Small molecule compound exhibiting cereblon-binding activity, and use thereof

Abstract

The present invention relates to: an improved small molecule compound having excellent cereblon (CRBN)-binding activity and enhanced anticancer activity; and a use thereof. The compound according to the present invention can effectively act as a novel anticancer agent for the treatment of various solid cancers and blood cancers on the basis of the binding affinity to cereblon.

Description

Improved low molecular weight compound having cereblon binding activity and its uses

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

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

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

[0004] Cereblon (CRBN) is known as a molecular target 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 for the treatment of multiple myeloma in the late 1990s, binds to Cereblon and modulates the substrate specificity of the CRL4CRBN ubiquitin ligase complex, and this mechanism forms the basis of thalidomide's pleiotropic effect on immune cells and cancer cells. However, as side effects of thalidomide were reported, various studies were conducted to develop analogs with higher efficacy and fewer side effects for its use as an anticancer treatment. Consequently, cereblon modulators such as lenalidomide, pomalidomide, CC-220, CC-122, CC-885, and TD-106 were developed, and their clinical applicability in hematological malignancies, such as multiple myeloma, myelodysplastic syndrome, lymphoma, and leukemia, has been demonstrated (Le Roy A et al: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities Front Immunol 2018; 9: 977).

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

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

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

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

[0009] Accordingly, the inventors have developed a novel small molecule compound capable of effectively killing tumor cells by possessing substrate specificity for cereblon (Korean Patent Publication No. 10-2024-0146608). In the present invention, structural changes capable of enhancing anticancer activity while maintaining cereblon binding characteristics were explored, and a new cereblon-bound small molecule compound exhibiting superior anticancer effects compared to existing compounds was developed.

[0010] The present invention aims to provide a cereblon-bound small molecule compound with improved anticancer activity and uses thereof.

[0011] To achieve the above objective, the present invention provides a compound represented by the following formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0012] Chemical formula (I)

[0013]

[0014] In chemical formula (I),

[0015] R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and

[0016] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

[0017] In the present invention, the above formula (I) can be represented by the following formula (II):

[0018] Chemical formula (II)

[0019]

[0020] R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and

[0021] R 2 to R 6 Each is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

[0022] In the present invention, the compound of formula (II) may be any one selected from the group consisting of formulas (i) to (xiv) below.

[0023] [Table 1]

[0024]

[0025]

[0026] The present invention also provides a pharmaceutical composition for the prevention or treatment of a benign tumor or cancer comprising, as an active ingredient, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt.

[0027] In the present invention, the cancer may be characterized as being a blood cancer or a solid tumor.

[0028] In the present invention, the blood cancer may be characterized as being selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0029] In the present invention, the solid tumor may be characterized as being selected from the group consisting of melanoma, myoma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer.

[0030] The present invention also provides a reagent composition comprising a compound, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, or a solvate thereof.

[0031] The compound according to the present invention can be utilized as an anticancer agent for the prevention and treatment of benign tumors or cancer based on its excellent cereblon binding affinity and enhanced cancer cell killing effect.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled expert in the art to which this invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

[0033] The inventors have selected compounds having excellent binding affinity to Cereblon (e.g., the following chemical formula (II-4)) and confirmed their tumor cell death effects (Korean Patent Publication No. 10-2024-0146608).

[0034] Chemical formula (II-4)

[0035]

[0036] Any benzene ring present in chemical formula (II-4) may be an unsubstituted benzene ring or a benzene ring in which one or more hydrogens are substituted, and any one or more hydrogens are each independently alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heterocycloalkylalkyl, halogen, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, urea, sulfonyl, hydroxy, aldehyde, carboxy, alkyl halide, cycloalkyloxy, aryloxy, heterocyclyloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); Amino, alkylamino, cycloalkylamino, arylamino, heterocyclilamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclilalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; hydroxyl; alkoxy; alkoxyalkyl; amino; Alkylamino; Carboxy; Nitro; Cyano; Thiol; Thioether; Imine; Imide; Amidine; Guanidine; Enamine; Aminocarbonyl; Acylamino; Phosphonate; Phosphine; Thiocarbonyl; Sulfinyl; Sulfon; Sulfonamide; Ketone; Aldehyde; Ester; Urea; Urethane; Oxime; Hydroxylamine; Alkoxyamine; Aralkoxyamine; N-Oxide; Hydrazine; Hydrazide; Hydrazone; Azide; Isocyanate; Isothiocyanate; Cyanate; Thiocyanate;It may be characterized by being substituted with B(OH)2 or O(alkyl)aminocarbonyl. Specific substituents are described in detail in Korean Patent Publication No. 10-2024-0146608, which is incorporated by reference into the present invention.

[0037] In the present invention, by introducing a structural modification to the above compound, a derivative was newly synthesized that maintains excellent binding affinity to Cereblon while enhancing the tumor cell death effect.

[0038] Specifically, the compound of the present invention may be a modified form of the compound of formula (II-4) into the compound of formula (A) below, which is a compound having a structure in which the carbon located between the sulfonamide group (-SO₂NH-) and the amide group (-NHCO-) ​​within the central benzene ring of the compound of formula (II-4) is substituted with nitrogen.

[0039] Chemical formula (A)

[0040]

[0041] Accordingly, in one aspect, the present invention relates to a compound represented by the following formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0042] Chemical formula (I)

[0043]

[0044] In chemical formula (I),

[0045] R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and

[0046] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

[0047] In the present invention, the above formula (I) can be represented by the following formula (II):

[0048] Chemical formula (II)

[0049]

[0050] In chemical formula (II),

[0051] R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl halide, alkoxy, or halogen, and

[0052] R 2 to R 6 Each is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

[0053] In the present invention, R 1 can be any one of the following:

[0054]

[0055] In the present invention, R 2 to R 6 Each can be independently any one of the following:

[0056]

[0057] In the present invention, the "alkyl" group has a linear or branched chain structure, and general formula C n H 2n+1It refers to a group represented by ). The alkyl group may be in an unsubstituted form or a substituted alkyl containing substituents such as halogen, hydroxy, amino, alkoxy, etc. In some embodiments, the alkyl group is methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH(CH3)2), sec-butyl (-CH(CH3)CH2CH3), tert-butyl (-C(CH3)3), pentyl (-CH2CH2CH2CH2CH3), isopentyl (-CH2CH2CH(CH3)2), neopentyl (-CH2C(CH3)3), hexyl (-(CH2)5CH3), and isohexyl (-CH2CH2CH2CH(CH3)2). It may be 3-methylpentyl, heptyl (-(CH2)6CH3), isoheptyl (-CH2CH2CH2CH2CH(CH3)2), 2-methylhexyl, octyl (-(CH2)7CH3), iso-octyl (-CH2CH2CH2CH2CH2CH(CH3)2), nonyl (-(CH2)8CH3), isononyl (-CH2CH2CH2CH2CH2CH2CH(CH3)2), decyl (-(CH2)9CH3), or isodecyl (-CH2CH2CH2CH2CH2CH2CH2CH(CH3)2). In some embodiments, the alkyl group is an unsaturated alkyl group, which is also referred to as an alkenyl or alkynyl group.

[0058] In the present invention, the "alkenyl" group is an unsaturated hydrocarbon group comprising one or more carbon-carbon double bonds (C=C) and may have a linear or branched chain structure. The alkenyl group may be optionally substituted and may include cis- or trans- isomers. In some embodiments, the alkenyl group may comprise carbon atoms having 2 to 10 carbon atoms, for example, ethenyl (-CH=CH2) (also called vinyl), propenyl (-CH=CHCH3), allyl (-CH2CH=CH2), 1-butenyl (-CH=CHCH2CH3), 2-butenyl (-CH2CH=CHCH3), 1-pentenyl (-CH=CH(CH2)2CH3), 2-pentenyl (-CH2CH=CHCH2CH3), 3-pentenyl (-CH2CH2CH=CHCH3), 4-pentenyl (-CH2CH2CH2CH=CH2), 1-hexenyl, These may include -CH=CH(CH2)3CH3), 2-hexenyl (-CH2CH=CH(CH2)2CH3), heptenyl (-CH=CH(CH2)4CH3), octenyl (-CH=CH(CH2)5CH3), nonenyl (-CH=CH(CH2)6CH3), or dekenyl (-CH=CH(CH2)7CH3) groups. These alkenyl groups may include various isomers (e.g., 3-pentenyl, 4-pentenyl, 3-hexenyl, 4-hexenyl, etc.) depending on the position of the double bond, stereochemical configuration, or substitution type.

[0059] In the present invention, the “alkynyl” group is an unsaturated hydrocarbon group comprising one or more carbon-carbon triple bonds (C≡C) and may have a linear or branched chain structure. The alkynyl group may optionally include one or more substituents. In some embodiments, the alkynyl group may comprise carbon atoms having 2 to 10 carbon atoms, for example, ethynyl (-C≡CH), 1-propynyl (-C≡CCH3), 2-propynyl (-CH2C≡CH), propargyl, 1-butynyl (-C≡CCH2CH3), 2-butynyl (-CH2C≡CCH3), 1-pentynyl (-C≡C(CH2)2CH3), 2-pentynyl (-CH2C≡CCH2CH3), 3-pentynyl (-CH2CH2C≡CCH3), 4-pentynyl, -CH2CH2CH2C≡CH), 1-hexynyl (1-hexynyl, -C≡C(CH2)3CH3), 2-hexynyl (2-hexynyl, -CH2C≡C(CH2)2CH3), 3-hexynyl (3-hexynyl, -CH2CH2C≡CCH2CH3), heptynyl (heptynyl, -C≡C(CH2)4CH3), octynyl (octynyl, -C≡C(CH2)5CH3), nonynyl (nonynyl, -C≡C(CH2)6CH3), or decinyl (decynyl, -C≡C(CH2)7CH3) groups may be included therein. These alkynyl groups may include various isomers (e.g., 2-butynyl, 3-fenthynyl, 4-fenthynyl, 3-hexinyl, etc.) depending on the position of the triple bond or the form of substitution.

[0060] In the present invention, alkyl groups, alkenyl groups, and alkynyl groups may be substituted or unsubstituted. When an alkyl group described herein is described as "substituted," it includes any substituent or substituted group such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogens; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocycliloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclilalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclilamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclilalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; Alkoxyamino; ar-alkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or may be substituted with -B(OH)2.In certain embodiments, where the alkyl group described herein is described as "substituted," these include any substituent or substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; It may be substituted with B(OH)2 or O(alkyl)aminocarbonyl. As used herein, “substituted alkyl,” “substituted alkenyl,” and “substituted alkynyl” refer to a group in which one or more hydrogen atoms are independently replaced by substituents, and such substituents may be the same or different and may be present at any position (including straight or branched) of the alkyl, alkenyl, or alkynyl chain.

[0061] In the present invention, the “cycloalkyl” group is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms having a single cyclic ring or a plurality of condensed or crosslinked rings that can be optionally substituted. In some embodiments, the cycloalkyl group may be a saturated cycloalkyl, which may include a single-ring structure or a polycyclic structure. Examples of a single-ring saturated cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, or 2-methylcyclooctyl. In another embodiment, the cycloalkyl group may be 1-bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, or adamantyl in a polycyclic or cross-linked ring structure. In yet another embodiment, the cycloalkyl group may be an unsaturated cycloalkyl, which comprises one or more carbon-carbon double bonds (C=C). Examples of unsaturated cycloalkyl groups may include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, or hexadienyl. The cycloalkyl group may be optionally substituted and may have substituents such as hydroxy, alkoxy, amino, or halogen.Specific examples of substituted cycloalkyls include cyclohexanol. Accordingly, the term “cycloalkyl” in this specification is used as a comprehensive term encompassing both saturated and unsaturated, and monocyclic and polycyclic structures.

[0062] In the present invention, the “haloalkyl” group is an alkyl group in which one or more hydrogen atoms are substituted with halogen atoms (F, Cl, Br, I), and may be straight-chain or branched. In some embodiments, the alkyl halide group is a saturated alkyl halide (C n H 2n+1-m X mIt may be ) and preferably includes 1 to 10 carbon atoms. Exemplarily, it may be -CH2X, -CH2CH2X, -CH2CH2CH2X, -CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2X, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2X. For example, the alkyl halide group may be fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), chloromethyl (-CH2Cl), bromomethyl (-CH2Br), trichloromethyl (-CCl3), trifluoroethyl (-CH2CF3), or pentafluoroethyl (-CF2CF3). In the present invention, “alkyl halide” is a comprehensive term including all alkyl fluorides (fluoroalkyl), alkyl chlorides (chloroalkyl), alkyl bromides (bromoalkyl), and alkyl iodides (iodoalkyl), and both single and multiple substituted forms are included within the scope of the present invention.

[0063] In the present invention, the “haloalkenyl” group is an unsaturated hydrocarbon group comprising one or more carbon-carbon double bonds (C=C) and one or more halogen atoms (F, Cl, Br, I), and may be linear or branched. In some embodiments, the haloalkenyl group may comprise 1 to 10 carbon atoms and may include both cis- and trans- isomers. Exemplarily, -CH=CHX, -CH=CHCH2X, -CH=CH(CH2)3X, -CH=CH(CH2)4X, -CH=CH(CH2)5X, -CH=CH(CH2)6X, -CH=CH(CH2)7X, -CH=CH(CH2)8X, -CH=CH(CH2)9X, or -CH=CH(CH2) 10 X may be, for example, fluoroethenyl (-CH=CHF), difluoroethenyl (-CF=CHF), trifluoroethenyl (-CF=CF2), chloroethenyl (-CH=CHCl), bromoethenyl (-CH=CHBr), dichloroethenyl (-CCl=CHCl), trichloroethenyl (-CCl=CCl2), trifluoropropenyl (-CH=CHCF3), chloropropenyl (-CH=CHCH2Cl) or bromobutenyl (-CH=CHCH2CH2Br). In other embodiments, the alkenyl halogen group may be a structure multiplely substituted with one or more halogen atoms, such as 1,1,2-trichloroethenyl (-CCl2=CHCl) or 1,2,3-trifluoropropenyl (-CH=CF-CF3).

[0064] In the present invention, the “haloalkynyl” group is an unsaturated hydrocarbon group comprising one or more carbon-carbon triple bonds (C≡C) and one or more halogen atoms (F, Cl, Br, I), and may be linear or branched. In some embodiments, the alkynyl halogen group may comprise one to ten carbon atoms. Exemplarily, the alkynyl halogen group is -C≡CX, -CH2C≡CX, -(CH2)2C≡CX, -(CH2)3C≡CX, -(CH2)4C≡CX, -(CH2)5C≡CX, -(CH2)6C≡CX, -(CH2)7C≡CX, -(CH2)8C≡CX, or -C≡C(CH2) n X (e.g., -C≡C(CH2)2F ,-C≡C(CH2)2Cl, -C≡C(CH2)2Br) can be In another embodiment, the alkynyl halide group is fluoroethynyl (-C≡CF), chloropropynyl (-CH2C≡CCl), bromobutynyl (-CH2CH2C≡CBr), fluorobutynyl (-C≡CCH2CH2F), chlorobutynyl (-C≡CCH2CH2Cl), bromobutynyl (-C≡CCH2CH2Br), trifluorobutynyl (-C≡CCH2CF3), pentafluoropentynyl (-CH2C≡C(CF2)2F), difluorohexynyl (-CH2(CH2)3C≡CF2) or chlorodecynyl, It may be -CH2(CH2)7C≡CCl). In other embodiments, the alkynyl halogen group may be a structure in which one or more halogen atoms are multiplely substituted, for example, difluoroethynyl (-CF2C≡CH), trifluoropropynyl (-CH2C≡CCF3), dichlorobutynyl (-CHClC≡CCH2Cl), bromofluorohexynyl (-(CH2)3C≡CCF2Br), pentafluoropentynyl (-CH2C≡CCF2CF3), or trichlorodecynyl (-CH2(CH2)6C≡CCCl3).

[0065] In the present invention, the "alkoxy" group is -OR(R is alkyl), where alkyl is defined above. The alkyl portion of the alkoxy group may be optionally substituted. In some embodiments, the alkoxy group may include methoxy (-OCH3), ethoxy (-OCH2CH3), propoxy (-O(CH2)2CH3), isopropoxy (-OCH(CH3)2), butoxy (-O(CH2)3CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), pentoxy (-O(CH2)4CH3), or hexyloxy (-O(CH2)5CH3) groups.

[0066] In the present invention, "halogen (X)" is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0067] In the present invention, the “cyano” group is -CN, which is a functional group containing a triple bond (-C≡) between carbon and nitrogen. The cyano group can be bonded to a carbon skeleton, such as an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, and one or more cyano groups may exist within the same molecule. Additionally, other substituents or functional groups may be bonded to the nitrogen atom of the cyano group or to an adjacent carbon atom.

[0068] In the present invention, the “hydroxyalkyl” group is an alkyl group comprising one or more hydroxyl groups (-OH) and may be represented by the general formula R-OH (where R is an alkyl group). In some embodiments, the hydroxyalkyl group may be hydroxymethyl (-CH2OH), 2-hydroxyethyl (-CH2CH2OH), 3-hydroxypropyl (-CH2CH2CH2OH), 2-methyl-3-hydroxypropyl (-CH2CH(CH3)CH2OH), or 4-hydroxybutyl (-CH2CH2CH2CH2OH).

[0069] In the present invention, the “hydroxyalkenyl” group is an unsaturated hydrocarbon group comprising one or more hydroxyl groups (-OH) and a carbon-carbon double bond (C=C) simultaneously, and may have a linear or branched structure. In some embodiments, the hydroxyalkenyl group has the form -(CH2)nCH=CH(CH2)mOH, where (CH2)n and (CH2)m may each be an alkylene group having 0 to 6 carbon atoms. In another embodiment, the hydroxyalkenyl group may be a 2-hydroxyethenyl (-CH=CHOH), 3-hydroxypropenyl (-CH2CH=CHOH), 2-hydroxybutenyl (-CH(OH)CH=CHCH3 or -CH2C(OH)=CHCH3) or 3-hydroxypentenyl (-CH2CH2CH(OH)CH=CH2) group.

[0070] In the present invention, the "hydroxyalkynyl" group is an unsaturated hydrocarbon group comprising one or more hydroxyl groups (-OH) and a carbon-carbon triple bond (C≡C), and may have a linear or branched structure. In some embodiments, the hydroxyalkynyl group has the form -(CH2)nC≡C(CH2)mOH, where (CH2)n and (CH2)m may each be an alkylene group having 0 to 6 carbon atoms. In other embodiments, the hydroxyalkinyl group may be 2-hydroxyethynyl (-C≡COH), 3-hydroxypropynyl (-C≡CCH2OH), 4-hydroxybutynyl (-C≡C(CH2)2OH), 5-hydroxypentynyl (-C≡C(CH2)3OH), or 6-hydroxyhexynyl (-C≡C(CH2)4OH), and both substituted and unsubstituted forms may be included within the scope of the invention. In some embodiments, the hydroxyalkinyl group may comprise a propargylic structure (e.g., -CH(OH)C≡CR(R is alkyl) or -C≡CCH2OH).

[0071] In the present invention, the “aminoalkyl” group is an alkyl group comprising one or more amino groups (-NH2, -NHR, or -NR2) and may be represented by the general formula R-NH2 or R-NHR' (wherein R and R' may each independently be an alkyl group). In some embodiments, the aminoalkyl group may comprise 1 to 10 carbon atoms. In some embodiments, the aminoalkyl group may comprise an aminomethyl (-CH2NH2), 2-aminoethyl (-CH2CH2NH2), 3-aminopropyl (-CH2CH2CH2NH2), 2-(dimethylamino)ethyl (-CH2CH2N(CH3)2), or 4-aminobutyl (-CH2CH2CH2CH2NH2) group.

[0072] In the present invention, the “aminoalkenyl” group is an unsaturated hydrocarbon group comprising one or more amino groups and a carbon-carbon double bond (C=C). In some embodiments, the aminoalkenyl group may comprise 2 to 10 carbon atoms. In some embodiments, the aminoalkenyl group may comprise 2-aminoethenyl (-CH=CHNH2), 3-aminopropenyl (-CH2CH=CHNH2), 2-(dimethylamino)ethenyl (-CH=CHN(CH3)2), or 4-aminobutenyl (-CH2CH2CH=CHNH2).

[0073] In the present invention, the “aminoalkynyl” group is an unsaturated hydrocarbon group comprising one or more amino groups and a carbon-carbon triple bond (C≡C). In some embodiments, the aminoalkynyl group may comprise 2 to 10 carbon atoms. In some embodiments, the aminoalkynyl group may comprise 2-aminoethynyl (-C≡CCH2NH2), 3-aminopropynyl (-CH2C≡CCH2NH2), 4-aminobutynyl (-CH2CH2C≡CCH2NH2), or 5-aminopentynyl (-CH2CH2CH2C≡CCH2NH2).

[0074] In the present invention, the compound of formula (II) may be any one selected from the group consisting of formulas (i) to (xiv) below.

[0075] [Table 1]

[0076]

[0077]

[0078]

[0079] Since the compound according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, the above-mentioned prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. Furthermore, the compound has a chiral carbon, so stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0080] The term "prodrug" refers to a substance that is modified into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be able to achieve bioavailability by oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, the prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to expose the active site of the peptide.

[0081] The term "hydrate" means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0082] The term "solvate" means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0083] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or stereochemically. Such isomers include structural isomers such as tautomers, and stereoisomers such as optical isomers (R-type or S-type) having an asymmetric carbon center, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0084] The term "pharmaceuticalally acceptable salt" refers to a form of salt of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc.; organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0085] For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound according to the present invention can be converted into its salt by conventional methods.

[0086] The present invention provides a method for preparing a compound represented by the formula (I) above. The synthesis methods of Examples (i) to (xiv) are exemplified as a method for preparing a compound represented by the formula (I) of the present invention, but the synthesis methods of Examples (i) to (xiv) do not limit the method for preparing a compound represented by the formula (I) according to the present invention. The synthesis methods of Examples (i) to (xiv) are merely examples, and it is obvious that they can be easily modified by a person skilled in the art depending on specific substituents.

[0087] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt may be characterized by having cereblon binding power.

[0088] Cereblon (CRBN) is a core component protein of the E3 ubiquitin ligase complex and is known as a molecular conjugate that regulates intracellular signaling by inducing the degradation of specific target proteins upon drug binding (Chamberlain et al., Nat Rev Drug Discov. 2019;18(6):403-418). In particular, CRBN is a direct binding receptor for immunomodulator (IMiD) class drugs (e.g., Thalidomide, Lenalidomide, Pomalidomide), and these drugs have been reported to inhibit tumor cell proliferation and regulate immune responses in the tumor microenvironment by binding to CRBN and selectively degrading transcription factors such as Ikaros and Aiolos.

[0089] The compound according to the present invention has a structure in which a carbon located between the sulfonamide group (-SO₂NH-) and the amide group (-NHCO-) ​​within the central benzene ring is substituted with nitrogen, and it has been confirmed that this enhances anticancer activity through the Cereblon-mediated protein degradation pathway. This increase in activity is interpreted as a result of improved enzymatic activity regulation ability against Cereblon through the nitrogen substitution, and increased efficiency of the ubiquitination reaction and degradation of the substrate protein by promoting a conformational rearrangement between the Cereblon-DDB1-CUL4 complex and the substrate protein.

[0090] Accordingly, in another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of a benign tumor or cancer comprising, as an active ingredient, a compound represented by the formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0091] In the present invention, the cancer may be characterized as being a blood cancer or a solid tumor.

[0092] In the present invention, the blood cancer may be characterized as being selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma, but is not limited thereto.

[0093] In the present invention, the solid tumor may be selected from the group consisting of melanoma, myoma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, bile duct cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer, but is not limited thereto.

[0094] In the present invention, the terms “pharmaceutical composition” or “pharmaceutical formulation” refer to a mixture comprising a novel compound of the present invention and a pharmaceutically acceptable excipient, such as a diluent or carrier, which makes the novel compound particularly suitable for in vivo or in vitro diagnostic or therapeutic use. According to some embodiments, a pharmaceutical composition comprising a composition of the present invention may be provided by a method of administering a therapeutically effective amount to a subject as needed. In some embodiments, a composition of the present invention may be administered to a human.

[0095] As used in the present invention, "effective amount" or "therapeutically-effective amount" refers to an amount of a compound or composition (e.g., a compound or composition of the present invention) sufficient to achieve a beneficial or desired result. The effective amount may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific formulation or route of administration.

[0096] The present invention also provides a method for the prevention or treatment of a benign tumor or cancer, comprising the step of administering to a patient in need a compound represented by the formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0097] The present invention also provides for the prevention or treatment of benign tumors or cancer of a compound represented by the formula (I), its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts, or pharmaceutical compositions containing the same.

[0098] The present invention also provides the use of a compound represented by formula (I), its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the manufacture of a drug for the prevention or treatment of a benign tumor or cancer.

[0099] The present invention also provides a composition or formulation comprising a compound represented by the formula (I), an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0100] The above composition may be a pharmaceutical composition for preventing or treating benign tumors or cancer.

[0101] The above additive may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavorings, and may be formulated according to conventional methods into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or into parenteral preparations such as topical liquids, topical suspensions, topical emulsions, gels (ointments, etc.), inhalants, sprays, or injections. The above preparation may be formulated in various forms, for example, as a single-dose or multi-dose administration form.

[0102] The pharmaceutical composition of the present invention may include excipients such as lactose and corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. If necessary, sweeteners and / or flavoring agents may be added.

[0103] The pharmaceutical composition of the present invention may be administered to mammals, such as livestock and humans, by various routes, for example, orally, desquamously, subcutaneously, intramuscularly, intravenously, intraperitoneally, intrarectally, intrauterine, dura mater or cerebrovascular injection, or by topical administration. Accordingly, the composition of the present invention may be formulated in various forms, such as tablets, capsules, aqueous solutions, or suspensions. For oral tablets, carriers such as lactose or corn starch and lubricants such as magnesium stearate may typically be added. For oral capsules, lactose and / or dried corn starch may be used as diluents. If an oral aqueous suspension is required, the active ingredient may be combined with an emulsifier and / or suspending agent. If necessary, specific sweeteners and / or flavoring agents may be added. For intramuscular, intraperitoneally, subcutaneously, and intravenously administration, a sterile solution of the active ingredient is typically prepared, and the pH of the solution must be appropriately adjusted and buffered. In the case of intravenous administration, the total concentration of the solute must be adjusted so as to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution with a pH of 7.4. The solution may be introduced into the intramuscular bloodstream of a patient by local injection.

[0104] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration, and can be appropriately adjusted according to the patient.

[0105] The pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, skin, abdominal cavity, rectum or vein, muscle, subcutaneously, intrauterine dura mater or intracerebroventricular injection.

[0106] The effective amount of the pharmaceutical composition according to the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration, and can be appropriately adjusted according to the patient. The pharmaceutical composition of the present invention may contain the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient in an amount of 0.001 to 90% by weight percentage relative to the total weight of the composition.

[0107] As used herein, "treating" means the alleviation, wholly or partially, of a disorder, disease, or condition, or of one or more symptoms associated with the disorder, disease, or condition, or the slowing or cessation of further progression or worsening of such symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease, or condition itself.

[0108] As used herein, "preventive" means a method of delaying, or preventing, the onset, recurrence, or spread of a disability, disease, or condition, wholly or partially; excluding the subject from acquiring a disability, disease, or condition; or reducing the risk of the subject acquiring a disability, disease, or condition.

[0109] The term "object" includes, but is not limited to, animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans.

[0110] In one embodiment, the present invention may be provided as a kit for treating a benign tumor or cancer disease in a subject suffering from said disease.

[0111] In some embodiments, the kit comprises i) instructions for administering the novel compound or pharmaceutical composition according to the present invention to a subject suffering from the said disease, and ii) the novel compound or pharmaceutical composition according to the present invention. In some embodiments, the kit may comprise one or more unit dosage forms containing the novel compound or pharmaceutical composition in a dose as described in the present invention that is effective in treating the said disease in a subject. In some embodiments, the subject is a human patient.

[0112] In some embodiments, the kit further comprises one or more selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.

[0113] In another aspect, the present invention relates to a reagent composition comprising the said compound, its optical isomer, its racemic mixture, its hydrate, its salt, or its solvate.

[0114] In one embodiment, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or its salt may be characterized as being usable as a reagent for biological research, diagnosis, or drug screening of cancer cells in vitro.

[0115] The present invention will be explained in more detail below through manufacturing examples, examples, and test examples. However, the following manufacturing examples and test examples are intended to illustrate the present invention and do not limit the scope of the present invention.

[0116]

[0117] Preparation Example

[0118] Manufacturing of Intermediate A and Intermediate B

[0119]

[0120] 1) Preparation of Compound 2

[0121] Compound 2 was obtained by adding Pd(dppf)Cl2 (CAS: 72287-26-4) and potassium carbonate (CAS: 584-08-7) to a 5:1 mixture of 1,4-dioxane (CAS: 123-91-1) and water (H2O), then adding compound 1 and compound 1A, and stirring at 90°C for 12 hours.

[0122] 2) Intermediate A manufacturing

[0123] Compound 2 and Palladium on carbon (CAS: 7440-05-3) were added to a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and methanol (Methanol, CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at 25°C for 4 hours to obtain Intermediate A.

[0124] 3) Preparation of Compound 3

[0125] Compound 3 was obtained by adding Intermediate A and 3-Nitrobenzenesulfonyl chloride (CAS: 121-51-7) to a mixture of methylene chloride (Dichloromethane, CAS: 75-09-2) and pyridine (Pyridine, CAS: 110-86-1) and stirring at 25°C for 12 hours.

[0126] 4) Manufacturing Intermediate B

[0127] Compound 3 and Palladium on carbon (CAS: 7440-05-3) were added to methanol (Methanol, CAS: 67-56-1), hydrogen gas (H2, 15 Psi) was injected, and the mixture was stirred at 25°C for 4 hours to obtain Intermediate B.

[0128] Manufacturing of Intermediate H and Intermediate G

[0129]

[0130] 1) Preparation of Compound 2

[0131] After adding Pd(dppf)₂ and sodium carbonate (CAS: 497-19-8) to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O), Compound 1 and Compound 1A were added. The reaction mixture was stirred at 80 °C for 2 hours to obtain Compound 2.

[0132] 2) Preparation of Compound 3

[0133] Compound 2 and Compound 2A were added to a mixture of methylene chloride (Dichloromethane, CAS: 75-09-2) and pyridine (Pyridine, CAS: 110-86-1). The reaction mixture was stirred at 25 °C for 2 hours to obtain Compound 3.

[0134] 3) Preparation of Intermediate H

[0135] Compound 3 and Palladium on carbon (CAS: 7440-05-3) were added to a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and ethanol (Ethanol, CAS: 64-17-5), hydrogen gas (H₂, 50 psi) was injected, and the mixture was stirred at 50 ℃ for 20 hours to obtain Intermediate H.

[0136] 4) Intermediate G manufacturing

[0137] Compound 2 and Palladium on carbon (CAS: 7440-05-3) were added to a mixed solvent of tetrahydrofuran (THF, CAS: 109-99-9) and ethanol (Ethanol, CAS: 64-17-5), hydrogen gas (H₂, 50 psi) was injected, and the mixture was stirred at 50 °C for 15 hours to obtain Intermediate G.

[0138] Manufacturing of Intermediate G2

[0139]

[0140] 1) Preparation of Compound 2

[0141] After adding Pd(dppf)Cl2 (CAS: 72287-26-4) and sodium carbonate (CAS: 497-19-8) to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O), compound 1 and compound 1A were added, and compound 2 was obtained by stirring at 90 °C for 12 hours.

[0142] 2) Preparation of Compound 3

[0143] Compound 3 was obtained by adding Palladium on carbon (CAS: 7440-05-3) to a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and methanol (MeOH, CAS: 67-56-1) and injecting hydrogen gas (H2, 50 Psi) and stirring at room temperature for 24 hours.

[0144] 3) Preparation of Compound 4 (Intermediate G1)

[0145] Compound 3 was dissolved in 1,4-dioxane (CAS: 123-91-1). Hydrogen chloride (HCl) solution (dioxane solvent) was added to this, and the mixture was stirred at 25 °C for 3 hours to obtain Compound 4 (Intermediate G1).

[0146] 4) Preparation of Compound 5

[0147] Compound 4 was dissolved in a mixed solvent of tetrahydrofuran (THF, CAS: 109-99-9) and pyridine (CAS: 110-86-1). 4-nitrobenzenesulfonyl chloride (CAS: 98-74-8) was added to this, and the mixture was stirred at 65 °C for 12 hours to obtain compound 5.

[0148] 5) Intermediate G2 manufacturing

[0149] Compound 5 was dissolved in tetrahydrofuran (THF, CAS: 109-99-9). SnCl₂ (CAS: 7772-99-8) was added to this, and the mixture was stirred at 70 °C for 5 hours to obtain Intermediate G2.

[0150] Manufacturing of Intermediate M

[0151]

[0152] 1) Preparation of Compound M_2

[0153] After adding Pd(dppf)Cl₂ (CAS: 72287-26-4) and sodium carbonate (CAS: 497-19-8) to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O), compound M_1 and compound M_1A were added and stirred at 80 °C for 3 hours to obtain compound M_2.

[0154] 2) Intermediate M manufacturing

[0155] Compound M_2 was mixed with a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and ethanol (Ethanol, EtOH, CAS: 64-17-5), Palladium on carbon (CAS: 7440-05-3), and hydrogen gas (H2, 50 Psi) was injected and stirred at 50 °C for 12 hours to obtain Intermediate M.

[0156] Manufacturing of Intermediate N

[0157]

[0158] 1) Preparation of Compound N_2

[0159] After adding Pd(dppf)Cl₂ (CAS: 72287-26-4) and sodium carbonate (CAS: 497-19-8) to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O), compound M_1 and compound N_1A were added and stirred at 80 °C for 3 hours to obtain compound N_2.

[0160] 2) Intermediate N manufacturing

[0161] Compound N_2 was mixed with a mixture of tetrahydrofuran (THF, CAS: 109-99-9) and ethanol (EtOH, CAS: 64-17-5), with Palladium on carbon (CAS: 7440-05-3) added and hydrogen gas (H2, 50 Psi) injected, and stirred at 50 °C for 12 hours to obtain Intermediate N.

[0162] Manufacturing of Intermediate R

[0163]

[0164] 1) Preparation of Compound 322_2A

[0165] Compound 322_1A, compound 322_1B, t-BuONa (CAS: 865-48-5), and potassium fluoride (KF, CAS: 7789-23-3) were added to dimethylformamide (DMF, CAS: 68-12-2) and stirred at 90 °C for 12 hours to obtain compound 322_2A.

[0166] 2) Preparation of Compound 322_3A

[0167] Compound 322_2A and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixture of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and reacted at 20 °C to obtain compound 322_3A.

[0168] 3) Preparation of Compound 322_4A

[0169] Compound 322_3A and Intermediate M were added to a mixed solution of dichloromethane (DCM, CAS: 75-09-2) and pyridine (CAS: 110-86-1), and stirred at 20°C for 2 hours to obtain compound 322_4A.

[0170] 4) Intermediate R

[0171] Compound 322_4A and hydrogen chloride (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to ethyl acetate (EtOAc, CAS: 141-78-6) and stirred at 20°C for 6 hours to obtain Intermediate R.

[0172] Manufacturing of Intermediate V

[0173]

[0174] 1) Preparation of Compound V_2

[0175] Intermediate M was added to a mixture of dichloromethane (DCM, CAS: 75-09-2) and pyridine (Pyridine, CAS: 110-86-1), and 0.7 equivalents of compound V_1 were added. V_2 was obtained by stirring at 0 ℃ for 1 hour.

[0176] 2) Preparation of Compound Intermediate V

[0177] Compound V_2 was placed in ethanol (EtOH, CAS: 64-17-5), and iron (Fe, CAS: 7439-89-6) and ammonium chloride (Ammonium chloride, NH₄Cl, CAS: 12125-02-9) were added. The mixture was stirred at 80 °C for 2 hours to obtain Intermediate V.

[0178] Preparation of compounds AB41010, AB41011, and AB41013

[0179]

[0180] 1) Preparation of compound ArCOCl (Ar = AB41010, AB41011, AB41013)

[0181] Each Building Block (Ar-COCl) was used as a starting material, thionyl chloride (SOCl₂, CAS: 7719-09-7) was added, and the mixture was reacted at 70°C to obtain the compound ArCOCl (A = AB41010, AB41011, AB41013).

[0182] 2) Preparation of compounds AB41010, AB41011, and AB41013

[0183] Intermediate B, compound ArCOCl (Ar = AB41010, AB41011, AB41013), and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 25 °C for 0.1 hours to obtain the corresponding compounds (AB41010, AB41011, AB41013).

[0184] Compound AB41165G manufacturing

[0185]

[0186] 1) Preparation of Compound 2B

[0187] Compound 3A and hydrogen chloride (HCl, CAS: 7647-01-0) were added to 1,4-dioxane (1,4-Dioxane, CAS: 123-91-1) and stirred at 25 ℃ to obtain compound 2B.

[0188] 2) Preparation of Compound 3B

[0189] Compound 2B and compound 4A were added to pyridine (CAS: 110-86-1), and the reaction mixture was stirred at 25°C to obtain compound 3B.

[0190] 3) Preparation of Compound 4B

[0191] Compound 3B, Compound 1, Pd(dppf)Cl₂ (CAS: 72287-26-4), and sodium carbonate (Na₂CO₃, CAS: 497-19-8) were added to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O, CAS: 7732-18-5). The reaction mixture was stirred to obtain Compound 4B.

[0192] 4) Preparation of Compound Intermediate G1

[0193] Compound 4B and Palladium on carbon (CAS: 7440-05-3) were added to a mixed solvent of tetrahydrofuran (THF, CAS: 109-99-9) and methanol (MeOH, CAS: 67-56-1), and hydrogen gas (H₂, 50 psi) was injected. The reaction mixture was stirred at 25 °C for 24 hours to obtain Intermediate G1.

[0194] 5) Preparation of compound AB41165G

[0195] Intermediate G1, Compound 2, and Potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5). The reaction mixture was stirred at 25 °C to obtain Compound AB41165G.

[0196] Preparation of compound AB41166G

[0197]

[0198] 1) Preparation of compound AB41166G

[0199] Intermediate G2, compound 1a, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25°C for 1 hour to obtain compound AB41166G.

[0200] Preparation of compound AB41167G

[0201]

[0202] 1) Preparation of Compound 2B

[0203] Compound 3A and hydrogen chloride (HCl, CAS: 7647-01-0) were added to 1,4-dioxane (1,4-Dioxane, CAS: 123-91-1) and stirred at 25 ℃ to obtain compound 2B.

[0204] 2) Preparation of Compound 3B

[0205] Compound 2B and compound 4A were added to pyridine (CAS: 110-86-1) and stirred at 25°C to obtain compound 3B.

[0206] 3) Preparation of Compound 4B

[0207] Compound 3B, Compound 1, Pd(dppf)Cl2 (CAS: 72287-26-4), and sodium carbonate (Na₂CO₃, CAS: 497-19-8) were added to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O). The reaction mixture was stirred to obtain Compound 4B.

[0208] 4) Preparation of Compound Intermediate G3

[0209] Compound 4B 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 25 ℃ for 12 hours to obtain Intermediate G3.

[0210] 5) Preparation of compound AB41167G

[0211] AB41167G was obtained by adding compound 2, intermediate G3, and potassium carbonate (K₂CO₃, CAS: 584-08-7) to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirring at 25 °C.

[0212] Preparation of compound AB41168G

[0213]

[0214] 1) Preparation of Compound 2

[0215] Compound 1 and hydrogen chloride (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to ethyl acetate (EtOAc, CAS: 141-78-6) and stirred at 20°C for 6 hours to obtain compound 2.

[0216] 2) Preparation of Compound 3

[0217] Compound 2 and compound 4A were added to pyridine (CAS: 110-86-1) and stirred at 25°C to obtain compound 3.

[0218] 3) Preparation of Compound 4

[0219] Compound 3, compound 5A, Pd(dppf)Cl₂ (CAS: 72287-26-4), and sodium bicarbonate (NaHCO₃, CAS: 144-55-8) were added to a mixed solvent of 1,4-dioxane (CAS: 123-91-1) and water (H₂O), and stirred at 85 °C for 4 hours to obtain compound 4.

[0220] 4) Preparation of Compound Intermediate G4

[0221] Compound 4 and Palladium on carbon (CAS: 7440-05-3) were added to a mixed solvent of methanol (Methanol, MeOH, CAS: 67-56-1) and tetrahydrofuran (Tetrahydrofuran, THF, CAS: 109-99-9), hydrogen gas (H₂, 15 psi) was injected, and the mixture was stirred at room temperature for 4 hours to obtain Intermediate G4.

[0222] 5) Preparation of compound AB41168G

[0223] Intermediate G4, compound 6A, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 85 °C for 12 hours to obtain AB41168G.

[0224] Preparation of compound AB41179

[0225]

[0226] 1) Preparation of Compound 2

[0227] Compound 1, benzyl mercaptan (benzenemethanethiol, BnSH, CAS: 100-53-8), sodium tert-butoxide (tBuONa, CAS: 865-48-5), and potassium fluoride (KF, CAS: 7789-23-3) were added to N,N-dimethylformamide (DMF, CAS: 68-12-2), and stirred at 90 °C for 12 hours to obtain compound 2.

[0228] 2) Preparation of Compound 3

[0229] Compound 2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred at 0-25 °C for 1 hour to obtain compound 3.

[0230] 3) Preparation of Compound 4

[0231] Compound 3 and Intermediate A were added to a mixed solvent of dichloromethane (DCM, CAS: 75-09-2) and pyridine (CAS: 110-86-1) and stirred to obtain compound 4.

[0232] 4) Preparation of Compound Intermediate H1

[0233] Compound 4 and hydrogen chloride (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to ethyl acetate (EtOAc, CAS: 141-78-6) and stirred at 25°C for 3 hours to obtain Intermediate H1.

[0234] 5) Preparation of compound AB41179

[0235] Intermediate H1, compound 1a, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 25 °C for 1 hour to obtain AB41179.

[0236] Preparation of compound AB41180

[0237]

[0238] 1) Preparation of Compound 2

[0239] Compound 1, benzyl mercaptan (Benzenemethanethiol, BnSH, CAS: 100-53-8), N,N-diisopropylethylamine (DIEA, CAS: 7087-68-5), Pd₂(dba)₃ (CAS: 51364-51-3) and Xantphos (CAS: 161265-03-8) were added to toluene (Toluene, CAS: 108-88-3), and the mixture was stirred at 110 °C to obtain compound 2.

[0240] 2) Preparation of Compound 3

[0241] Compound 2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred to obtain compound 3.

[0242] 3) Preparation of Compound 4

[0243] Compound 3 and Intermediate A were added to a mixed solvent of dichloromethane (DCM, CAS: 75-09-2) and pyridine (CAS: 110-86-1) and stirred to obtain compound 4.

[0244] 4) Preparation of Compound Intermediate H2

[0245] Compound 4 and hydrogen chloride (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to ethyl acetate (EtOAc, CAS: 141-78-6) and stirred to obtain Intermediate H2.

[0246] 5) Preparation of compound AB41180

[0247] Intermediate H2, compound 1A, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred to obtain AB41180.

[0248] Preparation of compound AB41182 (chemical formula (i))

[0249]

[0250] 1) Preparation of Compound 182_2

[0251] Compound 182_1 (2-chloro-5-(tert-butoxycarbonylamino)pyridine), benzyl mercaptan (Benzyl mercaptan, BnSH, CAS: 100-53-8), potassium tert-butoxide (t-BuOK, CAS: 865-48-5), and potassium fluoride (KF, CAS: 7789-23-3) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2), and stirred at 90 °C for 12 hours to obtain compound 182_2.

[0252] 2) Preparation of Compound 182_3

[0253] Compound 182_2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixture of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and the mixture was stirred at 20°C for 2 hours to obtain compound 182_3.

[0254] 3) Preparation of Compound 182_4

[0255] Compound 182_3 and Intermediate A were added to a mixed solvent of dichloromethane (DCM, CAS: 75-09-2) and pyridine (CAS: 110-86-1), and stirred at 25 °C for 12 hours to obtain compound 182_4.

[0256] 4) Preparation of Compound 182_5

[0257] Compound 182_4 and hydrogen chloride (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to ethyl acetate (EtOAc, CAS: 141-78-6) and stirred at 25°C for 3 hours to obtain compound 182_5.

[0258] 5) Preparation of compound AB41182

[0259] Compound 182_5, compound 1A (4-n-heptylbenzoyl chloride), and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5), and stirred at 25°C for 3 hours to obtain compound AB41182.

[0260] Preparation of compounds AB41268 (formula (iii)) and AB41269 (formula (iv)) (using compound 182_5)

[0261]

[0262] 1) Preparation of compound ArCOCl (A = AB41268, AB41269)

[0263] Using each Building Block (Ar-COCl) as a starting material, thionyl chloride (SOCl₂, CAS: 7719-09-7) was added and reacted at 70 °C to obtain the compound ArCOCl (A = AB41268, AB41269).

[0264] 2) Preparation of compounds AB41268 and AB41269

[0265] Compound 182_5, ArCOCl (A = AB41268, AB41269), and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 25 °C for 1 hour to obtain the corresponding compounds (AB41268, AB41269).

[0266] Preparation of compound AB41273 (formula (xiii)) (using compound 182_2)

[0267]

[0268] 1) Preparation of Compound 273_3

[0269] Compound 182_2 was added to a solution of hydrochloric acid (Hydrogen chloride, HCl, CAS: 7647-01-0) dissolved in ethyl acetate (EtOAc, CAS: 141-78-6), and the mixture was stirred at 25°C for 12 hours to obtain compound 273_3.

[0270] 2) Preparation of Compound 273_4

[0271] Compound 273_3, compound 1A, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 25 °C for 12 hours to obtain compound 273_4.

[0272] 3) Preparation of Compound 273_5

[0273] Compound 273_4 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred at 20°C for 1 hour to obtain compound 273_5.

[0274] 4) Preparation of compound AB41273

[0275] Compound 273_5, Intermediate G, and pyridine (CAS: 110-86-1) were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 20 °C to obtain compound AB41273.

[0276] Preparation of compound AB41253

[0277]

[0278] 1) Preparation of Compound 253_2

[0279] Compound 253_1, compound 253_1B, tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄, CAS: 14221-01-3), copper(I) iodide (CuI, CAS: 7681-65-4), and triethylamine (TEA, CAS: 121-44-8) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 60°C for 12 hours to obtain compound 253_2.

[0280] 2) Preparation of Compound 253_3

[0281] Compound 253_2 and Palladium on carbon (CAS: 7440-05-3) were added to methanol (Methanol, MeOH, CAS: 67-56-1), hydrogen gas (H₂) was injected, and the mixture was stirred at 50 °C for 12 hours to obtain Compound 253_3.

[0282] 3) Preparation of compound AB41253

[0283] Compound 253_3 and oxalyl chloride ((COCl)₂, CAS: 79-37-8) were added to a mixed solvent of dichloromethane (DCM, CAS: 75-09-2) and dimethylformamide (DMF, CAS: 68-12-2), and stirred at 20°C for 1 hour.

[0284] Then, Intermediate H and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to the reaction mixture and stirred at 20°C for 1 hour to obtain compound AB41253.

[0285] Compound AB41254

[0286]

[0287] 1) Preparation of Compound 2

[0288] Compound 1, compound 1B, and iron(III) acetylacetonate (Fe(AcAc)₃, CAS: 14416-18-3) were added to a mixed solvent of tetrahydrofuran (THF, CAS: 109-99-9) and N-methyl-2-pyrrolidone (NMP, CAS: 872-50-4), and stirred at 0-25°C from 0°C to 25°C for 2 hours to obtain compound 2.

[0289] 2) Preparation of Compound 3

[0290] Compound 2 and lithium hydroxide monohydrate (LiOH·H₂O, CAS: 1310-66-3) were added to a mixed solvent of tetrahydrofuran (THF, CAS: 109-99-9), methanol (MeOH, CAS: 67-56-1), and water (H₂O), and the mixture was stirred at 25 °C for 12 hours to obtain compound 3.

[0291] 3) Preparation of Compound AB41254

[0292] Compound 3, Intermediate H, hexafluorophosphate oxytris peptidylurenium (HATU, CAS: 148893-10-1), and N,N-diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound AB41254.

[0293] Preparation of compound AB41255

[0294]

[0295] 1) Preparation of Compound 255_2

[0296] Compound 255_1, compound 253_1B, tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄, CAS: 14221-01-3), copper(I) iodide (CuI, CAS: 7681-65-4), and triethylamine (TEA, CAS: 121-44-8) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 60°C for 12 hours to obtain compound 255_2.

[0297] 2) Preparation of Compound 255_3

[0298] Compound 255_2 and a palladium carbon catalyst (Palladium on carbon, Pd / C, CAS: 7440-05-3) were added to methanol (Methanol, MeOH, CAS: 67-56-1), hydrogen gas (H₂, 15 psi) was injected, and the mixture was stirred at 50 °C for 24 hours to obtain compound 255_3.

[0299] 3) Preparation of compound AB41255

[0300] Compound 255_3, Intermediate H, hexafluorophosphate oxytris peptidylurenium (HATU, CAS: 148893-10-1), and N,N-diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound AB41255.

[0301] Preparation of compound AB41274 (chemical formula (xiv))

[0302]

[0303] 1) 274_2 Manufacturing

[0304] Compound 274_1, oxalyl chloride ((COCl)₂, CAS: 79-37-8), and dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 25 °C for 2 hours to obtain compound 274_2.

[0305] 2) AB41274 manufacturing

[0306] Compound 274_2, Intermediate R, and potassium carbonate (Potassium carbonate, K₂CO₃, CAS: 584-08-7) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 3 hours to obtain compound AB41274.

[0307] Preparation of compound AB41276

[0308]

[0309] 1) Preparation of Compound 276_2

[0310] Compound 276_1, benzenemethanethiol (BnSH, CAS: 100-53-8), potassium tert-butoxide (t-BuOK, CAS: 865-48-5), and potassium fluoride (KF, CAS: 7789-23-3) were added to N,N-dimethylformamide (DMF, CAS: 68-12-2),

[0311] Compound 276_2 was obtained by stirring at 90 ℃ for 12 hours.

[0312] 2) Preparation of Compound 276_3

[0313] Compound 276_2 was added to a solution of hydrochloric acid (HCl, CAS: 7647-01-0) dissolved in 1,4-dioxane (CAS: 123-91-1), and the mixture was stirred at 25°C for 5 hours to obtain compound 276_3.

[0314] 3) Preparation of Compound 276_4

[0315] Compound 276_3, compound 1A, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 25 °C for 12 hours to obtain compound 276_4.

[0316] 4) Preparation of Compound 276_5

[0317] Compound 276_4 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and the mixture was stirred at 20 ℃ to obtain compound 276_5.

[0318] 5) Preparation of compound AB41276

[0319] Compound 276_5, Intermediate G, and pyridine (CAS: 110-86-1) were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 20 °C to obtain compound AB41276.

[0320] Preparation of compound AB41277

[0321]

[0322] 1) Preparation of compound AB41277

[0323] Intermediate M, compound 276_5, and pyridine (CAS: 110-86-1) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 20 °C to obtain compound AB41277.

[0324] Preparation of compounds AB41279 and AB41280

[0325] 1. Preparation of Compound 279_5 (Used in the preparation of AB41279 and AB41280)

[0326]

[0327] 1) Preparation of Compound 279_2

[0328] Compound 279_1, benzenethiol (Benzenethiol, BnSH, CAS: 108-98-5), N,N-diisopropylethylamine (N,N-Diisopropylethylamine, DIEA, CAS: 7087-68-5), Pd₂(dba)₃ (CAS: 51364-51-3), and Xantphos (CAS: 161265-03-8) were added to toluene (Toluene, CAS: 108-88-3), and stirred at 110 °C for 12 hours to obtain compound 279_2.

[0329] 2) Preparation of Compound 279_3

[0330] Compound 279_2 and hydrochloric acid (Hydrogen chloride, HCl, CAS: 7647-01-0) were added to 1,4-dioxane (Dioxane, CAS: 123-91-1) and stirred at 25 ℃ for 3 hours to obtain compound 279_3.

[0331] 3) Preparation of Compound 279_4

[0332] Compound 279_3, compound 1A, and potassium carbonate (K₂CO₃, CAS: 584-08-7) were added to dimethylacetamide (N,N-Dimethylacetamide, DMA, CAS: 127-19-5) and stirred at 5 ℃ for 3 hours to obtain compound 279_4.

[0333] 4) Preparation of Compound 279_5

[0334] Compound 279_4 and N-chlorosuccinimide (N-Chlorosuccinimide, NCS, CAS: 128-09-6) were added to a reaction solution mixed with acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and the mixture was stirred at 20°C for 1 hour to obtain compound 279_5.

[0335] 2. Preparation of Compound AB41279

[0336]

[0337] 1) Preparation of compound AB41279

[0338] Compound 279_5 and Intermediate G, pyridine (CAS: 110-86-1), were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 20 ℃ to obtain compound AB41279.

[0339] 3. Preparation of Compound AB41280

[0340]

[0341] 1) Preparation of compound AB41280

[0342] Intermediate M, compound 279_5, and pyridine (CAS: 110-86-1) were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 20 °C to obtain compound AB41280.

[0343] Preparation of Compound 282_2 (used in the preparation of Compounds AB41293, 298_5)

[0344]

[0345] 1) Preparation of Compound 282_2

[0346] Compound 182_2 was dissolved in ethyl acetate (EtOAc, CAS: 141-78-6), and hydrochloric acid (Hydrogen chloride, HCl, CAS: 7647-01-0) was added. The reaction mixture was stirred at 25 °C for 12 hours to obtain compound 282_2.

[0347] Preparation of compound AB41293 (chemical formula (vi))

[0348]

[0349] 1) Preparation of Compound 293_2

[0350] Compound 282_2, compound 290_3, HATU (CAS: 148893-10-1), and N,N-Diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to N,N-Dimethylformamide (DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 293_2.

[0351] 2) Preparation of Compound 293_3

[0352] Compound 293_2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solution of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and the mixture was stirred at 20 ℃ to obtain compound 293_3.

[0353] 3) Preparation of compound AB41293

[0354] Compound 293_3 and Intermediate G, pyridine (CAS: 110-86-1), were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 20°C for 2 hours to obtain compound AB41293.

[0355] Preparation of compound AB41295 (chemical formula (v))

[0356]

[0357] 1) Preparation of Compound 255_2

[0358] Compound 255_1, compound 253_1B, tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄, CAS: 14221-01-3), copper(I) iodide (CuI, CAS: 7681-65-4), and triethylamine (TEA, CAS: 121-44-8) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 60°C for 12 hours to obtain compound 255_2.

[0359] 2) Preparation of Compound 255_3

[0360] Compound 255_2 and a palladium carbon catalyst (Palladium on carbon, Pd / C, CAS: 7440-05-3) were added to methanol (Methanol, MeOH, CAS: 67-56-1), and hydrogen gas (H₂, 50 psi) was injected. The reaction mixture was stirred at 50 °C for 12 hours to obtain Compound 255_3.

[0361] 3) Preparation of Compound 295_4

[0362] Compound 255_3, compound 282_2, HATU (CAS: 148893-10-1), and N,N-Diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to N,N-Dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 295_4.

[0363] 4) Preparation of Compound 295_5

[0364] Compound 295_4 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solution of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and the mixture was stirred at room temperature (rt) to obtain compound 295_5.

[0365] 5) Preparation of compound AB41295

[0366] Compound 295_5 and Intermediate G, pyridine (CAS: 110-86-1), were added to dichloromethane (DCM, CAS: 75-09-2) and stirred at 25°C for 2 hours to obtain compound AB41295.

[0367] Preparation of compounds AB41298 (formula (vii)), AB41299 (formula (viii)), AB41300 (formula (ix)), and AB41301 (formula (x)).

[0368] 1. Preparation of Compound 298_5 (used in the preparation of AB41298, AB41299, AB41300, and AB41301)

[0369]

[0370] 1) Preparation of Compound 253_2

[0371] Compound 253_1, compound 253_1B, tetrakis(triphenylphosphine)palladium(0), Pd(PPh₃)₄, CAS: 14221-01-3), copper(I) iodide (CuI, CAS: 7758-06-7), and triethylamine (TEA, CAS: 121-44-8) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2) and stirred at 60 °C for 12 hours to obtain compound 253_2.

[0372] 2) Preparation of Compound 253_3

[0373] Compound 253_2 and a ruthenium / silicon dioxide catalyst (Ruthenium on silica, Ru / SiO₂, CAS: 12938-00-6) were added to a mixed solvent of methanol (MeOH, CAS: 67-56-1) and tetrahydrofuran (THF, CAS: 109-99-9), and hydrogen gas (H₂, 1.5 MPa) was injected. The reaction mixture was stirred at 50 °C for 4 hours to obtain Compound 253_3.

[0374] 3) Preparation of Compound 298_4

[0375] Compound 253_3, compound 282_2, HATU (CAS: 148893-10-1), and N,N-Diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 298_4.

[0376] 4) Preparation of Compound 298_5

[0377] Compound 298_4 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred at 20°C for 2 hours to obtain compound 298_5.

[0378] 2. Preparation of Compound AB41298

[0379]

[0380] 1) Preparation of compound AB41298

[0381] Compound 298_5 and Intermediate G were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 20 °C for 2 hours to obtain compound AB41298.

[0382] 3. Preparation of Compound AB41299

[0383]

[0384] 1) Preparation of compound AB41299

[0385] Compound 298_5 and Intermediate M were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 20 °C for 2 hours to obtain compound AB41299.

[0386] 4. Preparation of Compound AB41300

[0387]

[0388] 1) Preparation of compound AB41300

[0389] Compound 298_5 and Intermediate N were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 20 °C for 2 hours to obtain compound AB41300.

[0390] 5. Preparation of Compound AB41301

[0391]

[0392] 1) Preparation of compound AB41301

[0393] Compound 298_5 and Intermediate A were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 20 °C for 2 hours to obtain compound AB41301.

[0394] Preparation of compound AB41302

[0395]

[0396] 1) Preparation of Compound 302_2

[0397] Compound 253_3, compound 285_4C, HATU (CAS: 148893-10-1), and diisopropylethylamine (N,N-Diisopropylethylamine, DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 302_2.

[0398] 2) Preparation of Compound 302_3

[0399] Compound 302_2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred at 25 °C for 2 hours to obtain compound 302_3.

[0400] 3) Preparation of compound AB41302

[0401] Compound 302_3 and Intermediate M were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 25 °C for 2 hours to obtain compound AB41302.

[0402] Preparation of compound AB41303

[0403]

[0404] 1) Preparation of Compound 302_2

[0405] Compound 253_3, compound 285_4C, HATU (CAS: 148893-10-1), and diisopropylethylamine (N,N-Diisopropylethylamine, DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 302_2.

[0406] 2) Preparation of Compound 302_3

[0407] Compound 302_2 and in a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O)

[0408] N-chlorosuccinimide (NCS, CAS: 128-09-6) was added and stirred at 25°C for 2 hours to obtain compound 302_3.

[0409] 3) Preparation of compound AB41303

[0410] Compound 302_3 and Intermediate N were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 25 °C for 2 hours to obtain compound AB41303.

[0411] Preparation of compound AB41304

[0412]

[0413] 1) Preparation of Compound 302_2

[0414] Compound 253_3, compound 285_4C, HATU (CAS: 148893-10-1), and diisopropylethylamine (N,N-Diisopropylethylamine, DIEA, CAS: 7087-68-5) were added to dimethylformamide (N,N-Dimethylformamide, DMF, CAS: 68-12-2) and stirred at 25 °C for 12 hours to obtain compound 302_2.

[0415] 2) Preparation of Compound 302_3

[0416] Compound 302_2 and N-chlorosuccinimide (NCS, CAS: 128-09-6) were added to a mixed solvent of acetic acid (AcOH, CAS: 64-19-7) and water (H₂O), and stirred at 25 °C for 2 hours to obtain compound 302_3.

[0417] 3) Preparation of compound AB41304

[0418] Compound 302_3 was added to a mixture of pyridine (CAS: 110-86-1) and dichloromethane (CAS: 75-09-2), and Intermediate A was added. The mixture was stirred at 25 °C for 2 hours to obtain AB41304.

[0419] Preparation of compound AB41349 (chemical formula (xi))

[0420]

[0421] 1) Preparation of compound AB41349

[0422] Compound 349_1 and Intermediate R were added to pyridine (CAS: 110-86-1), and oxychloride phosphate (POCl₃, CAS: 10025-87-3) was added. The reaction mixture was stirred at 0 °C for 1 hour to obtain compound AB41349.

[0423] Preparation of compound AB41441 (chemical formula (xii))

[0424]

[0425] 1) Preparation of compound AB41441

[0426] Compound 441_1 and Intermediate R were added to a mixed solvent of acetonitrile (MeCN, CAS: 75-05-8) and pyridine (CAS: 110-86-1), and oxychloride phosphate (POCl₃, CAS: 10025-87-3) was added. The reaction mixture was stirred at 0 °C for 1 hour to obtain compound AB41441.

[0427] Preparation of compound AB41442

[0428]

[0429] 1) Preparation of Compound V_2

[0430] Intermediate M and compound V_1 (0.7 equivalents) were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2), and pyridine (Pyridine, CAS: 110-86-1) was added. The reaction mixture was stirred at 0 °C for 1 hour to obtain compound V_2.

[0431] 2) Preparation of Compound Intermediate V

[0432] Compound V_2, iron (Fe, CAS: 7439-89-6), and ammonium chloride (Ammonium chloride, NH₄Cl, CAS: 12125-02-9) were added to ethanol (Ethanol, EtOH, CAS: 64-17-5), and stirred at 80 °C for 8 hours. After the reaction was complete, the mixture was filtered and concentrated to obtain Intermediate V.

[0433] 3) Preparation of compound AB41442

[0434] Intermediate V and Compound 349_1 were added to Acetonitrile (MeCN, CAS: 75-05-8), and Phosphorus oxychloride (POCl₃, CAS: 10025-87-3) and Pyridine (CAS: 110-86-1) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain Compound AB41442.

[0435] Preparation of compound AB41443

[0436]

[0437] 1) Preparation of compound AB41443

[0438] Intermediate V and Compound 441_1 were added to Acetonitrile (MeCN, CAS: 75-05-8), and Phosphorus oxychloride (POCl₃, CAS: 10025-87-3) and Pyridine (CAS: 110-86-1) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain Compound AB41443.

[0439] Preparation of compound AB41446 (chemical formula (ii))

[0440]

[0441] 1) Preparation of compound AB41446

[0442] Compound 446_1, Intermediate R, and Phosphorus oxychloride (POCl₃, CAS: 10025-87-3) were added to a mixed solvent of pyridine (Pyridine, CAS: 110-86-1) and acetonitrile (Acetonitrile, MeCN, CAS: 75-05-8), and stirred at 0 °C for 1 hour to obtain AB41446.

[0443] Preparation of compound AB41448

[0444]

[0445] 1) Preparation of compound AB41448

[0446] Intermediate V and Compound 446_1 were added to Acetonitrile (MeCN, CAS: 75-05-8), and Phosphorus oxychloride (POCl₃, CAS: 10025-87-3) and Pyridine (CAS: 110-86-1) were added. The reaction mixture was stirred at 0 °C for 3 hours to obtain Compound AB41448.

[0447] Preparation of compound AB41475

[0448]

[0449] 1) Preparation of Compound 475_2

[0450] Compound 475_1, benzenemethanethiol (BnSH, CAS: 100-53-8), Pd₂(dba)₃ (CAS: 51364-51-3), ligand Xantphos (CAS: 161265-03-8), and N,N-diisopropylethylamine (DIEA, CAS: 7087-68-5) were added to 1,4-dioxane (CAS: 123-91-1). The reaction mixture was stirred at 110 °C for 2 hours to obtain compound 475_2.

[0451] 2) Preparation of Compound 475_3

[0452] Compound 475_2 was added to a mixed solvent of acetonitrile (MeCN, CAS: 75-05-8) and water (H₂O), and dichlorodimethylhydantoin (DCDMH, CAS: 118-52-5) and acetic acid (AcOH, CAS: 64-19-7) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain Compound 475_3.

[0453] 3) Preparation of Compound 475_4

[0454] Compound 475_3 and Intermediate M were added to dichloromethane (DCM, CAS: 75-09-2), and pyridine (CAS: 110-86-1) was added. The reaction mixture was stirred at 25 °C for 1 hour to obtain compound 475_4.

[0455] 4) Preparation of Compound 475_5

[0456] Compound 475_4 was dissolved in 1,4-dioxane (CAS: 123-91-1), and hydrochloric acid (dioxane solution, HCl / dioxane, approx. 4 N) was added. The reaction mixture was stirred at 20 °C for 5 hours to obtain compound 475_5.

[0457] 5) Preparation of compound AB41475

[0458] Compound 475_5 was added to acetonitrile (ACN, CAS: 75-05-8), and oxychloride phosphate (POCl₃, CAS: 10025-87-3) and pyridine (CAS: 110-86-1) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain compound AB41475.

[0459] Preparation of compound AB41476

[0460]

[0461] 1) Preparation of Compound 476_2

[0462] Compound 476_1 was dissolved in 1,4-dioxane (CAS: 123-91-1), and benzyl mercaptan (BnSH, CAS: 100-53-8), Pd₂(dba)₃ (CAS: 51364-51-3), xantphos (CAS: 161265-03-8), and diisopropylethylamine (DIEA, CAS: 7087-68-5) were added. The reaction mixture was stirred at 110 °C for 2 hours to obtain compound 476_2.

[0463] 2) Preparation of Compound 476_3

[0464] Compound 476_2 was dissolved in a mixed solvent of acetonitrile (MeCN, CAS: 75-05-8) and water (H₂O), and dichlorodimethylhydantoin (DCDMH, CAS: 118-52-5) and acetic acid (AcOH, CAS: 64-19-7) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain Compound 476_3.

[0465] 3) Preparation of Compound 476_4

[0466] Compound 476_3 and Intermediate M were added to dichloromethane (Dichloromethane, DCM, CAS: 75-09-2). Pyridine (Py, CAS: 110-86-1) was added, and the reaction mixture was stirred at 25 °C for 1 hour to obtain compound 476_4.

[0467] 4) Preparation of Compound 476_5

[0468] Compound 476_4 was dissolved in 1,4-dioxane (CAS: 123-91-1), and hydrochloric acid (dioxane solution, HCl / dioxane, approx. 4 N) was added. The reaction mixture was stirred at 20 °C for 8 hours to obtain Compound 476_5.

[0469] 5) Preparation of compound AB41476

[0470] Compounds 476_5 and 349_1 were added to acetonitrile (ACN, CAS: 75-05-8), and phosphorus trichloride (POCl₃, CAS: 10025-87-3) and pyridine (Py, CAS: 110-86-1) were added. The reaction mixture was stirred at 0 °C for 1 hour to obtain compound AB41476.

[0471]

[0472] For compounds for which a separate source was not specified in the preparation examples, commercial products purchased from conventional reagent suppliers (e.g., WuXi, Bide, Zesheng, Sigma Aldrich, etc.) were used.

[0473]

[0474] Experimental Example 1. Evaluation of Cereblon binding activity (CRBN binding assay)

[0475] Thalidomide-based compounds are known to regulate the function of immune cells and exert various pharmacological effects by binding to the E3 ligase cereblon (CRBN) and degrading the transcription factors Aiolos and Ikaros as substrates. Accordingly, the binding affinity of each compound to cereblon was confirmed in vitro.

[0476] The binding affinity to Cereblon was measured using the Fluorescence Resonance Energy Transfer (FRET)-based 'AlphaScreen' method. The test was conducted using the PROTAC optimization kit for BET Bromodomain-Cereblon binding kit (#79770, BPS Bioscience, CA USA) according to the 'Competitive Inhibition of the PROTAC assay' indicated in the kit's manual. All reagents included in the kit were used, with the exception of the candidate substance, DMSO, and Flag / Glutathione bead (#6765300, PerkinElmer, USA).

[0477] As a result, the cereblon binding activity as shown in Table 2 was confirmed.

[0478] [Table 2]

[0479]

[0480]

[0481] Experimental Example 2. Evaluation of Anticancer Activity (Comparison of Cytotoxicity)

[0482] Cytotoxicity was evaluated by treating the triple-negative breast cancer cell line MDA-MB-231 with each compound at various concentrations. The cell line was purchased from the American Type Culture Collection (ATCC, HTB-26, USA). Cells were cultured for 24 hours in DMEM medium (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) at 37°C in a 5% CO2 incubator. Cells were cultured at 6 × 10⁶ 4 Cells were seeded into a 96-well plate and cultured for 24 hours. After treating with compounds at different concentrations and culturing for an additional 3 days, analysis was performed using a CCK analysis kit (Dojindo, Japan) according to the manufacturer's manual.

[0483] 2-1. Comparison based on the presence or absence of nitrogen substitution

[0484] To compare anticancer activity based on the presence or absence of nitrogen substitution, unsubstituted compounds and nitrogen-substituted compounds were treated under the same conditions, and their anticancer activity was evaluated.

[0485] As a result, as shown in Table 2, it was confirmed that the anticancer activity was significantly improved by significantly reducing the survival rate of breast cancer cell lines compared to non-substituted compounds.

[0486] [Table 3]

[0487]

[0488]

[0489] 2-2. Comparison based on nitrogen substitution position

[0490] To compare anticancer activity according to the nitrogen substitution position within the benzene ring, compounds with nitrogen introduced at different positions were treated under the same conditions, and cell viability was evaluated.

[0491] As a result, as shown in Table 4, it was confirmed that the anticancer activity was significantly enhanced when nitrogen substitution was introduced to the carbon located between the sulfonamide group (-SO2NH-) and the amide group (-NHCO-) ​​in the central benzene ring.

[0492] [Table 4]

[0493]

[0494]

Claims

1. A compound represented by the following chemical formula (I), its optical isomer, its racemic mixture, its hydrate, its solvate, or its pharmaceutically acceptable salt: Chemical formula (I) In chemical formula (I), R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

2. In claim 1, the above formula (I) is a compound, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof represented by the following formula (II): Chemical formula (II) R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, or halogen, and R 2 to R 6 Each is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alkyl halide, alkenyl halide, alkynyl halide, cyano, halogen, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, or aminoalkynyl.

3. In Paragraph 2, The compound of formula (II) above is any one of the compounds selected from the group consisting of formulas (i) to (xiv) below, its optical isomers, its racemic mixtures, its hydrates, its solvates, or its pharmaceutically acceptable salts: [Table 1] 4. A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer comprising, as an active ingredient, a compound of any one of claims 1 to 3, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in paragraph 4, the cancer is a blood cancer or a solid tumor.

6. A pharmaceutical composition for the prevention or treatment of a benign tumor or cancer, characterized in that, in claim 5, the blood cancer is selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

7. In Paragraph 5, A pharmaceutical composition for the prevention or treatment of benign tumors or cancers, characterized in that the above-mentioned solid tumor is selected from the group consisting of melanoma, myoma, head and neck cancer, nasopharyngeal cancer, esophageal cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, gastric cancer, bladder cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, anal cancer, liver cancer, gallbladder cancer, bile duct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, lung cancer, breast cancer, ovarian cancer, fallopian tube cancer, uterine cancer, vaginal cancer, vulvar cancer, penile cancer, kidney cancer, adrenal cancer, urothelial carcinoma, prostate cancer, testicular tumor, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, spinal tumor, Kaposi's sarcoma, squamous cell carcinoma, pleural mesothelioma, and primary peritoneal cancer.

8. A reagent composition comprising a compound of any one of claims 1 to 3, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, or a solvate thereof.

Images