide to produce a compound represented by formula (xii).

[0202] In one embodiment, a method for producing the compound represented by 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; [ka]

[0203] As a preferred embodiment, the compound represented by formula (13) can be produced by a manufacturing method comprising the following steps: [ka] (a) The step of reacting methyl 4-(4-hydroxybutyl)benzoate with thionyl chloride to halogenate it and produce methyl 4-(4-chlorobutyl)benzoate; (b) The step of adding lithium hydroxide to methyl 4-(4-chlorobutyl)benzoate to demethylate it and produce 4-(4-chlorobutyl)benzoic acid; and (c) A step of reacting 4-(4-chlorobutyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide to produce a compound represented by formula (xiii).

[0204] In one embodiment, a method for producing the compound represented by formula (xiv)(4-(5-chloropentyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzmid) may include the step of reacting 4-(5-chloropentyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide; [ka]

[0205] As a preferred embodiment, the compound represented by formula (xiv) can be produced by a manufacturing method comprising the following steps: [ka] (a) The step of reacting methyl 4-iodobenzoate with penta-4-yn-1-ol to produce methyl 4-(5-hydroxypenta-1-yn-1-yl)benzoate; (b) The step of reacting methyl 4-(5-hydroxypenta-1-in-1-yl)benzoate with hydrogen to produce methyl 4-(5-hydroxypentyl)benzoate; (c) The step of reacting methyl 4-(5-hydroxypentyl)benzoate with thionyl chloride to halogenate it and produce methyl 4-(5-chloropentyl)benzoate; (d) The step of adding lithium hydroxide to methyl 4-(5-chloropentyl)benzoate to demethylate it and produce 4-(5-chloropentyl)benzoic acid; and (e) A step of reacting 4-(5-chloropentyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide to produce a compound represented by formula (xiv).

[0206] In one embodiment, a method for producing the compound represented by 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; [ka]

[0207] As a preferred embodiment, the compound represented by formula (xv) can be produced by a manufacturing method comprising the following steps: [ka] (a) The step of reacting methyl 4-iodobenzoate with hex-5-yn-1-ol to produce methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate; (b) The step of reacting methyl 4-(6-hydroxyhexa-1-in-1-yl)benzoate with hydrogen to produce methyl 4-(6-hydroxyhexyl)benzoate; (c) The step of reacting methyl 4-(6-hydroxyhexyl)benzoate with thionyl chloride to halogenate it and produce methyl 4-(6-chlorohexyl)benzoate; (d) The step of demethylating methyl 4-(6-chlorohexyl)benzoate with lithium hydroxide to produce 4-(6-chlorohexyl)benzoic acid; and (e) A step of reacting 4-(6-chlorohexyl)benzoic acid with 3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide to produce a compound represented by formula (xv).

[0208] In another aspect, the present invention relates to a cereblon activity inhibitor or a cereblon activity inhibitory composition comprising the compound, its optical isomers, its racemic mixtures, its hydrates, or its solvates.

[0209] In one embodiment, the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or salts thereof can be provided as experimental reagents used to inhibit cereblon activity in a test tube.

[0210] The present invention will be described in more detail below through manufacturing examples and embodiments. However, the following manufacturing examples and embodiments are for illustrative purposes only and do not limit the scope of the present invention.

[0211] Manufacturing example Production of intermediate B [ka]

[0212] Manufacturing of Compound 2 To a 5:1 mixture of 1,4-dioxane (CAS: 123-91-1) and water (H2O), PD(dppf)Cl2 ([1,1′ CAS: 72287-26-4) and potassium carbonate (CAS: 584-08-7) were added. Then, compound 1 (2,6-bis(benzyloxy)-3-bromopyridine, CAS: 16727-47-2) and 3-aminophenylboronic acid (3-Aminophenylboronic acid) were added. Acid (CAS: 206658-89-1) was added and the mixture was stirred at 90°C for 12 hours to obtain compound 2 (3-(2,6-bis(benzyloxy)pyridin-3-yl)aniline).

[0213] Production of intermediate A Compound 2 and palladium on carbon (CAS: 7440-05-3) were added to a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and methanol (CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 4 hours to obtain intermediate A (3-(3-aminophenyl)piperidine-2,6-dione).

[0214] Manufacturing of Compound 3 Intermediate A (3-(3-aminophenyl)piperidine-2,6-dione) and 3-nitrobenzenesulfonyl chloride (CAS:121-51-7) were added to a mixture of methylene chloride (Dichloromethane, CAS:75-09-2) and pyridine (Pyridine, CAS:110-86-1), and the mixture was stirred at room temperature for 12 hours to obtain compound 3 (N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide).

[0215] Production of intermediate B Compound 3 (N-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3-nitrobenzenesulfonamide) and palladium on carbon (CAS: 7440-05-3) were added to methanol (CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 4 hours to obtain intermediate B (3-amino-N-(3-(2,6-dioxopiperidin-3-yl)phenyl)benzenesulfonamide).

[0216] Manufacturing Example 1. Preparation of compound (i) (AEV41009) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5) and dissolved. Intermediate B and benzoyl chloride (CAS: 98-88-4) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41009 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-methylbenzamide). [ka]

[0217] Manufacturing Example 2. Preparation of compound (ii) (AEV41010) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and 2-phenylacetyl chloride (CAS: 103-80-0) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41010 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-ethylbenzamide). [ka]

[0218] Manufacturing Example 3. Preparation of compound (iii) (AEV41011) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and 3-phenylpropanoyl chloride (CAS: 645-45-4) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41011 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-propylbenzamide). [ka]

[0219] Manufacturing Example 4. Preparation of compound (iv) (AEV41012 or AEV40154) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5) and dissolved. Intermediate B and 4-phenylbutanoyl chloride (CAS: 18496-54-3) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41012 (4-butyl-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0220] Manufacturing Example 5. Preparation of compound (v) (AEV41013) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5) and dissolved. Intermediate B and 5-phenylpentanoyl chloride (CAS: 20371-41-9) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound (v) AEV41013 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-pentylbenzamide). [ka]

[0221] Manufacturing Example 6. Preparation of compound (vi) (AEV41083) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5) and dissolved. Intermediate B and 6-phenylhexanoyl chloride (CAS: 21389-46-8) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41083 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-hexylbenzamide). [ka]

[0222] Manufacturing Example 7. Manufacturing of compound (vii) (AEV40204) [ka] Compound 204-1 (7-phenylheptanoic acid, CAS: 40228-90-8) and thionyl chloride (CAS: 7719-09-7) were added and stirred at 70°C to obtain compound 204-2 (7-phenylheptanoyl chloride). [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and compound 204-2 (6-phenylhexanoyl chloride) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV40204 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide). [ka]

[0223] Manufacturing Example 8. Preparation of compound (viii) (AEV40264) [ka] Intermediate B and 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 (N,N-Dimethylacetamide, CAS: 127-19-5), and triethylamine (CAS: 121-44-8) were stirred at 30°C for 12 hours to obtain compound AEV40264 (N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)-4-heptylbenzamide). [ka]

[0224] Manufacturing Example 9. Preparation of compound (ix) (AEV41001) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and 4-chlorobenzoyl chloride (CAS: 104-83-6) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound (ix) AEV41001 (4-chloro-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0225] Manufacturing Example 10. Preparation of compound (x) (AEV41002) [ka] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (N,N-Dimethylacetamide, CAS: 127-19-5) and dissolved. Intermediate B and 4-(chloromethyl)benzoyl chloride (CAS: 63024-77-1) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound (x) AEV41002 (4-(chloromethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0226] Manufacturing Example 11. Preparation of compound (xi) (AEV41003) [ka] Toluene (CAS: 108-88-3) was mixed with methyl 4-(2-oxopropyl)benzoate (CAS: 46190-45-8), pyridine (CAS: 110-86-1), and thionyl chloride (CAS: 7719-09-7), and the mixture was stirred at 60°C for 8 hours to obtain compound 3-2 (methyl 4-(2-chloroethyl)benzoate). Compound 3-2 (methyl 4-(2-chloroethyl)benzoate) and lithium hydroxide (Lithium hydroxide, CAS: 1310-65-2) were added to a mixture of methanol (Methanol, CAS: 67-56-1) and water, and the mixture was stirred at room temperature for 8 hours to obtain compound 3-3 (4-(2-chloroethyl)benzoic acid). [ka]

[0227] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and compound 3-3 (4-(2-chloroethyl)benzoic acid) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41003 (4-(2-chloroethyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0228] Manufacturing Example 12. Preparation of compound (xii) (AEV41004) [ka] To acetonitrile (CAS: 75-05-8), add PD(dppf)Cl2 ([1,1′(diphenylphosphino)ferrocene]dichloropalladium(II), CAS: 72287-26-4), copper(I)iodide (CAS: 7681-65-4), compound 4-1 (methyl 4-iodobenzoate, CAS: 619-44-3), and triethylamine (CAS: 121-44-8). Then add prop-2-yn-1-ol (CAS: 107-19-7), stir at 60°C for 12 hours, and compound 4-2 (methyl 4-(3-hydroxypropa-1-yl)benzoate) (methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate (CAS: 61266-36-2) was obtained.

[0229] Compound 4-2 (methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate, CAS: 61266-36-2) and Palladium on carbon (CAS: 7440-05-3) were added to methanol (CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 12 hours to obtain compound 4-3 (methyl 4-(3-hydroxypropyl)benzoate, CAS: 15403-22-2). [ka]

[0230] Compound 4-4 (methyl 4-(3-chloropropyl)benzoate) was obtained by adding compound 4-3 (methyl 4-(3-hydroxypropyl)benzoate, CAS: 15403-22-2) and thionyl chloride, CAS: 7719-09-7 to toluene (CAS: 108-88-3) and stirring at 60°C for 8 hours.

[0231] Compound 4-4 (methyl 4-(3-chloropropyl)benzoate) and lithium hydroxide (Lithium hydroxide, CAS: 1310-65-2) were added to a mixture of methanol (Methanol, CAS: 67-56-1) and water, and the mixture was stirred at room temperature for 5 hours to obtain compound 4-5 (4-(3-chloropropyl)benzoic acid, CAS: 90919-20-3). [ka]

[0232] Potassium carbonate (CAS: 584-08-7) was added to N-dimethylacetamide (CAS: 127-19-5) and dissolved. Intermediate B and compound 4-5 (4-(3-chloropropyl)benzoic acid) (CAS: 90919-20-3) were added, and the mixture was stirred at room temperature for 6 minutes to obtain compound AEV41004 (4-(3-chloropropyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0233] Manufacturing Example 13. Preparation of compound (xiii) (AEV41005) [ka] 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 to toluene (CAS: 108-88-3), and the mixture was stirred at 60°C for 8 hours to obtain compound 5-2 (methyl 4-(4-chlorobutyl)benzoate). Compound 5-2 (methyl 4-(4-chlorobutyl)benzoate) and lithium hydroxide (Lithium) were added to a mixture of methanol (CAS: 67-56-1) and water. Hydroxide (CAS: 1310-65-2) was added and the mixture was stirred at room temperature for 8 hours to obtain compound 5-3 (4-(4-chlorobutyl)benzoic acid). [ka]

[0234] N-dimethylacetamide (CAS: 127-19-5) was dissolved in potassium carbonate (CAS: 584-08-7), and intermediate B and compound 5-3 (4-(4-chlorobutyl)benzoic acid) were added. The mixture was stirred at room temperature for 6 minutes to obtain compound AEV41005 (4-(4-chlorobutyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0235] Manufacturing Example 14. Manufacturing of compound (xiv) (AEV41047) [ka] To acetonitrile (CAS: 75-05-8), add PD(dppf)Cl2 ([1,1′(diphenylphosphino)ferrocene]dichloropalladium(II), CAS: 72287-26-4), copper(I)iodide (CAS: 7681-65-4), compound 47-1 (methyl 4-iodobenzoate, CAS: 619-44-3), and triethylamine (CAS: 121-44-8). Then add pent-4-yn-1-ol (CAS: 619-44-3), stir at 60°C for 12 hours, and obtain compound 47-2 (methyl 4-(5-hydroxypento-1-in-1-yl)benzoate) (methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate was obtained.

[0236] Compound 47-2 (methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate) and palladium on carbon (CAS: 7440-05-3) were added to methanol (CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 12 hours to obtain compound 47-3 (methyl 4-(5-hydroxypentyl)benzoate). [ka]

[0237] Toluene (CAS: 108-88-3) was mixed with pyridine (CAS: 110-86-1) and thionyl chloride (CAS: 7719-09-7), compound 47-3 (methyl 4-(5-hydroxypentyl)benzoate) was added, and the mixture was stirred at 60°C for 8 hours to obtain compound 47-4 (methyl 4-(5-chloropentyl)benzoate).

[0238] Compound 47-4 (methyl 4-(5-chloropentyl)benzoate) and lithium hydroxide (Lithium hydroxide, CAS: 1310-65-2) were added to a mixture of methanol (Methanol, CAS: 67-56-1) and water, and the mixture was stirred at room temperature for 5 hours to obtain compound 47-5 (methyl 4-(5-chloropentyl)benzoic acid). [ka]

[0239] Potassium carbonate (CAS: 584-08-7) was dissolved in N-dimethylacetamide (CAS: 127-19-5), and intermediate B and compound 47-5 (methyl 4-(5-chloropentyl)benzoic acid) were added. The mixture was stirred at room temperature for 6 minutes to obtain compound AEV41047 (4-(5-chloropentyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0240] Manufacturing Example 15. Preparation of compound (xv) (AEV41048) [ka] To acetonitrile (CAS: 75-05-8), add PD(dppf)Cl2 ([1,1′(diphenylphosphino)ferrocene]dichloropalladium(II), CAS: 72287-26-4), copper(I)iodide (CAS: 7681-65-4), compound 48-1 (methyl 4-iodobenzoate, CAS: 619-44-3), and triethylamine (CAS: 121-44-8), then add hexa-5-yn-1-ol (CAS: 28916-38-3), stir at 60°C for 12 hours, and obtain compound 48-2 (methyl 4-(6-hydroxyhexa-1-in-1-yl)benzoate) (methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate was obtained.

[0241] Compound 48-2 (methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate) and palladium on carbon (CAS: 7440-05-3) were added to methanol (CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at room temperature for 12 hours to obtain compound 48-3 (methyl 4-(6-hydroxyhexyl)benzoate). [ka]

[0242] Toluene (CAS: 108-88-3) was mixed with thionyl chloride (CAS: 7719-09-7) and pyridine (CAS: 110-86-1), compound 48-3 (methyl 4-(6-hydroxyhexyl)benzoate) was added, and the mixture was stirred at 60°C for 8 hours to obtain compound 48-4 (methyl 4-(6-chlorohexyl)benzoate).

[0243] Compound 48-4 (methyl 4-(6-chlorohexyl)benzoate) and lithium hydroxide (Lithium hydroxide, CAS: 1310-65-2) were added to a mixture of methanol (CAS: 67-56-1) and water, and the mixture was stirred at room temperature for 5 hours to obtain compound 48-5 (methyl 4-(6-chlorohexyl)benzoic acid). [ka]

[0244] N-dimethylacetamide (CAS: 127-19-5) was dissolved in potassium carbonate (CAS: 584-08-7), and intermediate B and compound 48-5 (methyl 4-(6-chlorohexyl)benzoic acid) were added. The mixture was stirred at room temperature for 6 minutes to obtain compound AEV41048 (4-(6-chlorohexyl)-N-(3-(N-(3-(2,6-dioxopiperidin-3-yl)phenyl)sulfamoyl)phenyl)benzamide). [ka]

[0245] Example 1. In vitro CRBN binding assay Thalidomide-type compounds are known to regulate the function of immune cells and exert diverse pharmacological effects by binding to cereblon (CRBN), an E3 ligase, and degrading the transcription factors Aiolos and Ikaros, which serve as its substrates. We compared the cereblon-binding affinity of various compounds in vitro.

[0246] The binding affinity to cereblon was measured using the Fluorescence Resonance Energy Transfer (FRET)-based "AlphaScreen" method. This test was performed using the PROTAC Optimization kit for BET Bromodomain-Cereblon binding kit (#79770, BPS bioscience, CA USA), following the "Competitive Inhibition of the PROTAC assay" instructions in the kit manual. All reagents included in the kit were used, excluding the candidate substance, DMSO, and Flag / Glutathione bead (#6765300, PerkinElmer, USA).

[0247] As a result, we identified compounds with cereblon-binding activity as shown in Table 1. [Table 1] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0248] Example 2. Apothesis effect on tumor cells We investigated whether the compounds possessing CRBN binding activity according to the present invention exert an apoptosis effect on tumor cells using human multiple myeloma cell lines (MM.1S, MM.1R-LR), human breast cancer cell line (MDA-MB-231), human lung cancer cell line (A549), human rhabdomyosarcoma cell line (RD), and human lymphoma cell line (Jeko-1).

[0249] The 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 divided into 1 × 10⁶ cells. 4 The compounds were dispensed into 96-well plates at a cell / well rate and incubated for 24 hours. After incubation, the compounds were treated with dimethyl sulfoxide (Cas no.: 67-68-5), diluted stepwise to a 10 μM concentration, and incubated for a further 2 to 5 days. Finally, the compounds were analyzed using the CCK-8 analysis kit (Dojindo, Japan) according to the manufacturer's guidelines. [Table 2] [Table 2]

[0250] As a result, as shown in Table 3, we were able to confirm the apoptosis effect of compounds exhibiting CRBN binding activity on tumor cell lines. [Table 3] [Table 3]

Claims

1. Compounds represented by the following formula (I), their optical isomers, their racemic mixtures, their hydrates, their solvates, or their pharmaceutically acceptable salts: 【Chemistry 1】 In formula (I), (i) R is independently hydrogen (H), halogen (X), hydroxyl (OH), amino (NH) ２ ), alkyl, alkylamine, aminocarbonylalkyl, aminocarbonylaryl, aminohydroxynylalkyl, aminocarbonyl alcohol, aminohydroxynylaryl, aminohydroxynylalkyl, aminoalkylaryl, aminocarbonylaminoaryl, alkylaminocarbonylalkoxy, aminohydroxynylaminocarbonylaminoaryl, aminoarylalkylcarboxyalkyl, aminoarylalkylaminocarboxyalkyl, aminoarylalkylaminocarbonylaminoaryl, aminohydroxynylarylaminocarbonylarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoarylalkoxy, aminoarylalkylcarbonylaminoalkylcarboxyalkyl, aminoarylalkylcarbonylaminoalkylcarboxylic acid, aminoarylaminocarbonylalkylcarbonylaminoaryl, aminoarylaminocarbonylaryl, or aminohydroxynylarylaminocarbonylaryl, (ii) R is a heterocycloalkyl group comprising CONH, wherein the heterocycloalkyl group forms a fusion ring of two rings with the benzene ring, the hydrogen (H) bonded to the nitrogen (N) of CONH is either unsubstituted or substituted, and the carbon (C) of the heterocycloalkyl group is either unsubstituted or substituted with oxygen (O). Any benzene ring in formula (I) is either unsubstituted or has one or more hydrogen atoms substituted within it.

2. The compound according to claim 1, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof, characterized in that formula (I) is represented by the following formula (II). 【Chemistry 2】 [In formula (II), R １ is null, or CH ２ CO or SO ２ And, R ２ is null, or C ６ H ４ NHKCO, Any benzene ring present in formula (II) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.

3. The compound represented by formula (II) is the compound according to claim 2, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvide thereof, or a pharmaceutically acceptable salt thereof, which is represented by any formula selected from the group consisting of formulas (II-1) to (II-5) below. 【Transformation 3】 [Any benzene ring present in formula (II-1) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.] 【Chemistry 4】 [Any benzene ring present in formula (II-2) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.] 【Transformation 5】 [Any benzene ring present in formula (II-3) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.] 【Transformation 6】 [Any benzene ring present in formula (II-4) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.] 【Transformation 7】 [Any benzene ring present in formula (II-5) is either an unsubstituted benzene ring or a benzene ring in which one or more hydrogen atoms within the benzene ring are substituted.]

4. Any benzene ring present in formula (I) is one or more hydrogen atoms in the benzene ring that are independently alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amide, urea, sulfonyl, hydroxy, aldehyde, carboxy, halogenated alkyl, alkoxy, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo (= O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heterocycloalkyl Alkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl Amine; alkoxyamine; aralcoxiamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH) ２ The compound according to claim 1, characterized by being substituted with O(alkyl)aminocarbonyl, its optical isomers, racemic mixtures thereof, its hydrates, its solvates, or pharmaceutically acceptable salts thereof.

5. Any benzene ring present in any of the formulas (II-1) to (II-5) is such that any one or more hydrogens within the benzene ring are each independently -F, -Cl, -Br, -I, (C １ -C １０ ), an alkyl group, an amino group (-NH ２ ), a nitro group (-NO ２ ), -CF ３ -CF ２ H, -CFH ２ -CCl ２ -CCl ２ H, -CClH ２ -(CH ２ ) ｎ Cl, (C １ -C １０ ), an alkoxy group, a hydroxy group (-OH), (C １ -C １０ ), an alkoxyaryl group, and C ６ -C ３０ aryl group, and is characterized by being substituted with any one selected from the group consisting of, the compound according to claim 3, its optical isomers, its racemic mixture, its hydrate, its solvate or its pharmaceutically acceptable salts.

6. Any benzene ring present in formula (II-4) is such that any one or more hydrogen atoms within the benzene ring are independently a halogen, C １－１０ Alkyl, C １－１０ The compound according to claim 3, characterized by being substituted with an alkyl halide, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof.

7. The compound described above is characterized by being represented by the following formula (III), the compound according to claim 1, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof. 【Transformation 8】 [In formula (III), R １ is halogen (X), C １－１０ Alkyl, C １－１０ It is an alkyl halide.

8. The compound, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof, characterized in that the compound, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof, possesses cereblon-binding affinity.

9. A compound, its optical isomer, its racemic mixture, its hydrate, its solvide, or a pharmaceutically acceptable salt thereof, characterized by being one of the compounds shown in Table 1 below: [Table 1] Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21

10. A pharmaceutical composition for the prevention or treatment of positive tumors or cancer, comprising as an active ingredient a compound according to any one of claims 1 to 9, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvide thereof, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition for the prevention or treatment of a positive tumor or cancer according to claim 10, characterized in that the cancer is a blood cancer or a solid tumor.

12. The pharmaceutical composition for the prevention or treatment of a positive tumor or cancer according to claim 11, characterized in that the blood cancer is selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

13. The pharmaceutically active composition for the prevention or treatment of a positive tumor or cancer according to claim 11, characterized in that the solid tumor is selected from the group consisting of melanoma, sarcoma, multiple myeloma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastric 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.

14. A composition for inhibiting cereblon activity, comprising a compound according to any one of claims 1 to 9, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, or a solvide thereof.

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