Novel oxadiazole derivative and composition for preventing or treating cancer comprising same

Abstract

The present invention relates to a novel oxadiazole derivative and a composition for preventing or treating cancer, comprising same. The oxadiazole derivative compound according to the present invention has the activity of inhibiting MDH1 and MDH2 enzymes, exhibits proliferation inhibitory and tumor inhibitory activities against cancer cells and effective proliferation inhibitory efficacy against KRAS-LKB1 co-mutation cancer cells, and exhibits an excellent anticancer effect when co-administered with an anticancer agent such as an anti-PD-1 inhibitor or gefitinib. Therefore, the oxadiazole derivative compound according to the present invention is expected to be effectively used as a therapeutic agent for various cancers.

Description

Novel oxadiazole derivatives and compositions containing the same for preventing or treating cancer

[0001] The present invention relates to a novel oxadiazole derivative and a composition for preventing or treating cancer comprising the same.

[0002] This invention claims priority to Republic of Korea Patent Application No. 10-2024-0042127, filed March 27, 2024, the entire disclosure of which is incorporated herein by reference.

[0003] Cancer is an incurable, chronic disease that, despite treatment with surgery, radiation, and chemotherapy, often fails to achieve a fundamental cure, causing suffering and ultimately leading to death. Worldwide, over 20 million people suffer from cancer, with over 6 million dying each year from the disease. This number is projected to reach 11 million by 2020, making cancer a critical disease requiring urgent treatment. While the prevalence varies across countries, cancer accounts for over 20% of all deaths in developed countries and South Korea.

[0004] Compared to normal cells, cancer cells exhibit various metabolic changes, including increased aerobic glycolysis, fatty acid synthesis, and rapid glutamine metabolism. In particular, activation of glycolysis induces changes in ATP production, biosynthesis of biomolecules, and redox regulation. The malate-asphalic acid shuttle is a crucial mechanism for transporting cytosolic NADH generated during glycolysis to mitochondria. This shuttle is carried out by malate dehydrogenases (MDHs) and glutamate oxaloacetate transaminases (GOTs), both present in the cytosol and mitochondria. Aminooxyacetic acid (AOA), an inhibitor of the malic acid-asphalic acid shuttle, inhibits breast cancer cell proliferation by preventing glucose from becoming a product of the tricarboxylic acid cycle. Furthermore, it has been reported that acetylation of mitochondrial GOT2 in pancreatic cancer promotes the transport of NADH via malic acid-asphalic acid, contributing to the production of ATP, essential for cancer cell proliferation.

[0005] Meanwhile, MDH1 and MDH2 isoenzymes, produced by different MDH genes, exist in the cytoplasm and mitochondrial matrix. MDH1 and MDH2 reversibly convert malate and oxalic acid (OAA) using the NAD / NADH cofactor system. Cytoplasmic MDH1 reduces oxalate to malate, which in turn oxidizes NADH to NAD+. Malate is transported into the mitochondria via the malate-asphalic acid shuttle, where it is reoxidized to oxalate by mitochondrial MDH2, generating NADH. The generated NADH then generates ATP via the electron transport chain. MDH2, involved in the TCA cycle, also participates in ATP production during respiration.

[0006] Recently, the association of MDH1 and MDH2 with cancer has been reported, and it has been reported that MDH1 is required for glutamine metabolism reprogramming and maintaining the intracellular redox state in glutamine-dependent pancreatic ductaladenocarcinoma (PDAC) cells. Knockdown of MDH1 caused PDAC cell death and also inhibited the proliferation of ERBB2 (Erb-B2 receptor tyrosine kinase 2)-positive BT474 breast cancer cells by inhibiting fatty acid synthesis. In addition, prostate cancer cells with high MDH2 expression have been reported to exhibit chemotherapy resistance and short relapse-free survival. We confirmed that knockdown of MDH2 in such prostate cancer cell lines induced metabolic inefficiency in the cancer cell lines, which increased cell proliferation and sensitivity to docetaxel. Currently, various attempts are being made to treat cancer, but there are problems such as side effects such as resistance, and although research on the cancer-related effects of MDH1 and MDH2 has been reported, there are no active attempts to develop MDH1 and MDH2 inhibitors as anticancer agents.

[0007] Accordingly, the inventors of the present invention synthesized a novel oxadiazole derivative compound having MDH1 and MDH2 inhibitory activity and attempted to utilize it as an anticancer agent for various cancers.

[0008] The present inventors have studied to overcome the limitations of the prior art as described above and to develop an effective treatment for cancer, and as a result, have synthesized an oxadiazole derivative compound having MDH1 and MDH2 enzyme inhibitory activity and cancer cell proliferation inhibition and tumor suppression activity, and have completed the present invention based on this.

[0009] Accordingly, the purpose of the present invention is to provide an oxadiazole derivative or a salt thereof.

[0010] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising an oxadiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011]

[0012] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0013]

[0014] To achieve the above purpose, the present invention provides an oxadiazole derivative or a salt thereof represented by the following chemical formula 1:

[0015] [Chemical Formula 1]

[0016]

[0017] (In the above chemical formula 1,

[0018] W is carbon (C) or nitrogen (N),

[0019] R1 is hydrogen (H), a hydroxyl group (OH), a halogen element, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aryl group, a C1-C6 alkyl group, a C1-C6 alkenyl group, or a C1-C6 alkoxy group,

[0020] R2 is hydrogen (H), a hydroxyl group (OH), a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, or a heteroaryl group,

[0021] At this time, when R1 and R2 are each independently a C1-C6 alkyl group or a C1-C6 alkenyl group, Cy is formed by being fused and connected to each other, and forms an unsaturated ring having 4 to 6 carbon atoms including one or more double bonds, including R1 and R2.

[0022] R3 is hydrogen (H), a hydroxyl group (OH), or a substituted or unsubstituted C1-C6 alkoxy group,

[0023] R4 is hydrogen (H), hydroxyl group (OH), C1-C6 alkoxy group, or

[0024] And,

[0025] R5 is a heteroaryl group or

[0026] And,

[0027] At this time, the above R4 and R5 When, N of R4 and R5 are connected to each other to form a heterocycle,

[0028] X is N-R6, -C=O-NH-, or -NH-C=O-,

[0029] R6 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group,

[0030] The above 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of one or more halogen elements, C1-C6 alkyl groups, C1-C6 alkyl ester groups, C1-C6 alkoxy groups, C1-C6 alkyl groups substituted with one or more halogen elements or C1-C6 alkoxy groups, cyano groups (C≡N), aryl groups, C≡CH, and CH2N(CH3)2.

[0031] In one embodiment of the present invention, the heteroaryl group is a 5-membered or 6-membered heteroaryl group including at least one heteroatom selected from the group consisting of oxygen (O), nitrogen (N), and sulfur (S).

[0032] The aryl group is a phenyl group or a benzyl group,

[0033] C1-C6 alkyl group is a methyl group, ethyl group, propyl group, or butyl group,

[0034] The C1-C6 alkenyl group is an ethenyl group, a propenyl group, or a butenyl group,

[0035] The C1-C6 alkoxy group may be, but is not limited to, a methoxy group.

[0036] As another embodiment of the present invention, the halogen element may be at least one selected from the group consisting of F, Cl, Br, and I, but is not limited thereto.

[0037] As another embodiment of the present invention, the compound represented by the above chemical formula 1 may be one or more selected from the group consisting of the following compounds, but is not limited thereto.

[0038] (1)N-(5-(2'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 1)

[0039] (2)N-(5-([1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 2)

[0040] (3)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 3)

[0041] (4)N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 4)

[0042] (5)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 5)

[0043] (6)N-(5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 6)

[0044] (7)N-(5-(3'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 7)

[0045] (8) 3-cyano-N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 8)

[0046] (9) 3-cyano-N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 9)

[0047] (10)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 10)

[0048] (11)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 11)

[0049] (12)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-carboxamide (Compound 12)

[0050] (13)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 13)

[0051] (14) 3-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 14)

[0052] (15) 4-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 15)

[0053] (16)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzamide (Compound 16)

[0054] (17) 2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide) (Compound 17)

[0055] (18) 2,3-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 18)

[0056] (19) 3-cyano-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 19)

[0057] (20) 3-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 20)

[0058] (21)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 21)

[0059] (22) 2,6-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 22)

[0060] (23)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 23)

[0061] (24) 3-methyl-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 24)

[0062] (25) 4-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 25)

[0063] (26) 2-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 26)

[0064] (27)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethoxy)benzamide (Compound 27)

[0065] (28) Methyl 3-((5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate (Compound 28)

[0066] (29)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)isonicotinamide (Compound 29)

[0067] (30)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)picolinamide (Compound 30)

[0068] (31) 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (Compound 31)

[0069] (32)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)benzamide (Compound 32)

[0070] (33) 4-iodo-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 33)

[0071] (34)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 34)

[0072] (35)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 35)

[0073] (36) 5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine (5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine) (Compound 36)

[0074] (37)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-6-(trifluoromethyl)picolinamide (Compound 37)

[0075] (38)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)nicotinamide (Compound 38)

[0076] (39)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 39)

[0077] (40) 3-cyano-N-(5-(naphthalen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 40)

[0078] (41)N-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 41)

[0079] (42)N-(1-(3-hydroxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 42)

[0080] (43)N-(3-(3-bromophenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 43)

[0081] (44)N-(3-(3-(thiophen-2-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 44)

[0082] (45)N-(3-(3-(thiophen-3-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 45)

[0083] (46) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 46)

[0084] (47) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 47)

[0085] (48)N-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 48)

[0086] (49)N-(5-(4-methoxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 49)

[0087] (50)N-(5-(3-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 50)

[0088] (51)N-(5-(2-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 51)

[0089] (52)N-(5-(4-hydroxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 52)

[0090] (53)N-(5-(3-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 53)

[0091] (54)N-(5-(2-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 54)

[0092] (55)N-(5-(3-(prop-2-yn-1-yloxy)-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 55)

[0093] (56)N-(5-(3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 56)

[0094] (57)N-(5-(3-(5-((dimethylamino)methyl)thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 57)

[0095] (58) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 58)

[0096] (59)N-phenyl-3-(3-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 59)

[0097] (60) 3-(3-(thiophen-2-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 60)

[0098] (61) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 61)

[0099] (62) 3-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 62)

[0100] (63)N-(3-fluorophenyl)-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 63)

[0101] (64)N-phenyl-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 64)

[0102] (65) 3-(6-(thiophen-2-yl)pyridin-2-yl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 65)

[0103] (66)N-phenyl-3-(6-(thiophen-2-yl)pyridin-2-yl)isoxazole-5-carboxamide (Compound 66)

[0104] (67)N-phenyl-3-(4-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 67)

[0105] (68) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 68)

[0106] (69) 5-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 69)

[0107] (70) 5-(3-(furan-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 70)

[0108] (71)N-phenyl-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 71)

[0109] (72)N-(3-fluorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 72)

[0110] (73)N-(3-chlorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 73)

[0111] (74) 5-(4-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 74)

[0112] (75) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 75)

[0113] (76) 5-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 76)

[0114] (77) 5-(6-(thiophen-3-yl)pyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 77)

[0115] (78)N-(3-fluorophenyl)-5-(6-(thiophen-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 78).

[0116] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0117] As one embodiment of the present invention, the composition may inhibit the activity of at least one of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2), but is not limited thereto.

[0118] In another embodiment of the present invention, the cancer is lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, colorectal cancer, colon cancer, rectal cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, endometrial or uterine carcinoma, salivary gland cancer carcinoma, kidney and renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, biliary tract cancer, head and neck cancer, carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor,It may be one or more selected from the group consisting of mesothelioma, schwanoma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancy, squamous cell cancer, and epithelial squamous cell cancer, but is not limited thereto.

[0119] As another embodiment of the present invention, the composition may be administered in combination with an anticancer agent, but is not limited thereto.

[0120] As another embodiment of the present invention, the anticancer agent may be, but is not limited to, an immune checkpoint inhibitor or a chemotherapy agent.

[0121] In another embodiment of the present invention, the immune checkpoint inhibitor may be at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody, but is not limited thereto.

[0122] In another embodiment of the present invention, the chemotherapeutic agent is selected from the group consisting of gefitinib, docetaxel, paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, imatinib, carboplatin, oxaliplatin, tegafur, irinotecan, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, danuorubicin, chlorambucil, bryostatin-1, calicheamicin, mayatansine, levamisole, DNA recombinant interferon alfa-2a, mitoxantrone, nimustine, interferon alfa-2a, doxifluridine, formestane, leuprolide acetate, megestrol acetate, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, anastrozole, estramustine,It may be at least one selected from the group consisting of capecitabine, goserelin acetate, polysaccharide potassium, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, and actinomycin D, but is not limited thereto.

[0123] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering a composition containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient in a pharmaceutically effective amount to a subject in need thereof.

[0124] In addition, the present invention provides a use of a composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer.

[0125] In addition, the present invention provides a use for preparing a preparation for preventing or treating cancer, comprising a composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0126] The oxadiazole derivative compound according to the present invention exhibits MDH1 and MDH2 enzyme inhibitory activity, and exhibits proliferation inhibition and tumor suppression activity against cancer cells. It also exhibits effective proliferation inhibition efficacy against KRAS-LKB1 co-mutation cancer cells, and exhibits even more excellent anticancer effects when administered in combination with anti-PD-1 inhibitors or anticancer agents such as gefitinib. Therefore, the oxadiazole derivative compound according to the present invention is expected to be useful as a therapeutic agent for various cancers.

[0127] Figure 1a is a drawing showing the results of confirming the cancer cell proliferation inhibition ability when compound 21 is treated on cells expressing LKB1 in A549 cells, which are KRAS-LKB1 co-mutation cells according to one embodiment of the present invention.

[0128] FIG. 1b is a drawing showing the results of comparing the cancer cell proliferation inhibition efficacy against KRAS-LKB1 co-mutation and KRAS single mutant cells when compound 51 is treated on cancer cells according to one embodiment of the present invention.

[0129] FIG. 2 is a drawing showing the results of comparing the production of mito-ATP and glyco-ATP when treating cancer cells with compound 21 according to one embodiment of the present invention.

[0130] Figure 3a is a drawing showing changes in body weight when treating a cancer animal model with compounds 21 and 51 according to one embodiment of the present invention. Figure 3b is a drawing showing changes in tumor size when treating a cancer animal model with compounds 21 and 51 according to one embodiment of the present invention.

[0131] Figure 3c is a drawing showing the tumor weight when treating a cancer animal model with compounds 21 and 51 according to one embodiment of the present invention.

[0132] Figure 4a is a drawing confirming the change in body weight when a cancer animal model is treated with a combination of compound 21 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0133] Figure 4b is a drawing confirming the tumor size when a cancer animal model is treated with a combination of compound 21 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0134] Figure 4c is a drawing showing the tumor weight confirmed when a cancer animal model was treated with a combination of compound 21 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0135] Figure 5a is a drawing confirming the change in body weight when a cancer animal model is treated with a combination of compound 51 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0136] Figure 5b is a drawing confirming the tumor size when a cancer animal model is treated with a combination of compound 51 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0137] Figure 5c is a drawing showing the tumor weight confirmed when a cancer animal model was treated with a combination of compound 51 and an anti-PD-1 antibody according to one embodiment of the present invention.

[0138] Figure 6a is a drawing confirming the change in body weight when compound 51 and gefitinib are combined and treated in a cancer animal model according to one embodiment of the present invention.

[0139] Figure 6b is a drawing confirming the tumor size when compound 51 and gefitinib are combined and treated in a cancer animal model according to one embodiment of the present invention.

[0140] Figure 6c is a drawing showing the tumor weight confirmed when compound 51 and gefitinib were combined and treated in a cancer animal model according to one embodiment of the present invention.

[0141] The present invention provides an oxadiazole derivative or a salt thereof represented by the following chemical formula 1:

[0142] [Chemical Formula 1]

[0143]

[0144] (In the above chemical formula 1,

[0145] W is carbon (C) or nitrogen (N),

[0146] R1 is hydrogen (H), a hydroxyl group (OH), a halogen element, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aryl group, a C1-C6 alkyl group, a C1-C6 alkenyl group, or a C1-C6 alkoxy group,

[0147] R2 is hydrogen (H), a hydroxyl group (OH), a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, or a heteroaryl group,

[0148] At this time, when R1 and R2 are each independently a C1-C6 alkyl group or a C1-C6 alkenyl group, Cy is formed by being fused and connected to each other, and forms an unsaturated ring having 4 to 6 carbon atoms including one or more double bonds, including R1 and R2.

[0149] R3 is hydrogen (H), a hydroxyl group (OH), or a substituted or unsubstituted C1-C6 alkoxy group,

[0150] R4 is hydrogen (H), hydroxyl group (OH), C1-C6 alkoxy group, or And,

[0151] R5 is a heteroaryl group or

[0152] And,

[0153] At this time, the above R4 and R5 When, N of R4 and R5 are connected to each other to form a heterocycle,

[0154] X is N-R6, -C=O-NH-, or -NH-C=O-,

[0155] R6 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group,

[0156] The above 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of one or more halogen elements, C1-C6 alkyl groups, C1-C6 alkyl ester groups, C1-C6 alkoxy groups, C1-C6 alkyl groups substituted with one or more halogen elements or C1-C6 alkoxy groups, cyano groups (C≡N), aryl groups, C≡CH, and CH2N(CH3)2.

[0157] In the present invention, "C1-C6 alkyl group" means a monovalent alkyl group having 1 to 6 carbon atoms. This term includes functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl, etc. The alkyl and other substituents comprising alkyl moieties described in the present invention include both straight-chain and branched forms. "Substituted C1-C6 alkyl group" means that at least one hydrogen atom is substituted with another substituent, and the substituent includes, but is not limited to, a C1-C6 alkyl group, a halogen element, a C1-C6 alkoxy group, or benzene. According to one embodiment of the present invention, the substituted C1-C6 alkyl group may be, but is not limited to, a trifluoromethyl group (CF3).

[0158] In the present invention, the C1-C6 alkyl group may preferably be a C1-C4 alkyl group, and may be a methyl group, an ethyl group, a propyl group, or a butyl group, but is not limited thereto.

[0159] In the present invention, a "C1-C6 alkenyl group" refers to an alkyl group having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1-methylvinyl, -C(CH3)=CH2), butenyl (C4), pentenyl (C5), and hexenyl (C6).

[0160] In the present invention, when R1 and R2 are each independently a C2-C4 alkyl group or a C2-C4 alkenyl group, Cy is formed by being fused and connected to each other, and can form an unsaturated ring having 6 carbon atoms including one or more double bonds, including R1 and R2. That is, in this case, the compound of the chemical formula 1 It could be.

[0161] In the present invention, the R4 is and R5 When N of R4 and R5 are connected to each other, they can form a heterocycle, and in this case, the compound of the above chemical formula 1 is It could be.

[0162] In the present invention, a "heteroaryl group" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 1 to 5 ring atoms, wherein 1 to 5 ring atoms are heteroatoms, such as oxygen (O), nitrogen (N), or sulfur (S). The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. The heteroaryl group may comprise, for example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, 4 to 5, 1, 2, 3, 4, or 5 heteroatoms. The heteroaryl group may have, but is not limited to, 5 to 8 ring members, 5 to 7 ring members, 5 to 6 ring members, 5 ring members, or 6 ring members. According to one embodiment of the present invention, the heteroaryl group may have, but is not limited to, a 5-membered or 6-membered ring. The heteroaryl group may also include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxadiazole, oxazole, and isoxazole. Additionally, heteroaryl groups may be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0163] In the present invention, the substituted heteroaryl group may be a heteroaryl group substituted with one or more selected from the group consisting of a trifluoromethyl group (CF3), a phenyl group, and CH2N(CH3)2, but is not limited thereto.

[0164] In the present invention, "aryl group" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can include any suitable number of ring atoms, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 5 to 10, 5 to 12, or 5 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linkage. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have six ring members, such as phenyl. The aryl group may be substituted or unsubstituted. In the present invention, the aryl group may be, but is not limited to, a phenyl group or a benzyl group.

[0165] In the present invention, the substituted aryl group may be an aryl group substituted with one or more selected from the group consisting of F, Cl, I, trifluoromethyl group (CF3), cyano group (C≡N), phenyl group, OCF3, methyl group, COOCH3, and CH2N(CH3)2, but is not limited thereto.

[0166] In the present invention, “substitution” includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0167] In the present invention, the “halogen element” may be one or more selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), but is not limited thereto.

[0168] In the present invention, "C1-C6 alkoxy group" means an alkyl ether group -OR group, where R means "C1-C6 alkyl". The alkoxy group may include, for example, methoxy (OMe), ethoxy (OEt), n-propoxy (On-Pr), isopropoxy (Oi-Pr), n-butoxy (On-Bu), iso-butoxy (Oi-Bu), sec-butoxy (Osec-Bu), tert-butoxy (Otert-Bu), n-pentoxy (On-Pen), etc., and according to one embodiment of the present invention, it may be methoxy, but is not limited thereto. A substituted C1-C6 alkoxy group means that at least one hydrogen atom in a C1-C6 alkyl group of -O-(C1-C6 alkyl) is substituted with another substituent. According to one embodiment of the present invention, the substituted C1-C6 alkoxy group may be -OCH2-C≡CH, but is not limited thereto.

[0169] In the present invention, the compound represented by the chemical formula 1 may be one or more selected from the group consisting of the following compounds, but is not limited thereto.

[0170] (1)N-(5-(2'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (N-(5-(2'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide) (Compound 1)

[0171] (2)N-(5-([1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 2)

[0172] (3)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 3)

[0173] (4)N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 4)

[0174] (5)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 5)

[0175] (6)N-(5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 6)

[0176] (7)N-(5-(3'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 7)

[0177] (8) 3-cyano-N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 8)

[0178] (9) 3-cyano-N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 9)

[0179] (10)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 10)

[0180] (11)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 11)

[0181] (12)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-carboxamide (Compound 12)

[0182] (13)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 13)

[0183] (14) 3-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 14)

[0184] (15) 4-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 15)

[0185] (16)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzamide (Compound 16)

[0186] (17) 2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide) (Compound 17)

[0187] (18) 2,3-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 18)

[0188] (19) 3-cyano-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 19)

[0189] (20) 3-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 20)

[0190] (21)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 21)

[0191] (22) 2,6-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 22)

[0192] (23)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 23)

[0193] (24) 3-methyl-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 24)

[0194] (25) 4-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 25)

[0195] (26) 2-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 26)

[0196] (27)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethoxy)benzamide (Compound 27)

[0197] (28) Methyl 3-((5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate (Compound 28)

[0198] (29)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)isonicotinamide (Compound 29)

[0199] (30)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)picolinamide (Compound 30)

[0200] (31) 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (Compound 31)

[0201] (32)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)benzamide (Compound 32)

[0202] (33) 4-iodo-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 33)

[0203] (34)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 34)

[0204] (35)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 35)

[0205] (36) 5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine (5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine) (Compound 36)

[0206] (37)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-6-(trifluoromethyl)picolinamide (Compound 37)

[0207] (38)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)nicotinamide (Compound 38)

[0208] (39)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 39)

[0209] (40) 3-cyano-N-(5-(naphthalen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 40)

[0210] (41)N-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 41)

[0211] (42)N-(1-(3-hydroxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 42)

[0212] (43)N-(3-(3-bromophenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 43)

[0213] (44)N-(3-(3-(thiophen-2-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 44)

[0214] (45)N-(3-(3-(thiophen-3-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 45)

[0215] (46) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 46)

[0216] (47) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 47)

[0217] (48)N-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 48)

[0218] (49)N-(5-(4-methoxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 49)

[0219] (50)N-(5-(3-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 50)

[0220] (51)N-(5-(2-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 51)

[0221] (52)N-(5-(4-hydroxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 52)

[0222] (53)N-(5-(3-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 53)

[0223] (54)N-(5-(2-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 54)

[0224] (55)N-(5-(3-(prop-2-yn-1-yloxy)-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 55)

[0225] (56)N-(5-(3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 56)

[0226] (57)N-(5-(3-(5-((dimethylamino)methyl)thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 57)

[0227] (58) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 58)

[0228] (59)N-phenyl-3-(3-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 59)

[0229] (60) 3-(3-(thiophen-2-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 60)

[0230] (61) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 61)

[0231] (62) 3-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 62)

[0232] (63)N-(3-fluorophenyl)-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 63)

[0233] (64)N-phenyl-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 64)

[0234] (65) 3-(6-(thiophen-2-yl)pyridin-2-yl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 65)

[0235] (66)N-phenyl-3-(6-(thiophen-2-yl)pyridin-2-yl)isoxazole-5-carboxamide (Compound 66)

[0236] (67)N-phenyl-3-(4-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 67)

[0237] (68) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 68)

[0238] (69) 5-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 69)

[0239] (70) 5-(3-(furan-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 70)

[0240] (71)N-phenyl-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 71)

[0241] (72)N-(3-fluorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 72)

[0242] (73)N-(3-chlorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 73)

[0243] (74) 5-(4-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 74)

[0244] (75) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 75)

[0245] (76) 5-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 76)

[0246] (77) 5-(6-(thiophen-3-yl)pyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 77)

[0247] (78)N-(3-fluorophenyl)-5-(6-(thiophen-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 78).

[0248] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0249] In the present invention, the composition may inhibit the activity of at least one of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2), but is not limited thereto.

[0250] In the present invention, "cancer" is a general term for a disease caused by cells having an aggressive characteristic in which cells divide and grow while ignoring normal growth limits, an invasive characteristic in which cells infiltrate surrounding tissues, and a metastatic characteristic in which cells spread to other parts of the body, and the cancer includes lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, colorectal cancer, colon cancer, rectal cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer, Ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney and renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer,It may be one or more selected from the group consisting of biliary tract cancer, head and neck cancer, carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma, schwanoma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancy, squamous cell cancer, and epithelial squamous cell cancer, but is not limited thereto.

[0251] In the present invention, the composition may further include an anticancer agent or may be administered in combination with an anticancer agent, but is not limited thereto.

[0252] In the present invention, the anticancer agent may be an immune checkpoint inhibitor or a chemotherapy agent, but is not limited thereto.

[0253] In the present invention, the immune checkpoint inhibitor may be at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody, but is not limited thereto.

[0254] In the present invention, the chemotherapeutic agent is gefitinib, docetaxel, paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, imatinib, carboplatin, oxaliplatin, tegafur, irinotecan, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, danuorubicin, chlorambucil, bryostatin-1, calicheamicin, mayatansine, levamisole, DNA recombinant interferon alfa-2a, mitoxantrone, nimustine, interferon alfa-2a, doxifluridine, formestane, leuprolide acetate, megestrol acetate, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, anastrozole, estramustine, capecitabine,It may be at least one selected from the group consisting of goserelin acetate, polysaccharide potassium, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, and actinomycin D, but is not limited thereto.

[0255] The term “combination administration” as used herein can be achieved by administering the individual components of a treatment regimen simultaneously, sequentially, or separately. It is a method of obtaining a combined therapeutic effect by administering two or more drugs simultaneously or sequentially, or alternately at regular or indefinite intervals, etc. Combination therapy is not limited thereto, but can be defined as a combination therapy that provides a synergistic effect while being therapeutically superior to the efficacy that can be obtained by administering one or the other of the components of the combination therapy at a regular dose, as measured by, for example, the degree of response, the rate of response, the time until disease progression, or the duration of survival.

[0256] In the present invention, when the compound of the present invention was treated to various cancer cells, including lung cancer cells, an anti-tumor effect was confirmed based on activities such as inhibition of cancer cell proliferation and tumor size. In addition, it was confirmed that the anti-cancer activity was significantly increased when treated in combination with an anti-cancer agent. Therefore, the composition of the present invention can exhibit a synergistic effect with the anti-cancer effect of an anti-cancer agent, particularly, an immune checkpoint inhibitor or a chemotherapy agent, thereby enhancing the anti-cancer effect. Here, “enhancing the anti-cancer effect” refers to all effects that can ultimately strengthen the function of the anti-cancer agent, and includes not only enhancing the anti-cancer effect of the anti-cancer agent, such as inhibition of tumor growth, inhibition of tumor metastasis, and inhibition of tumor recurrence, but also inhibiting the formation of resistance or tolerance of cancer cells to the anti-cancer agent, thereby ultimately enhancing the anti-cancer effect. In other words, the composition according to the present invention can be used as a compound for combination administration with known anti-cancer agents, particularly, an immune checkpoint inhibitor or a chemotherapy agent, for the purpose of enhancing the anti-cancer effect. That is, the composition of the present invention can be used for combined administration with an immune checkpoint inhibitor or a chemotherapy agent, thereby enhancing the anticancer effect of the anticancer agent.

[0257] In one embodiment of the present invention, the composition may be administered concurrently with, separately from, or sequentially with an anticancer agent, but is not limited thereto. Even when administered sequentially with an anticancer agent, the administration order is not limited; however, the administration regimen may be appropriately adjusted depending on the type of cancer, the type of anticancer agent, the patient's condition, etc.

[0258] Additionally, the composition according to the present invention may be administered simultaneously, separately, or sequentially with the anticancer agent or another anticancer agent before or after resistance to the anticancer agent is developed in the subject.

[0259] That is, the composition according to the present invention may be in a form in which the composition and the anticancer agent are each formulated and administered simultaneously, separately, or sequentially. In this case, the composition may be a pharmaceutical composition for combination administration for simultaneous or sequential administration, comprising a first pharmaceutical composition containing a pharmaceutically effective amount of the compound of the present invention as an active ingredient; and a second pharmaceutical composition containing a pharmaceutically effective amount of the anticancer agent as an active ingredient. In this case, in the case of sequential administration, the administration order is not limited, and the administration regimen may be appropriately adjusted depending on the patient's condition, etc.

[0260] That is, when the pharmaceutical composition is a pharmaceutical composition for combination administration for sequential administration, the composition may be such that the compound of the present invention or a pharmaceutically effective salt thereof (“first component”) is administered first and then the anticancer agent (“second component”) is administered, and the reverse order is also possible.

[0261] In the present invention, “pharmaceutically acceptable salt” includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.

[0262] Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, they can be prepared by heating equimolar amounts of the compound and the acid or alcohol in water, followed by evaporation of the mixture to dryness, or by suction filtration of the precipitated salt.

[0263] Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salt, and the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0264] The pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. The excipients may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.

[0265] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipsoids, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, according to a conventional method, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

[0266] Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0267] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0268] The additives of the tablets, powders, granules, capsules, pills, and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

[0269] As additives of the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. can be used.

[0270] The syrup according to the present invention may include a solution of white sugar, other sugars, or sweeteners, and may also include a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity increasing agent, and the like, as needed.

[0271] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0272] The suspension according to the present invention may include suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

[0273] The injection according to the present invention includes a solvent such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; a solubilizing agent such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nitrile acid amide, hexamine, and dimethylacetamide; a buffer such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; oxidizing agents such as sodium bisulfite 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cis-methylenediamine, sodium alginate, Tween 80, and aluminum monostearate.

[0274] The suppository according to the present invention comprises cocoa butter, lanolin, withepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), Tezester triglyceride basis (TG-95, MA, 57) can be used.

[0275] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0276] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0277] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0278] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0279] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0280] The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with various related factors such as the disease to be treated, route of administration, age, sex, weight of the patient, and severity of the disease.

[0281]

[0282] In addition, the present invention provides a food composition for preventing or improving cancer, comprising an oxadiazole derivative or a food-related acceptable salt thereof as an active ingredient.

[0283] In the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0284] In the present invention, “food-wise acceptable salt” includes a salt derived from a food-wise acceptable organic acid, inorganic acid, or base.

[0285] When the oxadiazole derivative of the present invention or its food-related acceptable salt is used as a food additive, the oxadiazole derivative or its food-related acceptable salt may be added as is or used together with other foods or food ingredients, and may be used appropriately according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the oxadiazole derivative of the present invention or its food-related acceptable salt may be added in an amount of 15 wt% or less, or 10 wt% or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may also be used in an amount above the above range.

[0286] There are no specific restrictions on the types of the above foods. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and all health functional foods in the conventional sense are included.

[0287] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages. The natural carbohydrates mentioned above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g, per 100 mL of the composition of the present invention.

[0288] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used independently or in combination. The proportion of these additives is not particularly critical, but is typically selected within the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0289] In the present invention, "health functional food" is the same term as food for special health use (FoSHU), and means a food with high medical or healthcare effects that is processed to efficiently exhibit a bioregulatory function in addition to providing nutrition. The food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain a useful effect in preventing or improving obesity.

[0290] The health functional food of the present invention can be manufactured using methods commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly used in the art. Furthermore, unlike conventional drugs, it has the advantage of being food-based, eliminating the side effects that can occur with long-term use of drugs, and can be highly portable.

[0291] The above health functional food has the advantage of having even better effects when consumed in the form of inner beauty food. The inner beauty is referred to as an "edible cosmetic or beauty food" and refers to a food that changes the skin constitution to a healthy one by allowing various skin-friendly ingredients to be absorbed into the body. Just as one selects cosmetics that suit one's skin type, one can select and consume inner beauty food that suits one's skin condition and lifestyle. For example, when a cosmetic containing the above cosmetic composition is combined with an inner beauty food containing a rottlerin derivative or its salt, the effect is significantly enhanced compared to using cosmetics or medication alone, and can have the advantage of having a more effective skin pigmentation prevention or improvement effect as well as a whitening effect.

[0292] In the present invention, the term "subject" means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.

[0293] In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method. Therefore, in the present invention, "administration" includes not only injection or ingestion into a subject, but also application.

[0294] In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, “treatment” means any action that improves or beneficially changes a target disease and its metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administering a composition according to the present invention.

[0295] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering a composition containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient in a pharmaceutically effective amount to a subject in need thereof.

[0296] In addition, the present invention provides a use of a composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer.

[0297] In addition, the present invention provides a use for preparing a preparation for preventing or treating cancer, comprising a composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0298] Hereinafter, preferred examples and experimental examples are presented to aid in understanding the present invention. However, the following examples and experimental examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples and experimental examples.

[0299]

[0300] [Example] Synthesis process of oxadiazole derivatives

[0301] Example 1. Synthesis of different types of oxydiazole derivatives (Reaction Schemes 1 and 1a)

[0302] [Reaction Formula 1]

[0303]

[0304] Reagents and conditions: (a) sodium acetate, MeOH, room temperature (RT), reaction time 2 hours; (b) iodine, Cs2CO3, 1,4-dioxane, 75°C, reaction time 2 hours; (c) pyridine, room temperature, reaction time 2 hours; (d) boronic acid, Xphos Pd G3, Cs2CO3, DMF:EtOH:water, 110°C, reaction time 2 hours (MW units).

[0305]

[0306] [Reaction Scheme 1a]

[0307]

[0308] Reagents and conditions: (e) boronic acid, Xphos Pd G3, Cs2CO3, DMF:EtOH:water, 110 ℃, 12 h reaction; (c) pyridine, room temperature, 2 h reaction.

[0309]

[0310] 1-1. Intermediate-3: (E)-2-(3-bromobenzylidene)hydrazinecarboxamide

[0311] Semicarbazide.HCl (1.82 g, 1.5 eq) was added little by little to a solution of MeOH (50 mL) containing 3-bromobenzaldehyde (2 g, 1.0 eq) and sodium acetate (2.68 g, 3.0 eq) at room temperature, and the solution was stirred at ambient temperature for 2 h. Then, the reaction mixture was diluted with 100 mL of water, and a solid precipitate was obtained. The resulting precipitate was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-3 (2.5 g, 95%) as a white solid. This was used without further purification as an off-white solid (1.3 g, 9%).

[0312] 1H NMR (400 MHz, DMSO) δ 8.06(s, 1H), 7.80(s, 1H), 7.64(d,J= 7.8Hz, 1H), 7.51(d,J= 7.5Hz, 1H), 7.33(t,J= 7.8Hz, 1H), 6.60(s, 2H). HRMS (EI) m / z calcd for C8H9BrN3O [M + H] 241.9929, was not observed.

[0313]

[0314] 1-2. Intermediate-4: 5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine

[0315] To a solution of (E)-2-(3-bromobenzylidene)hydrazinecarboxamide (2.7 g, 1.0 eq) in 1,4 dioxane (100 mL) were added Cs2CO3 (10.9 g, 3.0 eq) and iodine (4.26 g, 3.0 eq) at room temperature, and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched with 200 mL of saturated sodium thiosulfate solution and extracted with EtOAc (3 x 220 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. Then, the crude product was dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-4 (2.1 g, 80.7%) as a pale yellow solid, which was used without further purification.

[0316] 1 H NMR (400 MHz, DMSO) δ7.90 (s, 1H), 7.79 (d,J= 7.8 Hz, 1H), 7.72 (d,J= 8.1 Hz, 1H), 7.50 (t,J= 8.0 Hz, 1H), 7.36 (s, 2H). HRMS (EI) m / z calcd for C8H6BrN3O [M + H] 239.9772, found 239.9772.

[0317]

[0318] 1-3. Intermediate-6X:N-(5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)-3-cyanobenzamide

[0319] To a stirred solution of pyridine (15 mL) containing 5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine (2.0 g, 1.0 eq) was added acid chloride (2.62 g, 1.5 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL of water to obtain a solid precipitate, which was isolated by suction filtration, washed with 50 mL of ethanol and then 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-6X (2.3 g, 67%) as a white solid, which was used without further purification.

[0320] 1 H NMR (400 MHz, DMSO-d6) δ8.62 (d,J= 4.0 Hz, 1H), 8.41 (s, 1H), 8.34 (d,J= 7.6 Hz, 1H), 8.08 (s, 1H), 7.98 (d,J= 7.9 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.59 (t,J= 7.9 Hz, 1H), 7.49 - 7.44 (m, 1H); HRMS (EI) m / z calcd for C 16 H 10 BrN4O2[M + H] + 368.9987, found 368.9980.

[0321]

[0322] 1-4. Intermediate-6Y:N-(5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide

[0323] To a stirred solution of pyridine (15 mL) containing 5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine (2.0 g, 1.0 eq) was added acid chloride (2.62 g, 1.5 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL of water to obtain a solid precipitate, which was separated by suction filtration, washed with 50 mL of ethanol and then 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-6Y (2.3 g, 67%) as a white solid, which was used without further purification.

[0324] 1 H NMR (400 MHz, dmso) δ8.62 (d,J= 4.0 Hz, 1H), 8.41 (s, 1H), 8.34 (d,J= 7.6 Hz, 1H), 8.08 (s, 1H), 7.98 (d,J= 7.9 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.59 (t,J= 7.9 Hz, 1H), 7.49 - 7.44 (m, 1H). HRMS (EI) m / z calcd for C8H6BrN3O [M + H] 411.9908, Not matched.

[0325]

[0326] 1-5. General procedure for chemical formulas 7a-7g and intermediate 8

[0327] To a stirred solution of a mixture of DMF:EtOH:H2O (4.5:4.5:0.5) containing halide (1.0 eq) and boronic acid (1.2 eq) was added CS2CO3 (3.0 eq), and the resulting reaction mixture was purged with argon for 10 min, after which Xphos Pd G3 (0.1 eq) was added to the reaction mixture. The resulting reaction mixture was stirred in a microwave at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), filtered through Celite, and the filtrate was evaporated under reduced pressure. The crude product was purified with EtOAc / hexane.

[0328]

[0329] 1-6. Chemical formula-7a: N-(5-(2'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 1)

[0330] The product was obtained as an off-white solid (0.02 g, 19%) through the general procedure of the above Example 1-5.

[0331] 1 H NMR (400 MHz, DMSO) δ8.45 (s, 2H), 8.02 (s, 1H), 7.90 (m, 2H), 7.68 (m, 2H), 7.61 (m, 1H), 7.41 (t,J= 16 Hz, 1H), 7.35 (d,J= 7.9 Hz) 1H), 7.16 (d,J= 7.9 Hz, 1H), 7.07 (t,J= 7.9 Hz, 1H), 3.77 (s, 3H).

[0332]

[0333] 1-7. Chemical formula-7b: N-(5-([1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (compound 2)

[0334] The product was obtained as an off-white solid (0.025 g, 25.2%) through the general procedure of the above Example 1-5.

[0335] 1 H NMR (400 MHz, DMSO) δ8.44 (s, 2H), 8.11 (s, 1H), 7.93 - 7.58 (m, 8H), 7.46 (d,J= 27.3 Hz, 2H).

[0336]

[0337] 1-8. Chemical formula-7c: N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (compound 3)

[0338] The product was obtained as an off-white solid (0.015 g, 15.6%) through the general procedure of the above Example 1-5.

[0339] 1 H NMR (400 MHz, dmso) δ8.45 (d,J= 17.7 Hz, 2H), 8.34 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.85 (d,J= 8.2 Hz, 2H), 7.79 (s, 1H), 7.73 (s, 1H), 7.59 (t,J= 8.0 Hz, 1H), 7.03 (s, 1H).

[0340]

[0341] 1-9. Chemical formula -7d: N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (compound 4)

[0342] The product was obtained as a pink solid (0.080 g, 80%) through the general procedure of Example 1-5 above.

[0343] 1H NMR (500 MHz, DMSO) δ8.41 (s, 1H), 8.35 (d,J= 7.6 Hz, 1H), 8.24 - 8.14 (m, 1H), 8.12 (s, 1H), 7.94 (d,J= 9.2 Hz, 1H), 7.88 (dd,J= 13.2, 9.1 Hz, 2H), 7.77 - 7.72 (m, 1H), 7.72 - 7.66 (m, 1H), 7.63 (d,J= 7.1 Hz, 2H), 7.20 - 7.17 (m, 1H). HRMS (EI) m / z calcd for C 19 H 13 F3N3OS [M+H] 415.0602, found 416.0685.

[0344]

[0345] 1-10. Chemical formula-7e: N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (compound 5)

[0346] The product was obtained as a brown solid (0.055 g, 55%) through the general procedure of Example 1-5 above.

[0347] 1 H NMR (500 MHz, DMSO) δ8.41 (s, 1H), 8.35 (d,J= 6.4 Hz, 1H), 8.20 (t,J= 8.9 Hz, 1H), 8.16 (d,J= 7.8 Hz, 1H), 7.94 (d,J= 10.5 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.84 (d,J= 8.9 Hz, 1H), 7.82 (s, 1H), 7.77 - 7.71 (m, 1H), 7.66 - 7.59 (m, 1H), 7.12 (s, 1H), 6.64 (s, 1H); 13C NMR (101 MHz, DMSO) δ166.77, 166.51, 152.19, 144.04, 135.61, 133.61, 132.90, 132.56, 131.91, 131.65, 130.49, 130.44, 129.96, 126.65, 125.93, 125.89, 125.44, 125.03, 120.68 - 112.67, 107.57; HRMS (EI) m / z calcd for C 19 H 13 F3N3O2[M + H] 400.0909, found 400.0912.

[0348]

[0349] 1-11. Chemical formula -7f:N-(5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 6)

[0350] The product was obtained as an off-white solid (0.041 g, 38.56%) through the general procedure of the above Example 1-5.

[0351] 1 H NMR (400 MHz, DMSO) δ8.41 (d,J= 17.0 Hz, 2H), 8.05 (s, 1H), 7.83 (d,J= 6.4 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.67 (d,J= 8.3 Hz, 3H), 7.63 - 7.54 (m, 2H), 7.06 (d,J= 8.1 Hz, 2H), 3.82 (s, 3H); 13C NMR (101 MHz, DMSO) δ159.84, 141.36, 132.90, 131.60, 130.52, 130.27, 130.11, 129.86, 129.65, 128.51, 128.23, 125.63, 125.42, 124.83, 124.62, 124.31, 123.96, 123.81, 115.70, 114.94, 114.16, 55.75- 55.50; HRMS (EI) m / z calcd for C 22 H 17 F3N3O2[M + H] 440.1222, found 440.1235.

[0352]

[0353] 1-12. Chemical formula-7g: N-(5-(3'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (compound 7)

[0354] The product was obtained as an off-white solid (0.020 g, 18.8%) through the general procedure of the above Example 1-5.

[0355] 1 H NMR (400 MHz, dmso) δ8.53 - 8.41 (m, 2H), 8.15 (s, 1H), 7.96 (d,J= 6.1 Hz, 1H), 7.90 (d,J= 7.5 Hz, 2H), 7.68 (dd,J= 16.9, 8.9 Hz, 2H), 7.42 (t,J= 7.9 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.01 (dd,J= 8.4, 2.4 Hz, 1H), 3.84 (s, 3H).

[0356]

[0357] 1-13. Formula-7e-X: 3-cyano-N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 8)

[0358] The product was obtained as a brown solid (0.067 g, 69.7%) through the general procedure of Example 1-5 above.

[0359] 1 H NMR (500 MHz, DMSO) δ8.44 (s, 1H), 8.26 (s, 1H), 8.21 (d,J= 9.0 Hz, 1H), 8.07 (d,J= 7.2 Hz, 1H), 7.99 (d,J= 8.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd,J= 10.4, 7.2 Hz, 2H), 7.69 (dd,J= 14.7, 7.1 Hz, 2H), 7.08 (d,J= 28.6 Hz, 1H), 6.63 (s, 1H); 13 C NMR (101 MHz, DMSO) δ166.25, 152.21, 144.03, 136.45, 135.14, 134.17, 133.54, 133.18, 132.51, 131.61, 131.49, 130.42, 130.05, 125.11, 120.44, 118.56, 112.72, 112.25, 111.74, 107.54; HRMS (EI) m / z calcd for C 19 H 13 N4O2[M + H] 357.0988, found 357.0994.

[0360]

[0361] 1-14. Formula-7d-X: 3-cyano-N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 9)

[0362] The product was obtained as an off-white solid (0.0196 g, 19.4%) through the general procedure of the above Example 1-5.

[0363] 1H NMR (400 MHz, DMSO)δ8.44 (s, 1H), 8.27 (d,J= 6.7 Hz, 1H), 8.20 (dd,J= 14.9, 7.2 Hz, 1H), 8.07 (s, 1H), 8.01 (d,J= 9.1 Hz, 1H), 7.82 (s, 2H), 7.68 (dd,J= 12.2, 6.5 Hz, 2H), 7.61 (d,J= 2.7 Hz, 2H), 7.18 (s, 1H); 13 C NMR (101 MHz, DMSO)δ166.11, 137.02, 136.76, 136.59, 136.46, 135.24, 134.28, 134.25, 134.05, 133.56, 133.30, 133.07, 132.48, 132.46, 130.97, 130.72, 130.22, 129.97, 118.49, 112.36.; HRMS (EI) m / z calcd for C 19 H 14 N4OS [M + H] 373.0759, found 373.0753.

[0364]

[0365] 1-15. 중간체-8: 5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0366] Xphos Pd G3 (0.05 eq) was added to a degassed solution of 1,4-dioxane / H2O (30 mL, 9:1) containing a bromo compound (1.0 eq), the corresponding boronic acid (1.5 eq), and Cs2CO3 (2.0 eq). The resulting mixture was stirred at 110 °C for 3 h, and when TLC showed the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was dissolved in a mixture of solvents pentane and diethyl ether (100 mL, 7:3), and the resulting precipitate was collected by suction filtration. The obtained solid was washed again with pentane, diethyl ether (40 mL, 7:3), then with a mixture of ether and ethanol (40 mL, 5:5) and dried under vacuum to obtain intermediate-8 compound.

[0367] The product was obtained as an off-white solid (0.54 g, 59.54%) from 5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine (intermediate-4) according to the general procedure for converting hydrazinecarboxamide to 1,3,4-oxadiazol-2-amine B.

[0368] 1 H NMR (400 MHz, DMSO-d6) δ8.28(s, 1H), 7.98(s, 1H), 7.79 - 7.73(m, 2H), 7.68(d,J= 7.9Hz, 1H), 7.55(t,J= 7.9Hz, 1H), 7.26(s, 2H), 7.01(d,J=1.0Hz, 1H); HRMS (EI) m / z calcd for C 12 H 10 N3O2[M + H] + 228.0773, found 228.0771.

[0369]

[0370] 1-16. General procedure for chemical formulas 9a-d

[0371] Acid chloride (1.5 eq) was added to a stirred solution of pyridine (15 mL) containing 1,3,4-oxadiazol-2-amine (1.0 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with 50 mL of water to obtain a solid precipitate, which was separated by suction filtration, washed with 50 mL of ethanol and then 200 mL of diethyl ether, and dried under vacuum to obtain compounds of chemical formula 9a-d.

[0372]

[0373] 1-17. Chemical Formula 9a: N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 10)

[0374] The product was obtained as an orange solid (0.034 g, 35.6%) through the general procedure of Example 1-16 above.

[0375] 1 H NMR (400 MHz, dmso) δ12.55 - 12.27 (m, 1H), 9.16 (s, 1H), 8.80 (s, 1H), 8.33 (s, 2H), 8.13 (s, 1H), 7.81 (d,J= 26.5 Hz, 3H), 7.60 (s, 2H), 7.04 (s, 1H).

[0376]

[0377] 1-18. Chemical Formula-9b: N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 11)

[0378] The product was obtained as an off-white solid (35 mg, 39.3%) through the general procedure of Example 1-16 above.

[0379] 1 H NMR (500 MHz, DMSO) δ12.24 (s, 1H), 8.37 (s, 1H), 8.21 - 8.11 (m, 3H), 7.88 (dd,J= 14.9, 8.2 Hz, 4H), 7.83 - 7.76 (m, 3H), 7.65 (t,J= 7.8 Hz, 1H), 7.53 (t,J= 7.6 Hz, 2H), 7.45 (t,J= 7.3 Hz, 1H), 7.08 (s, 1H).

[0380]

[0381] 1-19. Chemical formula-9c: N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-carboxamide (Compound 12)

[0382] The product was obtained as an off-white solid (81 mg, 90.4%) through the general procedure of Example 1-16 above.

[0383] 1 H NMR (500 MHz, DMSO) δ12.33 (s, 1H), 8.37 (d,J= 7.1 Hz, 2H), 8.18 (s, 1H), 8.03 (d,J= 7.2 Hz, 1H), 7.98 (d,J= 7.3 Hz, 1H), 7.87 (t,J= 8.7 Hz, 2H), 7.81 (s, 3H), 7.72 - 7.60 (m, 2H), 7.53 (t,J= 7.4 Hz, 2H), 7.43 (t,J= 7.1 Hz, 1H), 7.07 (s, 1H).

[0384]

[0385] 1-20. Chemical formula -9d:N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 13)

[0386] The product was obtained as a beige solid (73 mg, 51.3%) through the general procedure of Example 1-16 above.

[0387] 1 H NMR (500 MHz, DMSO) δ12.22 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 8.08 (d,J= 7.5 Hz, 2H), 7.88 (dd,J= 13.5, 7.8 Hz, 2H), 7.82 (s, 1H), 7.67 (dt,J= 15.5, 7.5 Hz, 2H), 7.59 (t,J= 7.5 Hz, 2H), 7.08 (s, 1H).

[0388]

[0389] Example 2. Synthesis of different types of oxydiazole derivatives (Reaction Schemes 2 and 2a)

[0390] [Reaction Formula 2]

[0391]

[0392] [Reaction Scheme 2a]

[0393]

[0394] Reagents and conditions: (a) PdCl2(dppf)·DCM, Cs2CO3, DMF:water, 110°C, 2 h reaction; (b) sodium acetate, MeOH, room temperature, 2 h reaction; (c) iodine, Cs2CO3, 75°C, 2 h reaction; (d) pyridine, room temperature, 2 h reaction; (e) Cs2CO3, RT, 2 h reaction.

[0395]

[0396] 2-1. Intermediate-3: 3-(thiophen-3-yl)benzaldehyde

[0397] To a stirred solution of a DMF:H2O (9:1) mixture containing 3.0 g (1.0 eq) of halide and boronic acid (1.2 eq) was added CS2CO3 (3.0 eq). The resulting reaction mixture was purged with argon for 10 min, and PdCl2(dppf)·DCM (0.1 eq) was added to the reaction mixture and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered through Celite, and the filtrate was evaporated under reduced pressure. The crude product was purified with EtOAc / hexane to give intermediate-3 as an off-white solid (2.3 g, 73%).

[0398] 1 H NMR (400 MHz, CDCl3)δ10.05 (s, 1H), 8.09 (s, 1H), 7.85 (d,J= 7.3 Hz, 1H), 7.79 (d,J= 7.5 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.43 (s, 2H); HRMS (EI) m / z calcd for C 11 H9OS [M + H] 189.0374, found 189.0369.

[0399]

[0400] 2-2. Intermediate-3a: 3-(thiophen-2-yl)benzaldehyde

[0401] Intermediate-3a was obtained as an off-white solid (0.6 g, 59.02%) by the method of Example 2-1 using the reagents and conditions in the above reaction formula.

[0402] 1H NMR (400 MHz, cdcl3) δ10.06 (s, 1H), 8.11 (t,J= 1.4 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.79 (dt,J= 7.7, 1.2 Hz, 1H), 7.56 (t,J= 7.7 Hz, 1H), 7.41 (dd,J= 3.6, 1.0 Hz, 1H), 7.35 (dd,J= 5.1, 1.0 Hz, 1H), 7.12 (dd,J= 5.1, 3.7 Hz, 1H); HRMS (EI) m / z calcd for C 11 H9OS [M + H] 189.0374, found 189.0368.

[0403]

[0404] 2-3. Intermediate-5: (E)-2-(3-(thiophen-3-yl)benzylidene)hydrazinecarboxamide

[0405] Semicarbazide.HCl (2.5 g, 1.5 eq) was added portionwise to a solution of 3-(thiophen-3-yl)benzaldehyde (2.8 g, 1.0 eq) and sodium acetate (3.67 g, 3.0 eq) in MeOH (50 mL) at room temperature, and the solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 100 mL of water, and a solid precipitate was obtained. The resulting precipitate was isolated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-5 (3.49 g, 95.68%) as a white solid, which was used without further purification.

[0406] 1H NMR (400 MHz, DMSO) δ8.85 (s, 1H), 8.04 (d,J= 3.0 Hz, 1H), 7.71 (d,J= 5.5 Hz, 1H), 7.59 (d,J= 8.0 Hz, 1H), 7.55 (d,J= 6.2 Hz, 1H), 7.42 (td,J= 7.7, 4.2 Hz, 2H), 7.31 (d,J= 7.7 Hz, 1H), 6.60 (s, 1H), 6.16 (s, 2H) ; HRMS (EI) m / z calcd for C 12 H 12 N3OS [M+H] 246.0701, found 246.0695.

[0407]

[0408] 2-4. Intermediate-5a: (E)-2-(3-(thiophen-2-yl)benzylidene)hydrazinecarboxamide

[0409] Intermediate-5a was obtained as a white solid (0.76 g, 97.1%) by the method of Example 2-3 using the reagents and conditions in the above reaction formula, and was used without further purification.

[0410] 1 H NMR (400 MHz, dmso) δ8.00 (s, 1H), 7.87 (s, 1H), 7.63 (ddd,J= 5.9, 3.1, 1.2 Hz, 2H), 7.60 - 7.56 (m, 2H), 7.42 (t,J= 7.7 Hz, 1H), 7.16 (dd,J= 5.0, 3.6 Hz, 1H), 6.57 (s, 2H). HRMS (EI) m / z calcd for C 12 H 12 N3OS [M+H] 246.0701, found 246.0707.

[0411]

[0412] 2-5. Chemical Formula-6: 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (Compound 31)

[0413] To a solution of (E)-2-(3-(thiophen-3-yl)benzylidene)hydrazinecarboxamide (3.5 g, 1.0 eq) in 1,4 dioxane (100 mL) were added Cs2CO3 (14 g, 3.0 eq) and iodine (5.4 g, 3.0 eq) at room temperature, and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched with 200 mL of saturated sodium thiosulfate solution and extracted with EtOAc (3 x 220 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain the product (3.2 g, 92.17%) as a pale yellow solid, which was used without further purification.

[0414] 1 H NMR (400 MHz, DMSO) δ8.07 (s, 1H), 8.00 - 7.97 (m, 1H), 7.85 (d,J= 8.3 Hz, 1H), 7.70 (dd,J= 9.4, 5.7 Hz, 2H), 7.60 (d,J= 3.6 Hz, 1H), 7.57 (d,J= 7.9 Hz, 1H), 7.29 (s, 2H); 13 C NMR (101 MHz, DMSO) δ164.37, 157.67, 140.84, 136.42, 130.34, 128.49, 127.99, 126.50, 125.46, 124.13, 122.79, 122.46; HRMS (EI) m / z calcd for C 12 H 10 N3OS [M+H] 244.0545, found 244.0543.

[0415]

[0416] 2-6. Intermediate-6a: 5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0417] Intermediate-6a was obtained as a pale yellow solid (0.61 g, 85.3%) by the method of Example 2-5 using the reagents and conditions in the above reaction formula.

[0418] 1 H NMR (400 MHz, dmso) δ7.99 (s, 1H), 7.82 (d,J= 7.6 Hz, 1H), 7.73 (d,J= 7.6 Hz, 1H), 7.62 (t,J= 4.8 Hz, 2H), 7.57 (d,J= 7.7 Hz, 1H), 7.29 (s, 2H), 7.20 - 7.17 (m, 1H). HRMS (EI) m / z calcd for C 12 H 12 N3OS [M+H] 244.0545, found 244.0534.

[0419]

[0420] 2-7. General procedures for chemical formulas 8a-8g, 8i-8o, and 8r-8u

[0421] To a stirred solution of pyridine (10 mL) containing 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (100 mg, 1.0 eq) was added acid chloride (1.5 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 50 mL of diethyl ether and an ether:ethanol mixture, and dried under vacuum to obtain the pure product.

[0422]

[0423] 2-8. Chemical Formula 8a: 3-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 14)

[0424] The product was obtained as a white solid (0.02 g, 13.4%) through the general procedure of Example 2-7 above.

[0425] 1 H NMR (400 MHz, dmso) δ8.22 (s, 1H), 8.04 (s, 1H), 7.98 - 7.91 (m, 2H), 7.87 (t,J= 7.5 Hz, 2H), 7.71 (s, 1H), 7.65 (t,J= 6.9 Hz, 2H), 7.60 - 7.55 (m, 1H), 7.50 - 7.43 (m, 1H).

[0426]

[0427] 2-9. Chemical Formula-8b: 4-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 15)

[0428] The product was obtained as a white solid (0.035 g, 22.4%) through the general procedure of Example 2-7 above.

[0429] 1 H NMR (400 MHz, dmso) δ8.17 (d,J= 8.3 Hz, 3H), 8.01 (s, 1H), 7.84 (dd,J= 11.9, 8.5 Hz, 2H), 7.70 (d,J= 6.8 Hz, 1H), 7.62 (d,J= 5.6 Hz, 1H), 7.58 (d,J= 6.2 Hz, 1H), 7.44 (d,J= 9.1 Hz, 2H).

[0430]

[0431] 2-10. Chemical formula-8c: N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzamide (Compound 16)

[0432] The product was obtained as a white solid (0.035 g, 20.5%) through the general procedure of Example 2-7 above.

[0433] 1 H NMR (400 MHz, dmso) δ8.36 (d,J= 8.0 Hz, 2H), 8.17 (s, 1H), 8.01 (s, 1H), 7.89 - 7.81 (m, 2H), 7.75 (d,J= 8.1 Hz, 2H), 7.70 (s, 1H), 7.60 (dd,J= 15.3, 7.2 Hz, 2H).

[0434]

[0435] 2-11. Chemical Formula-8d: 2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 17)

[0436] The product was obtained as a white solid (0.035 g, 23.4%) through the general procedure of Example 2-7 above.

[0437] 1 H NMR (400 MHz, dmso) δ8.21 (s, 1H), 8.05 (s, 1H), 7.97 (d,J= 8.0 Hz, 1H), 7.86 (d,J= 7.6 Hz, 1H), 7.79 (t,J= 7.2 Hz, 1H), 7.71 (s, 1H), 7.65 (dd,J= 10.9, 6.2 Hz, 3H), 7.37 (dd,J= 15.7, 8.1 Hz, 2H).

[0438]

[0439] 2-12. Chemical Formula-8e: 2,3-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 18)

[0440] The product was obtained as a pink solid (0.0144 g, 9.13%) through the general procedure of Example 2-7 above.

[0441] 1 H NMR (400 MHz, DMSO) δ8.21 (s, 1H), 8.04 (s, 1H), 7.97 (d,J= 9.2 Hz, 1H), 7.86 (d,J= 8.1 Hz, 1H), 7.70 (dd,J= 4.9, 2.0 Hz, 2H), 7.68 - 7.60 (m, 4H), 7.36 (s, 1H); 13 C NMR (101 MHz, DMSO) δ140.57, 136.57, 130.56, 130.49, 129.73, 129.64, 128.05, 127.32 - 127.29, 126.50, 126.34 - 126.32, 126.03, 125.12, 125.06, 125.00, 124.57, 124.54, 123.59, 123.52, 122.71 - 122.70; HRMS (EI) m / z calcd for C 19 H 12 F2N3O2S [M + H] 384.0618, found 384.0605.

[0442]

[0443] 2-13. Formula-8f: 3-cyano-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 19)

[0444] The product was obtained as an ivory-colored solid (0.032 g, 21.1%) through the general procedure of Example 2-7 above.

[0445] 1H NMR (400 MHz, DMSO) δ8.46 (s, 1H), 8.39 (d,J= 5.3 Hz, 1H), 8.29 (s, 1H), 8.23 ​​(d,J= 7.3 Hz, 1H), 8.18 (d,J= 8.6 Hz, 1H), 8.08 (d,J= 8.2 Hz, 1H), 8.05 - 7.98 (m, 1H), 7.92 (d,J= 8.7 Hz, 1H), 7.85 (d,J= 8.2 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.63 (d,J= 6.8 Hz, 1H); 13 C NMR (101 MHz, DMSO) δ140.12, 135.92, 134.61, 133.63, 132.96, 132.63, 131.96, 130.94, 129.93, 129.89, 129.52, 128.71, 127.46, 125.95, 124.58, 124.18, 122.06, 118.03, 111.70, 111.19; HRMS (EI) m / z calcd for C 20 H 13 N4O2S [M + H] 373.0759, found 373.0750.

[0446]

[0447] 2-14. Chemical formula-8g: 3-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 20)

[0448] The product was obtained as a brown solid (0.018 g, 11.47%) through the general procedure of Example 2-7 above.

[0449] 1H NMR (400 MHz, DMSO) δ8.19 (s, 1H), 8.12 (s, 1H), 8.06 (d,J= 7.7 Hz, 1H), 8.03 (s, 1H), 7.90 (d,J= 8.0 Hz, 1H), 7.85 (d,J= 6.6 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.63 (d,J= 7.2 Hz, 2H), 7.60 - 7.55 (m, 2H), 7.51 - 7.47 (m, 1H); 13 C NMR (101 MHz, DMSO) δ140.77, 136.51, 133.29, 130.58, 130.29, 128.87, 128.73, 128.15, 127.80, 127.67, 127.52, 126.69, 125.47, 124.55, 123.31, 123.19, 122.64, 122.44, 120.85; HRMS (EI) m / z calcd for C 19 H 13 ClN3O2S [M + H] 382.0417, found 382.0415.

[0450]

[0451] 2-15. Chemical Formula-8i: 2,6-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 22)

[0452] The product was obtained as an ivory solid (0.0124 g, 7.87%) through the general procedure of Example 2-7 above.

[0453] 1 H NMR (400 MHz, DMSO) δ8.13 (s, 1H), 8.01 (s, 1H), 7.88 (d,J= 6.9 Hz, 1H), 7.79 (d,J= 7.8 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.62 (s, 1H), 7.58 (d,J= 7.7 Hz, 1H), 7.43 (s, 2H), 7.15 - 7.08 (t, 2H); 13C NMR (101 MHz, DMSO) δ163.57, 161.14, 141.58, 132.85, 127.77, 127.48, 127.04, 126.77, 125.26, 125.05, 122.95 - 122.92, 122.66, 121.57, 121.32, 115.83, 115.62, 115.39, 111.02, 110.73; HRMS (EI) m / z calcd for C 19 H 12 F2N3O2S [M + H] 384.0618, found 384.0612.

[0454]

[0455] 2-16. Chemical formula-8j: N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 23)

[0456] The product was obtained as a pink ivory solid (0.0545 g, 30.74%) through the general procedure of Example 2-7 above.

[0457] 1 H NMR (400 MHz, DMSO) δ8.21 (d,J= 11.0 Hz, 3H), 8.05 (d,J= 3.0 Hz, 1H), 7.96 (d,J= 7.3 Hz, 1H), 7.88 (d,J= 8.0 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.67 (s, 1H), 7.64 (d,J= 5.6 Hz, 1H), 7.53 (d,J= 8.2 Hz, 2H), 7.48 (d,J= 8.1 Hz, 1H); 13C NMR (101 MHz, DMSO) δ166.65, 160.33, 151.86, 151.50, 140.62, 136.62, 131.17, 130.78, 130.26, 128.30, 127.73, 126.82, 126.20, 124.71, 124.69, 123.62, 121.69, 121.35, 120.67, 119.12; HRMS (EI) m / z calcd for C 20 H 13 F3N3O3S [M + H] 432.0630, found 432.0621.

[0458]

[0459] 2-17. Chemical formula-8k: 3-methyl-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 24)

[0460] The product was obtained as a pink solid (0.0826 g, 55.61%) through the general procedure of Example 2-7 above.

[0461] 1 H NMR (400 MHz, DMSO) δ8.23 (s, 1H), 8.05 (s, 1H), 7.97 (d,J= 8.2 Hz, 1H), 7.89 (s, 1H), 7.86 (d,J= 9.6 Hz, 2H), 7.72 (d,J= 6.1 Hz, 1H), 7.66 (dd,J= 9.2, 6.3 Hz, 2H), 7.47 - 7.42 (m, 2H), 2.41 (s, 3H); 13 C NMR (101 MHz, DMSO) δ140.58, 138.33, 136.61, 133.59, 129.75, 129.38, 129.22, 128.79, 128.18, 127.95, 126.63, 126.39, 126.05, 125.85, 125.14, 124.65, 123.69, 123.60, 122.82, 122.66; HRMS (EI) m / z calcd for C 20 H 16N3O2S [M + H] 362.0963, found 362.0966.

[0462]

[0463] 2-18. Chemical Formula-8l: 4-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 25)

[0464] The product was obtained as an ivory-colored solid (0.0596 g, 39.69%) through the general procedure of Example 2-7 above.

[0465] 1 H NMR (400 MHz, DMSO) δ8.22 (s, 1H), 8.17 - 8.11 (m, 2H), 8.05 (s, 1H), 7.96 (d,J= 7.2 Hz, 1H), 7.88 (d,J= 8.1 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.65 (t,J= 6.9 Hz, 2H), 7.38 (t,J= 8.1 Hz, 2H), 7.31 (d,J= 8.6 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ166.89, 164.47, 140.64, 136.60, 132.55, 132.49, 131.72, 131.66, 130.52, 129.53, 128.04, 126.52, 124.95, 123.53, 122.69, 116.09, 115.95, 115.89, 115.74; HRMS (EI) m / z calcd for C 19 H 13 FN3O2S [M + H] 366.0713, found 366.0720.

[0466]

[0467] 2-19. Chemical Formula-8m: 2-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 26)

[0468] The product was obtained as a brown solid (0.036 g, 22.94%) through the general procedure of Example 2-7 above.

[0469] 1 H NMR (400 MHz, DMSO) δ8.14 (s, 1H), 8.01 (s, 1H), 7.89 (d,J= 7.8 Hz, 1H), 7.80 (d,J= 8.1 Hz, 2H), 7.70 (s, 1H), 7.63 - 7.57 (m, 2H), 7.47 (d,J= 9.7 Hz, 2H), 7.39 (s, 2H); 13 C NMR (101 MHz, DMSO) δ167.15, 133.32, 132.65, 132.61, 132.00, 131.98, 131.92, 131.89, 131.87, 131.68, 131.43, 131.37, 131.01, 130.98, 130.69, 127.98, 127.30; HRMS (EI) m / z calcd for C 19 H 13 ClN3O2S [M + H] 382.0417, found 382.0429.

[0470]

[0471] 2-20. Chemical formula -8n:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethoxy)benzamide (Compound 27)

[0472] The product was obtained as a pink solid (0.060 g, 33.84%) through the general procedure of Example 2-7 above.

[0473] 1H NMR (400 MHz, DMSO) δ8.18 (s, 1H), 8.04 (s, 1H), 7.96 (d,J= 7.7 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.71 (d,J= 5.8 Hz, 2H), 7.68 (d,J= 4.7 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.57 (d,J= 8.4 Hz, 1H), 7.53 (d,J= 7.7 Hz, 1H); 13 C NMR (101 MHz, DMSO) δ145.67, 140.59, 136.59, 133.27, 132.10, 130.51, 129.73, 128.24, 128.00, 127.90, 126.46, 125.00, 124.51, 124.28, 123.57, 122.62, 122.20, 121.72, 119.17, 116.59; HRMS (EI) m / z calcd for C 20 H 13 F3N3O3S [M + H] 432.0630, found 432.0647.

[0474]

[0475] 2-21. Chemical formula-8o: methyl 3-((5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate (compound 28)

[0476] The product was obtained as a white solid (0.012 g, 7.2%) through the general procedure of Example 2-7 above.

[0477] 1H NMR (500 MHz, DMSO) δ8.78 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.17 (d,J= 9.6 Hz, 1H), 8.08 (d,J= 6.9 Hz, 1H), 7.98 (s, 1H), 7.90 (d,J= 9.4 Hz, 1H), 7.86 (s, 1H), 7.65 (d,J= 4.8 Hz, 1H), 7.59 (d,J= 13.4 Hz, 2H), 3.86 (d,J= 11.6 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ166.48, 140.67, 140.02, 136.48, 135.28, 134.21, 133.71, 132.04, 130.40, 130.18, 129.92, 129.69, 129.06, 128.72, 127.90, 126.48, 125.16, 124.81, 123.28, 122.51, 52.62; HRMS (EI) m / z calcd for C 21 H 16 N3O4S [M + H] 406.0862, found 406.0881.

[0478]

[0479] 2-22. Chemical formula -8r:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)benzamide (Compound 32)

[0480] The product was obtained as a white solid (0.009 g, 5.27%) through the general procedure of Example 2-7 above.

[0481] 1 H NMR (400 MHz, dmso) δ8.12 (s, 1H), 8.00 (s, 1H), 7.86 (d,J= 7.4 Hz, 1H), 7.78 (d,J= 7.6 Hz, 1H), 7.71 (d,J= 7.3 Hz, 2H), 7.65 (d,J= 4.6 Hz, 2H), 7.62 - 7.55 (m, 3H), 7.54 (s, 1H). 13C NMR (151 MHz, dmso) δ168.27, 149.64, 133.06, 132.80, 132.79, 131.61, 130.10, 127.03, 126.93, 126.90, 126.86, 126.82, 126.71, 126.61, 126.53, 126.51, 124.89, 123.08, 121.27.

[0482]

[0483] 2-23. Chemical formula-8s: 4-iodo-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 33)

[0484] The product was obtained as an off-beige solid (300 mg, 77.1%) through the general procedure of Example 2-7 above.

[0485] 1 H NMR (500 MHz, DMSO) δ12.36 (s, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.96 (d,J= 7.3 Hz, 3H), 7.88 (d,J= 7.3 Hz, 1H), 7.83 (d,J= 7.8 Hz, 2H), 7.70 (s, 1H), 7.65 (dd,J= 13.0, 5.8 Hz, 2H).

[0486]

[0487] 2-24. Chemical formula -8t:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 34)

[0488] The product was obtained as an off-beige solid (73 mg, 51.3%) through the general procedure of Example 2-7 above.

[0489] 1H NMR (500 MHz, DMSO) δ12.23 (s, 1H), 8.26 (s, 1H), 8.07 (d,J= 7.3 Hz, 3H), 7.99 (d,J= 7.6 Hz, 1H), 7.90 (d,J= 7.5 Hz, 1H), 7.75 - 7.63 (m, 4H), 7.59 (t,J= 7.4 Hz, 2H).

[0490]

[0491] 2-25. Formula-8u:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 35)

[0492] The product was obtained as an off-white solid (300 mg, 29.4%) through the general procedure of Example 2-7 above.

[0493] 1 H NMR (400 MHz, dmso) δ8.42 (s, 1H), 8.35 (d,J= 7.9 Hz, 1H), 8.24 (s, 1H), 8.04 (d,J= 12.0 Hz, 2H), 7.98 (d,J= 7.9 Hz, 1H), 7.89 (d,J= 7.6 Hz, 1H), 7.82 (t,J= 7.8 Hz, 1H), 7.68 (dd,J= 16.5, 8.5 Hz, 3H).

[0494]

[0495] 2-26. General Procedure for Chemical Formulas 8h, 8p, and 8q

[0496] To a stirred solution of pyridine (10 mL) containing 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (100 mg, 1.0 eq) was added acid chloride (1.5 eq) at room temperature. The reaction mixture was stirred in a microwave at 120 °C for 2 h, diluted with 50 mL of water, and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 50 mL of diethyl ether and an ether:ethanol mixture, and dried under vacuum to obtain the pure product.

[0497]

[0498] 2-27. Chemical formula -8h:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 21)

[0499] The product was obtained as a yellowish-white solid (0.035 g, 24.4%) from 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine through the general procedure for acid chloride reaction C (Method-II) of Example 2-26.

[0500] 1 H NMR (400 MHz, dmso) δ9.28 (d,J=10 Hz, 2H), 8.67 (d,J=10 Hz, 1H), 8.43 (s, 1H), 8.17 (d,J=16 Hz, 1H), 7.95 (m, 3H), 7.58 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ158.43, 153.77, 153.44, 149.91, 149.58, 140.53, 136.67, 136.65, 130.84, 130.39, 130.06, 129.79, 128.36, 127.83, 126.78, 126.27, 125.34, 125.00, 124.36, 123.79, 122.92, 122.67; HRMS (EI) m / z calcd for C 18 H 13 N4O2S [M + H] + 349.0759, found 349.0746.

[0501]

[0502] 2-28. Chemical formula -8p:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)isonicotinamide (Compound 29)

[0503] The product was obtained as a yellowish-white solid (0.02 g, 20.2%) through the general procedure of Example 2-26 above.

[0504] 1 H NMR (400 MHz, dmso) δ8.68 (s, 2H), 8.16 (s, 1H), 7.97 (s, 3H), 7.92 (d,J= 7.7 Hz, 1H), 7.84 (d,J= 6.8 Hz, 1H), 7.66 (s, 1H), 7.62 - 7.56 (m, 2H).

[0505]

[0506] 2-29. Chemical formula -8q:N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)picolinamide (Compound 30)

[0507] The product was obtained as an off-white solid (0.015 g, 10.5%) through the general procedure of Example 2-26 above.

[0508] 1H NMR (500 MHz, dmso) δ12.10 (s, 1H), 8.78 (d,J= 4.3 Hz, 1H), 8.24 (s, 1H), 8.17 (d,J= 7.6 Hz, 1H), 8.11 (t,J= 7.0 Hz, 1H), 8.05 (s, 1H), 7.97 (d,J= 7.9 Hz, 1H), 7.88 (d,J= 8.0 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.70 (dd,J= 4.9, 2.9 Hz, 1H), 7.65 (dd,J= 9.8, 6.2 Hz, 2H).

[0509]

[0510] 2-30. Chemical Formula 10: 5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine (Compound 36)

[0511] To a solution of (E)-2-(3-(thiophen-3-yl)benzylidene)hydrazinecarboxamide (0.1 g, 1.0 eq) in ACN (20 mL) at room temperature was added Cs2CO3 (0.267 g, 2.0 eq), followed by bromide (0.098 g, 1.0 eq), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 50 mL of diethyl ether, and dried under vacuum to obtain a yellowish-white solid (0.03 g, 13.1%).

[0512] 1H NMR (400 MHz, cdcl3) δ8.14 (s, 1H), 7.78 (d,J= 7.8 Hz, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.59 (d,J= 7.2 Hz, 2H), 7.49 (dq,J= 15.5, 7.7 Hz, 7H), 7.38 (d,J= 3.6 Hz, 1H), 7.33 (d,J= 5.0 Hz, 1H), 7.11 (dd,J= 4.9, 3.8 Hz, 1H), 4.74 (s, 4H).

[0513]

[0514] Example 3. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 3)

[0515] [Reaction Formula 3]

[0516]

[0517] Reagents and conditions: (a) PdCl2(dppf).DCM, Cs2CO3, DMF:water, 110°C, reaction time 3 hours; (b) sodium acetate, MeOH, room temperature, reaction time 2 hours; (c) iodine, Cs2CO3, 75-90°C, reaction time 2 hours; (d) pyridine, room temperature, reaction time 2 hours.

[0518]

[0519] 3-1. Intermediate-3: 3-(furan-2-yl)benzaldehyde

[0520] Intermediate-3 was obtained as an off-white solid (1.83 g, 98.32%) from 3-bromobenzaldehyde (compound 1) according to the general procedure for Suzuki coupling reaction D (Method-I).

[0521] Suzuki coupling reaction: general procedure for DI

[0522] Pd(dppf)Cl2.DCM (0.05 eq) was added to a degassed solution of the corresponding bromo compound (1.0 eq) in 1,4-dioxane / water (30 mL, 9:1) containing boronic acid (1.5 eq) and Cs2CO3 (2.0 eq). The resulting mixture was stirred at 110 °C for 3 h, and when TLC showed the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was dissolved in a mixture of solvents pentane and diethyl ether (100 mL, 7:3), and the resulting precipitate was collected by suction filtration. The obtained solid was washed again with pentane and diethyl ether (40 mL, 7:3) and dried under vacuum to obtain intermediate-3 compound.

[0523] 1 H NMR (400 MHz, cdcl3) δ10.06 (s, 1H), 8.17 (s, 1H), 7.93 (d,J= 7.6 Hz, 1H), 7.77 (d,J= 7.4 Hz, 1H), 7.57 (d,J= 7.6 Hz, 1H), 7.52 (s, 1H), 6.78 (s, 1H), 6.52 (s, 1H). HRMS (EI) m / z calcd for C 11 H9O2[M + H] 173.0603, found 173.0595.

[0524]

[0525] 3-2. Intermediate-5: (E)-2-(3-(furan-2-yl)benzylidene)hydrazinecarboxamide

[0526] Intermediate-5 was obtained as a yellowish-white solid (2.41 g, 98.9%) from 3-(furan-2-yl)benzaldehyde (Intermediate-3) according to the general procedure for hydrazinecarboxamide A.

[0527] Hydrazinecarboxamide: General Procedure for A

[0528] To a solution of benzaldehyde (1.0 eq) and semicarbazide hydrochloride (2.0 eq) in EtOH or MeOH (50 mL) was added sodium acetate (2.0 eq) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with water (50 mL), and the resulting precipitate was collected by suction filtration. The obtained solid was washed with diethyl ether (40 mL) and dried under vacuum to obtain intermediate-5.

[0529] 1 H NMR (400 MHz, dmso) δ8.03 (s, 1H), 7.87 (s, 1H), 7.77 (d,J= 1.4 Hz, 1H), 7.67 (dd,J= 4.9, 3.6 Hz, 1H), 7.62 (d,J= 7.8 Hz, 1H), 7.43 (t,J= 7.8 Hz, 1H), 7.08 (d,J= 3.3 Hz, 1H), 6.64 - 6.60 (m, 1H), 6.57 (s, 2H). HRMS (EI) m / z calcd for C 12 H 12 N3O2[M + H] 230.093, found 230.0925.

[0530]

[0531] 3-3. Intermediate-6: 5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0532] Intermediate-6 was obtained as an off-white solid (1.59 g, 66.84%) from (E)-2-(3-(furan-2-yl)benzylidene)hydrazine-1-carboxamide (Intermediate-5) according to the general procedure for converting hydrazinecarboxamide to 1,3,4-oxadiazol-2-amine B.

[0533] General procedure for converting hydrazinecarboxamide to 1,3,4-oxadiazol-2-amine: B

[0534] To a stirred solution of 1,4-dioxane (100 mL) containing hydrazine-1-carboxamide (1.0 eq) and Cs2CO3 (3.0 eq), iodine (3.0 eq) was added little by little, and the resulting mixture was stirred at 75–90 °C for 2 h. When TLC showed the reaction was completed, the reaction mixture was cooled to room temperature, quenched with saturated sodium thiosulfate (200 mL), and the aqueous phase was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was dissolved in diethyl ether (100 mL), and the resulting solid was collected by suction filtration. The obtained solid was washed with ethanol (40 mL), then diethyl ether (40 mL), and dried in vacuo to obtain intermediate-6 compound.

[0535] 1 H NMR (400 MHz, dmso) δ8.08 (s, 1H), 7.85 (dd,J= 4.8, 4.1 Hz, 1H), 7.82 (s, 1H), 7.74 - 7.68 (m, 1H), 7.58 (t,J= 7.8 Hz, 1H), 7.31 (s, 2H), 7.08 (d,J= 3.3 Hz, 1H), 6.64 (dd,J= 3.4, 1.8 Hz, 1H). HRMS (EI) m / z calcd for C 12 H 10 N3O2[M + H] 228.0773, found 228.0765.

[0536]

[0537] 3-4. Chemical formula-7a: N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-6-(trifluoromethyl)picolinamide (Compound 37)

[0538] The compound of formula-7a was obtained as an off brown solid (0.046 g, 26.0%) from 5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (Intermediate-6) according to the general procedure for acid chloride reaction C (Method-II).

[0539] Acid-chloride reactions: general procedure for C-II

[0540] Benzoyl chloride (2.0 eq) was added to a solution of pyridine (30 mL) containing 1,3,4-oxadiazol-2-amine (1.0 eq) at room temperature. The resulting mixture was stirred in a microwave at 120 °C for 2 h, after which benzoyl chloride (1.38 mL, 2.0 eq) was added again, and stirring was continued for an additional 30 min. When TLC showed the reaction was completed, the reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure at 50 °C to remove pyridine. The crude residue was dissolved in diethyl ether (100 mL), and the resulting solid was collected by suction filtration. The obtained solid was washed with a mixture of diethyl ether and ethanol (40 mL, 7:3), followed by diethyl ether (40 mL), and dried under vacuum. The filtrate was evaporated and coagulated again as described above to obtain a compound of chemical formula 7a.

[0541] 1H NMR (400 MHz, cdcl3) δ10.63 (s, 1H), 8.56 (d,J= 7.9 Hz, 1H), 8.40 (d,J= 1.7 Hz, 1H), 8.22 (t,J= 7.8 Hz, 1H), 7.99 (dd,J= 7.8, 2.7 Hz, 2H), 7.85 (d,J= 7.9 Hz, 1H), 7.56 (d,J= 7.8 Hz, 1H), 7.53 - 7.51 (m, 1H), 6.81 (d,J= 3.4 Hz, 1H), 6.52 (dd,J= 3.4, 1.8 Hz, 1H); 13 C NMR (101 MHz, cdcl3) δ159.47, 152.51, 147.84, 147.59, 142.71, 140.04, 131.79, 129.47, 126.76, 125.85, 125.26, 124.37, 123.89, 121.77, 111.85, 106.32, 77.19, 29.67. HRMS (EI) m / z calcd for C 19 H 12 F3N4O3[M + H] 401.0861 found 401.0849.

[0542]

[0543] 3-5. Chemical formula-7b: N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)nicotinamide (Compound 38)

[0544] According to the general procedure for acid chloride reaction C (Method-II) of Example 3-4 above, the compound of chemical formula-7b was obtained as an off orange solid (0.036 g, 41.6%) from 5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (Intermediate-6).

[0545] 1H NMR (400 MHz, cdcl3) δ9.65 (s, 9H), 9.04 (s, 7H), 8.80 (s, 8H), 8.32 (s, 6H), 7.91 (d,J= 7.8 Hz, 15H), 7.55 (dd,J= 15.3, 8.4 Hz, 21H), 6.82 (d,J= 3.5 Hz, 8H), 6.55 - 6.52 (m, 7H), 3.55 - 3.51 (m, 11H); 13 C NMR (101 MHz, cdcl3) δ149.74 (s), 142.75 (s), 129.51 (s), 126.79 (s), 125.27 (s), 121.79 (s), 111.88 (s), 106.34 (s), 77.33 (s), 77.02 (s), 76.70 (s). HRMS (EI) m / z calcd for C 19 H 12 F3N4O3[M + H] 401.0861 found 401.0851.

[0546]

[0547] 3-6. Chemical formula-7c: N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 39)

[0548] According to the general procedure for acid chloride reaction C (Method-II) of Example 3-4 above, the compound of chemical formula-7c was obtained as an off orange solid (0.03 g, 35.6%) from 5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (Intermediate-6).

[0549] 1H NMR (400 MHz, cd3od) δ9.20 (dd,J= 4.4, 1.8 Hz, 1H), 9.11 (d,J= 1.9 Hz, 2H), 8.78 (d,J= 6.1 Hz, 1H), 8.71 (dd,J= 4.8, 1.7 Hz, 2H), 8.40 (dt,J= 7.8, 1.8 Hz, 2H), 7.97 - 7.90 (m, 1H), 7.62 (d,J= 7.6 Hz, 2H), 7.55 (dd,J= 8.0, 4.8 Hz, 3H.

[0550]

[0551] Example 4. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 4)

[0552] [Reaction Formula 4]

[0553]

[0554] Reagents and conditions: (b) sodium acetate, MeOH, room temperature, reaction time 2 hours; (c) iodine, Cs2CO3, 1,4-dioxane, 75-90 ℃, reaction time 2 hours; (d) pyridine, reaction time 2 hours at room temperature.

[0555]

[0556] 4-1. General Procedure

[0557] Semicarbazide.HCl (1.5 eq) was added little by little to a solution of aldehyde (1.0 eq) and sodium acetate (3.0 eq) in MeOH (50 mL) at room temperature, and the solution was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with 100 mL of water, and a solid precipitate was obtained. The resulting precipitate was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain the product, which was used without further purification.

[0558]

[0559] 4-2. Intermediate-2: (E)-2-(naphthalen-2-ylmethylene)hydrazinecarboxamide

[0560] To a stirred solution of EtOH containing aldehyde (1.0 eq) and semicarbazide (1.5 eq) was added sodium acetate (3.0 eq) at room temperature. The reaction mixture was then stirred at room temperature for 2 h and quenched with diluted water. After a solid was formed, the solid was filtered with ether (50 mL) and dried under reduced pressure to obtain intermediate-2 as an off-white solid (2.6 g, 95.18%).

[0561] 1 H NMR (400 MHz, dmso) δ8.10 (dd,J= 8.6, 1.2 Hz, 1H), 8.02 (d,J= 7.0 Hz, 2H), 7.95 - 7.87 (m, 3H), 7.52 (dd,J= 6.0, 2.4 Hz, 1H), 6.56 (s, 2H); HRMS (EI) m / z calcd for C 12 H 12 N3O [M + H] 214.0980, found 214.0971.

[0562]

[0563] 4-3. Intermediate-3: 5-(naphthalen-2-yl)-1,3,4-oxadiazol-2-amine

[0564] To a solution of 1,4 dioxane (100 mL) containing hydrazinecarboxamide (1.0 eq) were added Cs2CO3 (3.0 eq) and iodine (3.0 eq) at room temperature, and the reaction mixture was stirred at 75-90 °C for 2 h. The reaction mixture was quenched with 200 mL of saturated sodium thiosulfate solution and extracted with EtOAc (3 x 220 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to give intermediate-3 as an off-white solid, which was used without further purification.

[0565] 1 H NMR (400 MHz, dmso) δ8.32 (s, 1H), 8.07 (d,J= 8.7 Hz, 2H), 8.02 - 7.92 (m, 2H), 7.66 - 7.57 (m, 2H), 7.36 (s, 2H).

[0566]

[0567] 4-4. Formula-4: 3-cyano-N-(5-(naphthalen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 40)

[0568] To a stirred solution of pyridine (15 mL) containing 1,3,4-oxadiazol-2-amine (1.0 eq) was added acid chloride (1.5 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL of water, and a solid precipitate was obtained. The resulting precipitate was separated by suction filtration, washed with 50 mL of ethanol and then 200 mL of diethyl ether, and dried under vacuum to obtain the pure compound as a pink-white solid (0.018 g, 11.18%).

[0569] 1H NMR (400 MHz, DMSO) δ8.51 (d, J= 17.2 Hz, 2H), 8.39 (d, J= 8.8 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.15 (d, J= 8.6 Hz, 1H), 8.11 (d, J = 5.5 Hz, 1H), 8.07 (dd,J= 4.7, 3.0 Hz, 1H), 8.04 (d,J= 4.8 Hz, 1H), 7.95 (s, 1H), 7.77 - 7.72 (m, 1H), 7.67 - 7.63 (m, 1H); 13 C NMR (151 MHz, DMSO) δ205.21, 189.45, 144.48, 136.19, 134.57, 133.55, 132.90, 132.60, 130.61, 129.41, 129.24, 128.58, 128.45, 127.94, 126.85, 126.79, 118.56, 112.23, 110.21, 109.99; HRMS (EI) m / z calcd for C 20 H 13 N4O2[M + H] 341.1039, found 341.1049.

[0570]

[0571] Example 5. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 5)

[0572] [Reaction Formula 5]

[0573]

[0574] Reagents and conditions: (a) CuI, Cs2CO3, Trans N,N dimethyl cyclohexane diamine, DMF, 100 ℃, 12 h reaction; (b) 10% Pd / C, THF, H2, RT, 12 h reaction; (c) pyridine, RT, 2 h reaction; (d) DCM containing 1 M BBr3, RT, 2 h reaction.

[0575]

[0576] 5-1. Intermediate-3: 1-(3-methoxyphenyl)-4-nitro-1H-pyrazole

[0577] To a stirred solution of 1-iodo-3-methoxybenzene (2.0 g, 1.0 eq) and 4-nitro-1H-pyrazole (1.44 g, 1.5 eq) in 40 mL of DMF was added CS2CO3 (5.5 g, 2.0 eq). The resulting reaction mixture was purged with argon for 10 min, and then CuI (0.16 g, 0.1 eq) and TransN,N-dimethyl cyclohexane diamine (0.120 g, 0.1 eq) were added to the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), filtered through Celite, and the filtrate was evaporated under reduced pressure. The crude product was purified by Biotage (snap cartridge-50 g, 50% EtOAc / hexane) to obtain intermediate-3 (0.85 g, 45.6%) as an off-white solid.

[0578] 1 H NMR (400 MHz, cdcl3) δ8.62 (s, 1H), 8.26 (s, 1H), 7.42 (t,J= 8.2 Hz, 1H), 7.29 (t,J= 2.2 Hz, 1H), 7.27 - 7.22 (m, 2H), 6.97 (dd,J= 8.3, 2.4 Hz, 1H), 3.89 (s, 3H).

[0579]

[0580] 5-2. Intermediate-4: 1-(3-methoxyphenyl)-1H-pyrazol-4-amine

[0581] To a stirred solution of 1-(3-methoxyphenyl)-4-nitro-1H-pyrazole in THF (25 mL) was added 10% Pd / C (0.77 g, 0.2 eq). The reaction mixture was stirred at ambient temperature under a hydrogen gas balloon for 12 h. The reaction mixture was diluted with EtOAc (20 mL), filtered through Celite, and washed with EtOAc (20 mL). The filtrate was evaporated under reduced pressure to give intermediate-4 (0.6 g, 88%) as an off-white powder.

[0582] 1 H NMR (400 MHz, dmso) δ7.71 (d,J= 0.5 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.26 - 7.22 (m, 2H), 6.76 (ddd,J= 8.2, 2.3, 1.1 Hz, 1H), 4.18 (s, 2H), 3.80 (Bs, 3H).

[0583]

[0584] 5-3. Intermediate-6: N-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 41)

[0585] To a stirred solution of pyridine (15 mL) containing 1-(3-methoxyphenyl)-1H-pyrazol-4-amine (0.3 g, 1.0 eq) was added acid chloride (0.661 g, 2.0 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with ETOAc / hexane to give intermediate-6 (0.150 g, 29%) as an off-white solid.

[0586] 1H NMR (400 MHz, dmso) δ10.89 (s, 1H), 8.73 (s, 1H), 8.35 - 8.27 (m, 1H), 7.99 (d,J= 7.7 Hz, 1H), 7.93 (s, 1H), 7.82 (t,J= 7.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 6.91 - 6.85 (m, 1H), 3.81 (s, 3H).

[0587]

[0588] 5-4. Chemical Formula-7: N-(1-(3-hydroxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 42)

[0589] A solution of N-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (0.1 g, 1.0 eq) in DCM (40 mL) was cooled to 0 °C. Then, DCM containing 1 M BBr3 (0.55 mL, 2.0 eq) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 50 mL of water and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with ETOAc / hexane to obtain the compound of formula 7 (0.02 g, 21.5%) as an off-white solid.

[0590] 1 H NMR (400 MHz, dmso) δ10.88 (s, 1H), 9.83 (s, 1H), 8.61 (s, 1H), 8.35 - 8.26 (m, 2H), 7.99 (d,J= 7.7 Hz, 1H), 7.91 (s, 1H), 7.81 (t,J= 7.6 Hz, 1H), 7.28 (t,J= 7.9 Hz, 1H), 7.21 (d,J= 7.1 Hz, 2H), 6.71 (d,J= 8.7 Hz, 1H).

[0591]

[0592] Example 6. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 6)

[0593] [Reaction Formula 6]

[0594]

[0595] Reagents and conditions: (a) NH2OH HCl, NaOAc, EtOH:water (1:1), 80 °C, reaction time 3 h; (b) pyridine, room temperature, reaction time 2 h; (c) Xphos Pd G3, Cs2CO3, DMF:EtOH:water, reaction time 2 h at 110 °C in MW units.

[0596]

[0597] 6-1. Intermediate-2: 3-(3-bromophenyl)isoxazol-5-amine

[0598] To a solution of 3-(3-bromophenyl)-3-oxopropanenitrile (2.5 g, 1.0 eq) and hydroxyl amine HCl (1.84 g, 5.0 eq) in EtOH (50 mL) and water (50 mL) was added sodium acetate (5.49 g, 6.0 eq) at room temperature, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, evaporated, diluted with 50 mL of water, and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with ETOAc / hexane to give intermediate-2 (1 g, 38.6%) as a brown solid.

[0599] 1H NMR (400 MHz, cdcl3) δ7.88 (t,J= 1.7 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.54 (ddd,J= 8.0, 2.0, 1.1 Hz, 1H), 7.30 (t,J= 7.9 Hz, 1H), 5.43 (s, 1H), 4.54 (s, 2H); HRMS (EI) m / z calcd for C9H8BrN2O [M + H] 238.9820, found 238.9808.

[0600]

[0601] 6-2. Chemical Formula-4: N-(3-(3-bromophenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 43)

[0602] To a stirred solution of pyridine (15 mL) containing 3-(3-bromophenyl)isoxazol-5-amine (1.0 g, 1.0 eq) was added acid chloride (1.2 mL, 2.0 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. Then, the reaction mixture was diluted with 50 mL of water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with ETOAc / hexane to give intermediate-4 (compound of formula 4) (1.64 g, 94.8%) as an off-white solid.

[0603] 1 H NMR (400 MHz, DMSO) δ12.43 (s, 1H), 8.42 (s, 1H), 8.34 (d,J= 7.6 Hz, 1H), 8.11 (t,J= 1.7 Hz, 1H), 8.04 (d,J= 7.6 Hz, 1H), 7.94 (d,J= 7.7 Hz, 1H), 7.83 (t,J= 7.9 Hz, 1H), 7.75 - 7.71 (m, 1H), 7.50 (t,J= 7.9 Hz, 1H), 7.06 (s, 1H); 13C NMR (101 MHz, DMSO) δ162.65, 162.32, 161.41, 143.71, 133.37, 132.96, 132.23, 131.18, 130.87, 129.89, 129.40, 129.07, 128.90, 125.52, 124.66 - 124.63, 122.25, 87.32; HRMS (EI) m / z calcd for C 16 H 11 BrF3N2O [M + H] 383.0007, was not observed.

[0604]

[0605] 6-3. General procedure for chemical formulas 6a-b

[0606] The reaction was carried out using a solution of EtOH containing N-(3-(3-bromophenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (1.0 eq), boronic acid (1.2 eq), CS2CO3 (2.0 eq) and water (10 mL). The resulting reaction mixture was purged with argon gas for 3 min, and Xphos-PdG3 (0.05 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 80 °C under microwave conditions for 2 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds of formula 6a-6b.

[0607]

[0608] 6-4. Chemical formula-6a: N-(3-(3-(thiophen-2-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 44)

[0609] The product was obtained as an off-white solid (0.014 g, 13.9%) through the general procedure of Example 6-3 above.

[0610] 1 H NMR (400 MHz, DMSO) δ12.43 (s, 1H), 8.44 (s, 1H), 8.35 (d,J= 8.4 Hz, 1H), 8.16 (s, 1H), 8.04 (d,J= 7.8 Hz, 1H), 7.83 (dd,J= 15.0, 7.2 Hz, 3H), 7.72 (d,J= 4.3 Hz, 1H), 7.62 (d,J= 4.3 Hz, 1H), 7.58 (t,J= 7.8 Hz, 1H), 7.19 (dd,J= 5.0, 3.7 Hz, 1H), 7.11 (s, 1H); 13 C NMR (101 MHz, DMSO) δ162.82, 145.69, 142.85, 135.00, 134.00, 132.78, 130.44, 130.04, 129.93, 129.08, 127.64, 126.73, 126.07, 125.66, 125.20, 125.16, 125.08, 123.47, 122.93, 119.87, 87.90; HRMS (EI) m / z calcd for C 20 H 14 F3N2OS [M+H] 415.0728, found 415.0735.

[0611]

[0612] 6-5. Chemical formula-6b: N-(3-(3-(thiophen-3-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 45)

[0613] The product was obtained as an off-white solid (0.031 g, 30.78%) through the general procedure of Example 6-3 above.

[0614] 1H NMR (400 MHz, DMSO) δ12.40 (s, 1H), 8.44 (s, 1H), 8.35 (d,J= 7.9 Hz, 1H), 8.22 (d,J= 1.6 Hz, 1H), 8.09 (dd,J= 2.8, 1.4 Hz, 1H), 8.04 (d,J= 8.0 Hz, 1H), 7.86 (ddd,J= 19.3, 10.8, 4.4 Hz, 3H), 7.70 (ddd,J= 7.9, 5.0, 2.1 Hz, 2H), 7.57 (t,J= 7.8 Hz, 1H), 7.15 (s, 1H); 13 C NMR (101 MHz, DMSO) δ163.12, 162.79, 145.70, 141.13, 136.37, 133.88, 132.76, 130.33, 129.97, 129.85, 129.65, 128.21, 126.91, 125.66, 125.20, 124.63, 124.53, 122.94, 122.43, 122.27, 119.88; HRMS (EI) m / z calcd for C 20 H 14 F3N2OS [M+H] 415.0728, found 415.0727.

[0615]

[0616] Example 7. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 7)

[0617] [Reaction Formula 7]

[0618]

[0619] Reagents and conditions: (a) Trans-N,N-Dimethyl-1,2-cyclohexanediamine, Cu(I) Iodide, CS2CO3, DMF, 120°C, reaction time 12 hours; (b) sodium acetate, EtOH, room temperature, reaction time 2 hours; (c) iodine, Cs2CO3, 1,4 dioxane, 75°C, reaction time 2 hours; (d) pyridine, room temperature, reaction time 2 hours.

[0620]

[0621] 7-1. General procedure for intermediates 3a-3b

[0622] The reaction was carried out using DMF (20 mL) containing 3-bromobenzaldehyde (1.0 eq), amine (1.0 eq), and cesium carbonate (3.0 eq). The resulting reaction mixture was purged with argon for 4 min, and then trans-N,N-Dimethyl-1,2-cyclohexanediamine (0.3 eq) and Cu(I)Iodide (0.5 eq) were added to the reaction mixture. The resulting reaction mixture was stirred in a sealed tube at 120 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), filtered through Celite, and the filtrate was evaporated under reduced pressure. The crude product was purified with EtOAc / hexane to obtain intermediate-3a-b.

[0623]

[0624] 7-2. Intermediate-3a: 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde

[0625] The product was obtained as an off-white solid (0.92 g, 59.20%) through the general procedure of Example 7-1 above.

[0626] 1 H NMR (400 MHz, CDCl3)δ10.09 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 8.04 - 8.01 (m, 1H), 7.95 (s, 1H), 7.89 (d,J= 7.6 Hz, 1H), 7.69 (t,J=7.9 Hz, 1H); HRMS (EI) m / z calcd for C 11 H8F3N2O [M + H] 241.0589, found 241.0586.

[0627]

[0628] 7-3. Intermediate-3b: 3-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzaldehyde

[0629] The product was obtained as an off-orange liquid (0.542 g, 30.70%) through the general procedure of Example 7-1 above.

[0630] 1 H NMR (400 MHz, CDCl3)δ10.10 (s, 1H), 7.95 (s, 3H), 7.75 (t,J= 7.7 Hz, 1H), 7.72 - 7.70 (m, 1H), 7.69 (s, 1H); HRMS (EI) m / z calcd for C 11 H8F3N2O [M + H] 241.0589, found 241.0580.

[0631]

[0632] 7-4. General procedure for intermediates 5a-5b

[0633] Semicarbazide·HCl (1.5 eq) was added little by little to a solution of benzaldehyde (1.0 eq) and sodium acetate (3.0 eq) in EtOH (60 mL) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with 100 mL of water, and a solid precipitate was obtained. The resulting precipitate was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-5a-5b.

[0634]

[0635] 7-5. Intermediate-5a: (E)-2-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzylidene)hydrazinecarboxamide

[0636] The product was obtained as an off-white solid (1.03 g, 92.41%) through the general procedure of Example 7-4 above.

[0637] 1 H NMR (400 MHz, DMSO) δ9.24 (s, 1H), 8.24 (s, 1H), 8.23 ​​(s, 1H), 7.91 (s, 1H), 7.88 (d,J= 8.0 Hz, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.55 (t,J= 7.9 Hz, 1H), 6.62 (s, 2H); HRMS (EI) m / z calcd for C 12 H 11 F3N5O [M + H] 298.0916, found 298.0906.

[0638]

[0639] 7-6. Intermediate-5b: (E)-2-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzylidene)hydrazinecarboxamide

[0640] The product was obtained as an off-white solid (0.538 g, 83.41%) through the general procedure of Example 7-4 above.

[0641] 1 H NMR (400 MHz, DMSO) δ8.54 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.69 (t,J= 9.0 Hz, 2H), 7.55 (t,J= 7.9 Hz, 1H), 6.65 (s, 2H); HRMS (EI) m / z calcd for C 12 H 11 F3N5O [M + H] 298.0916, found 298.0910.

[0642]

[0643] 7-7. General procedure for intermediates 6a-6b

[0644] To a solution of 1,4 dioxane (50 mL) containing imine (1.0 eq), Cs2CO3 (3.0 eq) and iodine (3.0 eq) were added at room temperature, and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched with 200 mL of saturated sodium thiosulfate solution and extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in ether, and the resulting solid was separated by suction filtration, washed with 200 mL of diethyl ether, and dried under vacuum to obtain intermediate-6a-6b.

[0645]

[0646] 7-8. Intermediate-6a: 5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0647] The product was obtained as an off-ivory solid (0.331 g, 33.37%) through the general procedure of Example 7-7 above.

[0648] 1 H NMR (400 MHz, DMSO) δ9.33 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.04 (d,J= 8.1 Hz, 1H), 7.81 (d,J= 8.0 Hz, 1H), 7.71 (t,J= 8.0 Hz, 1H), 7.35 (s, 2H); HRMS (EI) m / z calcd for C 12 H9F3N5O [M + H] 296.0759, found 296.0751.

[0649]

[0650] 7-9. Intermediate-6b: 5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0651] The product was obtained as an off-yellow solid (0.237 g, 45.87%) through the general procedure of Example 7-7 above.

[0652] 1 H NMR (400 MHz, DMSO) δ8.53 (s, 2H), 8.04 (s, 1H), 7.82 (t,J=8.9 Hz, 2H), 7.69 (t,J=8.0 Hz, 1H), 7.33 (s, 2H); HRMS (EI) m / z calcd for C 12 H9F3N5O [M + H] 296.0759, found 296.0747.

[0653]

[0654] 7-10. General Procedure for Chemical Formulas 8a-8b

[0655] Acid chloride (0.3 ml, 6 eq) was added to a stirred solution of pyridine (10 mL) containing 5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-amine (0.1 g, 1.0 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with 50 mL of water to obtain a solid precipitate, which was separated by suction filtration, washed with 50 mL of ethanol and then 200 mL of diethyl ether, and dried under vacuum to obtain a compound of chemical formula-8a-b.

[0656]

[0657] 7-11. Formula-8a: 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 46)

[0658] The product was obtained as an off-yellowish solid (0.089 g, 56.18%) through the general procedure of the above Examples 7-10.

[0659] 1 H NMR (400 MHz, DMSO) δ12.64 - 12.53 (m, 1H), 9.39 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.35 (d, J= 7.8 Hz, 1H), 8.30 (s, 1H), 8.18 (d,J= 8.5 Hz, 1H), 8.05 (d,J= 7.3 Hz, 1H), 8.00 (d,J= 7.8 Hz, 1H), 7.84 (d,J= 8.9 Hz, 1H), 7.83 - 7.78 (m, 1H); 13 C NMR (151 MHz, DMSO) δ139.85, 139.07, 132.90, 131.42, 130.40, 129.70, 129.67, 129.22, 125.72, 125.43, 125.17, 125.08, 123.96, 123.36, 122.20, 122.15, 116.80, 114.81, 114.56, 114.31; HRMS (EI) m / z calcd for C 20 H 12 F6N5O2[M + H] 468.0895, found 468.0880.

[0660]

[0661] 7-12. Formula-8b: 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 47)

[0662] The product was obtained as an off-purple solid (0.02 g, 12.62%) through the general procedure of the above Examples 7-10.

[0663] 1H NMR (400 MHz, DMSO) δ12.61 - 12.48 (m, 1H), 8.62 (d,J= 6.1 Hz, 2H), 8.41 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.05 (d,J= 7.8 Hz, 1H), 8.01 (d,J= 8.2 Hz, 2H), 7.82 (dd,J= 14.8, 6.7 Hz, 2H); 13 C NMR (101 MHz, DMSO) δ138.23, 138.12, 137.27, 132.93, 132.29, 131.91, 131.54, 130.66, 130.53, 130.39, 130.33, 129.96, 126.03, 125.41, 125.02, 124.81, 123.63, 120.98, 119.15, 119.07; HRMS (EI) m / z calcd for C 20 H 12 F6N5O2[M + H] 468.0895, found 468.0885.

[0664]

[0665] Example 8. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 8)

[0666] [Reaction Formula 8]

[0667]

[0668] Reagents and conditions: (a) 4-methoxybenzoyl chloride, oil containing 60% NaH, DMF, room temperature, reaction time 1 hour; (b) sodium acetate, EtOH, room temperature, reaction time 2 hours; (c) iodine, Cs2CO3, 75°C, reaction time 2 hours; (d) 3-trifluoromethyl benzoyl chloride, pyridine, room temperature, reaction time 2 hours.

[0669]

[0670] 8-1. Intermediate-2: 1-(4-methoxybenzyl)-1H-indazole-3-carbaldehyde

[0671] To a stirred solution of 1H-indazole-3-carbaldehyde (2 g, 1.0 eq) and oil (0.49 g, 1.5 eq) containing 60% NaH in DMF (40 mL) at room temperature was added 4-methoxybenzoyl chloride, and the reaction mixture was stirred at 60 °C for 16 h under N2 condition. The reaction mixture was extracted with water (40 mL) and EtOAc (3 x 40 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate-2 (3.6 g, 98.82%) as an off-white solid.

[0672] 1 H NMR (400 MHz, cdcl3)δ10.26 (s, 1H), 8.31 (d,J= 8.0 Hz, 1H), 7.42 (d,J= 4.1 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.22 (d,J= 8.5 Hz, 2H), 6.85 (d,J= 8.6 Hz, 2H), 5.62 (s, 2H), 3.77 (s, 3H); HRMS (EI) m / z calcd for C 16 H 15 N2O2[M + H] 267.1134, found 267.1129.

[0673]

[0674] 8-2. Intermediate-3: (Z)-2-((1-(4-methoxybenzyl)-1H-indazol-3-yl)methylene)hydrazinecarboxamide

[0675] To a stirred solution of 1-(4-methoxybenzyl)-1H-indazole-3-carbaldehyde (3.6 g, 1.0 eq) and Semicarbazide (2.26 g, 1.5 eq) in EtOH (80 mL) was added sodium acetate (3.33 g, 3.0 eq) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with diluted water, and after a solid was formed, the solid was filtered with ether (50 mL) and dried under reduced pressure to obtain intermediate-3 (3.16 g, 72.28%) as an off-white solid.

[0676] 1 H NMR (400 MHz, DMSO) δ8.36 (d,J= 8.0 Hz, 1H), 8.19 (s, 1H), 7.73 (d,J= 8.5 Hz, 1H), 7.43 (t,J= 7.4 Hz, 1H), 7.24 - 7.21 (m, 3H), 6.86 (d,J= 8.7 Hz, 2H), 6.43 (s, 2H), 5.58 (s, 2H), 3.69 (s, 3H); HRMS (EI) m / z calcd for C 17 H 18 N5O2[M + H] 324.1460, found 324.1450.

[0677]

[0678] 8-3. Intermediate-4: 5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-amine

[0679] To a stirred solution of 1,4-dioxane (100 mL) containing (Z)-2-((1-(4-methoxybenzyl)-1H-indazol-3-yl)methylene)hydrazinecarboxamide (3.1 g, 1.0 eq) and CS2CO3 (9.37 g, 3.0 eq) was added iodine (7.3 g, 3.0 eq). The reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched with water (100 mL) containing sodium thiosulfate solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was separated by suction filtration with ether and dried under vacuum to obtain intermediate-4 (1.75 g, 56.79%) as an off-yellow solid.

[0680] 1 H NMR (400 MHz, DMSO) δ8.12 (d,J= 8.1 Hz, 1H), 7.87 (d,J= 8.3 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.35 (s, 1H), 7.31 (d,J= 7.7 Hz, 1H), 7.28 (d,J= 8.7 Hz, 2H), 7.26 - 7.23 (m, 1H), 6.88 (d,J= 8.6 Hz, 2H), 5.67 (s, 2H), 3.70 (s, 3H); HRMS (EI) m / z calcd for C 17 H 16 N5O2[M + H] 322.1304, found 322.1295.

[0681]

[0682] 8-4. Intermediate-5:N-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 48)

[0683] To a stirred solution of pyridine (30 mL) containing 5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-amine (1 g, 1.0 eq) was added 3-trifluoromethyl benzoylchloride (1.5 mL, 3.3 eq). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with diluted water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was isolated by suction filtration with ether and dried under vacuum to obtain intermediate-5 (0.52 g, 35.92%) as an off-ivory solid.

[0684] 1 H NMR (400 MHz, DMSO) δ12.58 - 12.52 (m, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.95 (d, J= 8.5 Hz, 1H), 7.84 (d,J= 7.3 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.44 - 7.38 (m, 1H), 7.31 (d,J= 8.5 Hz, 2H), 6.90 (d,J= 8.5 Hz, 2H), 5.75 (s, 2H), 3.70 (s, 3H); 13 C NMR (101 MHz, DMSO) δ166.43, 159.37, 159.27, 157.83, 144.79, 144.64, 143.65, 140.62, 133.69, 133.60, 132.98, 132.35, 130.28, 129.64, 129.51, 129.11, 128.91, 125.44, 121.90, 121.36, 121.24, 114.52, 111.58 -111.39, 55.63 - 55.41, 52.66; HRMS (EI) m / z calcd for C 25 H 19F3N5O3[M + H] 494.1440, found 494.1440.

[0685]

[0686] Example 9. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 9)

[0687] [Reaction Formula 9]

[0688]

[0689] Reagents and conditions: (a) 3-thiopheneboronic acid, PdCl2(dppf)-DCM, C2CO3, DMF:water (8:2), 110°C, 2 h reaction; (b) sodium acetate, EtOH, room temperature, 2 h reaction; (c) iodine, Cs2CO3, 75°C, 2 h reaction; (d) 3-trifluoromethyl benzoyl chloride, pyridine, room temperature, 2 h reaction; (e) BBr3, DCM, room temperature, 4 h reaction; (f) propargyl bromide, CS2CO3, Acetonitrile, room temperature, 3 h reaction.

[0690]

[0691] 9-1. General procedure for intermediates 2a-2c

[0692] To a stirred solution of 3-bromo-methoxy benzaldehyde (1.0 eq) and 3-thiophene boronic acid (1.5 eq) in DMF (30 mL) was added CS2CO3 (3.0 eq). The resulting reaction mixture was purged with argon gas for 3 min, and then Pd(dppf)Cl2.DCM (0.2 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 110 °C for 2 h, cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediates 2a-2c.

[0693]

[0694] 9-2. Intermediate-2a: 4-methoxy-3-(thiophen-3-yl)benzaldehyde

[0695] The product was obtained as an off-yellow liquid (2.20 g, 98.53%) through the general procedure of Example 9-1 above.

[0696] 1 H NMR (400 MHz, CDCl3)δ9.94 (s, 1H), 8.03 (d,J= 2.1 Hz, 1H), 7.82 (dd,J= 8.5, 2.1 Hz, 1H), 7.67 (dd,J= 3.0, 1.3 Hz, 1H), 7.46 (dd,J= 5.0, 1.3 Hz, 1H), 7.38 (dd,J= 5.0, 3.0 Hz, 1H), 7.09 (d,J= 8.5 Hz, 1H), 3.98 (d,J= 5.5 Hz, 3H); HRMS (EI) m / z calcd for C 12 H 11 O2S [M + H] 219.0480, found 219.0475.

[0697]

[0698] 9-3. Intermediate-2b: 3-methoxy-5-(thiophen-3-yl)benzaldehyde

[0699] The product was obtained as an off-pink liquid (2.58 g, 84.73%) through the general procedure of Example 9-1 above.

[0700] 1 H NMR (400 MHz, CDCl3)δ10.02 (s, 1H), 7.68 (s, 1H), 7.54 (dd,J= 2.3, 1.6 Hz, 1H), 7.42 (t,J= 2.1 Hz, 2H), 7.40 - 7.38 (m, 1H), 7.32 (s, 1H), 3.91 (s, 3H); HRMS (EI) m / z calcd for C 12 H 11O2S [M + H] 219.0480, found 219.0427.

[0701]

[0702] 9-4. Intermediate-2c: 2-methoxy-5-(thiophen-3-yl)benzaldehyde

[0703] The product was obtained as an off-orange liquid (2.6 g, 85.39%) through the general procedure of Example 9-1 above.

[0704] 1 H NMR (400 MHz, CDCl3)δ10.51 (s, 1H), 8.06 (d,J= 2.4 Hz, 1H), 7.79 (dd,J= 8.6, 2.4 Hz, 1H), 7.43 (dd,J= 2.6, 1.3 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.04 (d,J= 8.7 Hz, 1H), 3.97 (s, 3H); HRMS (EI) m / z calcd for C 12 H 11 O2S [M + H] 219.0480, found 219.0470.

[0705]

[0706] 9-5. General procedure for intermediates 3a-3c

[0707] To a stirred solution of EtOH containing aldehyde (1.0 eq) and semicarbazide (1.5 eq) was added sodium acetate (3.0 eq) at room temperature. The reaction mixture was then stirred at room temperature for 2 hours and quenched with diluted water. After a solid was formed, the solid was filtered with ether and dried under reduced pressure to obtain intermediate-3a-3c.

[0708]

[0709] 9-6. Intermediate-3a: (E)-2-(4-methoxy-3-(thiophen-3-yl)benzylidene)hydrazinecarboxamide

[0710] The product was obtained as an off-white solid (1.58 g, 56.93%) through the general procedure of Example 9-5 above.

[0711] 1 H NMR (400 MHz, DMSO) δ7.89 (d,J= 2.0 Hz, 1H), 7.82 (t,J= 2.0 Hz, 1H), 7.79 (s, 1H), 7.55 (dd,J= 9.9, 2.0 Hz, 3H), 7.08 (d,J= 8.6 Hz, 1H), 6.46 (s, 2H), 3.84 (s, 3H); HRMS (EI) m / z calcd for C 13 H 14 N3O2S [M + H] 276.0807, found 276.0801.

[0712]

[0713] 9-7. Intermediate-3b: (E)-2-(3-methoxy-5-(thiophen-3-yl)benzylidene)hydrazinecarboxamide

[0714] The product was obtained as an off-pink solid (3.01 g, 93.6%) through the general procedure of Example 9-5 above.

[0715] 1 H NMR (400 MHz, DMSO) δ8.00 (dd,J= 2.7, 1.3 Hz, 1H), 7.84 (s, 1H), 7.66 (dd,J= 5.0, 1.3 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.63 (s, 1H), 7.26 - 7.23 (m, 2H), 6.63 (s, 2H), 3.85 (s, 3H); HRMS (EI) m / z calcd for C 13 H 14 N3O2S [M + H] 276.0807, found 276.0797.

[0716]

[0717] 9-8. Intermediate-3c: (E)-2-(2-methoxy-5-(thiophen-3-yl)benzylidene)hydrazinecarboxamide

[0718] The product was obtained as an off-pink solid (3.27 g, 99.72%) through the general procedure of Example 9-5 above.

[0719] 1 H NMR (400 MHz, DMSO) δ8.28 (d,J= 2.3 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.70 (dd,J= 8.6, 2.3 Hz, 1H), 7.65 (d,J= 4.8 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.09 (d,J= 8.7 Hz, 1H), 6.59 (s, 2H), 3.85 (s, 3H); HRMS (EI) m / z calcd for C 13 H 14 N3O2S [M + H] 276.0807, found 276.0800.

[0720]

[0721] 9-9. General procedure for intermediates 4a-4c

[0722] Iodine (3.0 eq) was added to a stirred solution of 1,4-dioxane containing imine (1.0 eq) and CS2CO3 (3.0 eq). The reaction mixture was then stirred at 75°C for 2 h. The reaction mixture was quenched with water containing sodium thiosulfate solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was separated by suction filtration with ether and dried under vacuum to obtain intermediate-4a-4c.

[0723]

[0724] 9-10. Intermediate-4a: 5-(4-methoxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0725] The product was obtained as an off-white solid (0.28 g, 17.85%) through the general procedure of Example 9-9 above.

[0726] 1 H NMR (400 MHz, DMSO) δ7.88 (d,J= 2.1 Hz, 1H), 7.85 (d,J= 1.8 Hz, 1H), 7.73 (dd,J= 8.6, 2.2 Hz, 1H), 7.61 (dd,J= 5.0, 3.0 Hz, 1H), 7.47 (d,J= 4.0 Hz, 1H), 7.27 (d,J= 8.7 Hz, 1H), 7.16 (s, 2H), 3.89 (d,J= 13.7 Hz, 3H); HRMS (EI) m / z calcd for C 13 H 12 N3O2S [M + H] 274.0650, found 274.0640.

[0727]

[0728] 9-11. Intermediate-4b: 5-(3-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0729] The product was obtained as an off-yellow solid (0.9 g, 30.21%) through the general procedure of Example 9-9 above.

[0730] 1 H NMR (400 MHz, DMSO) δ8.01 (dd,J= 2.8, 1.2 Hz, 1H), 7.68 (dd,J= 5.0, 2.9 Hz, 1H), 7.66 (s, 1H), 7.60 (dd,J= 5.0, 1.2 Hz, 1H), 7.41 (d,J= 1.9 Hz, 1H), 7.30 (s, 2H), 7.22 (s, 1H), 3.88 (s, 3H); HRMS (EI) m / z calcd for C 13 H12 N3O2S [M + H] 274.0650, found 274.0640.

[0731]

[0732] 9-12. Intermediate-4c: 5-(2-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0733] The product was obtained as an off-white solid (0.161 g, 12.10%) through the general procedure of Example 9-9 above.

[0734] 1 H NMR (400 MHz, DMSO) δ7.95 (d,J= 2.3 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.54 (d,J= 3.9 Hz, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 7.19 (s, 2H), 3.88 (s, 3H); HRMS (EI) m / z calcd for C 13 H 12 N3O2S [M + H] 274.0650, found 274.0639.

[0735]

[0736] 9-13. General procedure for chemical formulas 5a-5c

[0737] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethyl benzoylchloride (4.0 eq). The reaction mixture was then stirred at room temperature for 2 h, quenched with diluted water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was separated by suction filtration with ether and dried under vacuum to obtain compounds of formula 5a-5c.

[0738]

[0739] 9-14. Formula-5a:N-(5-(4-methoxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 49)

[0740] The product was obtained as an off-white solid (0.13 g, 57.00%) through the general procedure of the above Examples 9-13.

[0741] 1 H NMR (400 MHz, DMSO) δ12.37 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.02 (s, 2H), 7.89 (dd,J= 8.7, 2.2 Hz, 1H), 7.87 (s, 1H), 7.80 (t,J= 7.7 Hz, 1H), 7.61 (dd,J= 5.0, 3.0 Hz, 1H), 7.48 (d,J= 4.6 Hz, 1H), 7.33 (d,J= 8.7 Hz, 1H), 3.92 (s, 3H); 13 C NMR (151 MHz, DMSO) δ159.13, 136.97, 132.91, 130.44, 130.39, 129.86, 129.65, 128.63, 127.48, 127.23, 126.13, 125.65, 125.44, 125.40, 125.20, 124.91, 123.39, 116.14, 113.15, 113.12, 56.47; HRMS (EI) m / z calcd for C 21 H 15 F3N3O3S [M + H] 446.0786, found 446.0700.

[0742]

[0743] 9-15. Formula-5b:N-(5-(3-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 50)

[0744] The product was obtained as an off-ivory solid (0.72 g, 73.48%) through the general procedure of the above Examples 9-13.

[0745] 1 H NMR (400 MHz, DMSO) δ12.50 (s, 1H), 8.42 (s, 1H), 8.35 (d,J= 7.5 Hz, 1H), 8.08 (d,J= 5.7 Hz, 1H), 8.06 (d,J= 8.2 Hz, 1H), 7.84 (s, 2H), 7.70 (d,J= 2.9 Hz, 1H), 7.66 (d,J= 4.9 Hz, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 3.93 (s, 3H); 13 C NMR (151 MHz, DMSO) δ183.75, 170.76, 160.57, 160.16, 140.91, 137.90, 137.10, 132.90, 132.50, 127.73, 127.69, 126.68, 126.60, 125.51, 122.73, 119.70, 116.51, 115.85, 115.04, 113.10, 109.32, 55.82; HRMS (EI) m / z calcd for C 21 H 15 F3N3O3S [M + H] 446.0786, found 446.0780.

[0746]

[0747] 9-16. Formula-5c:N-(5-(2-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 51)

[0748] The product was obtained as an off-white solid (0.076 g, 31.08%) through the general procedure of the above Examples 9-13.

[0749] 1H NMR (400 MHz, DMSO) δ12.39 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.97 (d, J= 6.7 Hz, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.68 - 7.64 (m, 1H), 7.58 (d,J= 4.8 Hz, 1H), 7.33 (d,J= 8.8 Hz, 1H), 3.94 (s, 3H); 13 C NMR (101 MHz, DMSO) δ158.48, 156.93, 146.94, 140.31, 134.22, 132.94, 131.51, 131.32, 130.47, 130.35, 129.96, 129.61, 128.57, 127.85, 127.71 - 127.60, 126.49 - 126.25, 125.49, 121.05 - 120.83, 113.69 - 113.53, 112.96, 56.59; HRMS (EI) m / z calcd for C 21 H 15 F3N3O3S [M + H] 446.0786, found 446.0776.

[0750]

[0751] 9-17. General procedure for chemical formulas 6a-6c

[0752] To a stirred solution of methoxy (1.0 eq) in DCM was added BBr3 (17% in DCM) (2.0 eq). The reaction mixture was then stirred at room temperature for 4 h under a N2 atmosphere. The reaction mixture was quenched with MeOH and evaporated under reduced pressure to obtain the crude product. The crude product was separated by suction filtration with ether and dried under vacuum to obtain compounds of formula 6a-6c.

[0753]

[0754] 9-18. Formula-6a:N-(5-(4-hydroxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 52)

[0755] The product was obtained as an off-brown solid (0.104 g, 82.56%) through the general procedure of Example 9-17 above.

[0756] 1 H NMR (400 MHz, DMSO) δ8.58 (d,J= 1.9 Hz, 1H), 8.39 (s, 1H), 8.33 (d,J= 7.8 Hz, 1H), 8.21 (d,J= 4.9 Hz, 1H), 8.11 (d,J= 4.7 Hz, 1H), 8.03 (d,J= 7.5 Hz, 1H), 7.94 (d,J= 6.8 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.58 (d,J= 3.0 Hz, 1H), 7.53 (d,J= 8.6 Hz, 1H); 13 C NMR (101 MHz, DMSO) δ167.59, 167.10, 166.81, 166.44, 165.60, 158.88, 158.08, 153.93, 137.97, 137.82, 135.54, 133.65, 129.70, 127.94, 123.46, 122.67, 122.14, 117.22, 116.67, 115.75; HRMS (EI) m / z calcd for C 20 H 13 F3N3O3S [M + H] 432.0630.

[0757]

[0758] 9-19. Formula-6b:N-(5-(3-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 53)

[0759] The product was obtained as an off-white solid (0.376 g, 64.56%) through the general procedure of the above Example 9-17.

[0760] 1 H NMR (400 MHz, DMSO) δ8.41 (s, 1H), 8.34 (d,J= 8.0 Hz, 1H), 8.05 (d,J= 7.0 Hz, 1H), 7.97 (s, 1H), 7.83 (t,J= 7.6 Hz, 1H), 7.70 - 7.67 (m, 2H), 7.56 (d,J= 3.9 Hz, 1H), 7.32 (s, 2H), 3.17 (s, 1H); 13 C NMR (151 MHz, DMSO) δ166.24, 165.10, 160.79, 158.89, 158.50, 158.46, 140.68, 138.09, 134.10, 132.93, 130.48, 129.64, 127.95, 126.49, 125.40, 125.18, 122.65, 116.92, 114.95, 111.72; HRMS (EI) m / z calcd for C 20 H 13 F3N3O3S [M + H] 432.0630, found 432.0630.

[0761]

[0762] 9-20. Formula-6c:N-(5-(2-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 54)

[0763] The product was obtained as an off-ivory solid (0.049 g, 84.14%) through the general procedure of Example 9-17 above.

[0764] 1H NMR (400 MHz, DMSO)δ10.48 - 10.33 (m, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.05 (d,J= 7.7 Hz, 1H), 8.01 (s, 1H), 7.82 (d,J= 8.5 Hz, 3H), 7.65 (d,J= 4.8 Hz, 1H), 7.52 (d,J= 4.9 Hz, 1H), 7.14 (d,J= 8.6 Hz, 1H); 13 C NMR (151 MHz, DMSO)δ155.82, 140.62, 132.94, 131.54, 130.45, 129.88, 129.73, 129.66, 127.70, 127.58, 126.41, 126.37, 126.32, 125.44, 125.41, 125.19, 123.39, 120.46, 118.02, 110.52; HRMS (EI) m / z calcd for C 20 H 13 F3N3O3S [M + H] 432.0630, found 432.0620.

[0765]

[0766] 9-21. 화학식-7:N-(5-(3-(prop-2-yn-1-yloxy)-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (화합물 55)

[0767] The reaction was carried out using a solution of N-(5-(3-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (0.2 g, 1.0 eq) and CS2CO3 (0.45 g, 3.0 eq) in ACN (40 mL). Subsequently, propargyl bromide (0.12 mL, 2.0 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 h and filtered with EtOAc (10 mL). The mixture was evaporated under reduced pressure to obtain the crude product, which was purified by PTLC to obtain the compound of formula 7 (0.015 g, 6.89%) as an off-white solid.

[0768] 1 H NMR (400 MHz, DMSO) δ8.39 (s, 1H), 8.35 (d,J= 7.8 Hz, 1H), 8.03 (d,J= 1.5 Hz, 1H), 7.77 (s, 1H), 7.73 (d,J= 7.7 Hz, 1H), 7.64 - 7.61 (m, 2H), 7.59 (d,J= 7.6 Hz, 1H), 7.40 (d,J= 13.0 Hz, 2H), 4.97 (d,J= 2.2 Hz, 2H), 3.63 (t,J= 2.2 Hz, 1H); 13 C NMR (101 MHz, DMSO) δ168.72, 158.51, 157.23, 140.60, 137.86, 132.81, 129.18, 128.83, 128.06, 127.54, 126.95, 126.87, 126.39, 126.12, 125.52, 123.41, 122.97, 122.65, 116.64, 116.20, 79.30, 78.88, 56.21; HRMS (EI) m / z calcd for C 23 H 15 F3N3O3S [M + H] 470.0786, found 470.0783.

[0769]

[0770] Example 10. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 10)

[0771] [Reaction Formula 10]

[0772]

[0773] Reagents and conditions: (a) Benzyl bromide, CS2CO3, DMF, room temperature, reaction time 1 hour; (b) (3-formylphenyl)boronic acid, Pdcl2(dppf)dcm, CS2CO3, dioxane:water (8:2), 100°C, reaction time 2 hours; (c) Na(CH3CO2)3BH, dimethylamine, DCM, room temperature, reaction time 12 hours; (d) Hydrazine, EtOH, 80°C, reaction time 2 hours; (e) Cyanic bromide, MeOH, 60°C, reaction time 3 hours; (f) 3-trifluoromethyl benzoyl chloride, pyridine, room temperature, reaction time 2 hours.

[0774]

[0775] 10-1. Intermediate-2: benzyl 3-bromobenzoate

[0776] To a stirred solution of 3-bromobenzoic acid (7 g, 1.0 eq) and Cs2CO3 (22.69 g, 2.0 eq) in DMF (80 mL) was added benzyl bromide (4.14 mL, 1.0 eq). The reaction mixture was stirred at room temperature for 12 h and filtered with EtOAc (10 mL). The mixture was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate-2 (7.63 g, 75.26%) as an off-colorless liquid.

[0777] 1H NMR (400 MHz, cdcl3) δ8.20 (t,J= 1.6 Hz, 1H), 8.02 - 7.99 (m, 1H), 7.68 (ddd,J= 8.0, 2.0, 1.0 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 (s, 1H), 7.38 (dd,J= 3.6, 1.7 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.31 (d,J= 7.9 Hz, 1H), 5.36 (s, 2H); HRMS (EI) m / z calcd for C 14 H 12 BrO2[M + H] 291.0021, was not observed.

[0778]

[0779] 10-2. General procedure for intermediates 3a-3b

[0780] CS2CO3 (3.0 eq) was added to a stirred solution of dioxane containing benzyl 3-bromobenzoate (1.0 eq) and boronic acid (1.5 eq). The resulting reaction mixture was purged with argon gas for 3 minutes, and then Pd(dppf)Cl 2· DCM (0.05 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 110 °C for 2 h, cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediates 3a-3c.

[0781]

[0782] 10-3. Intermediate-3a: benzyl 3'-formyl-[1,1'-biphenyl]-3-carboxylate

[0783] The product was obtained as an off-color-less liquid (2.38 g, 73.04%) through the general procedure of Example 10-2 above.

[0784] 1 H NMR (400 MHz, CDCl3)δ10.11 (d,J= 5.6 Hz, 1H), 8.33 (d,J= 1.6 Hz, 1H), 8.13 - 8.09 (m, 2H), 7.91 - 7.87 (m, 2H), 7.84 - 7.81 (m, 1H), 7.64 (t,J= 7.7 Hz, 1H), 7.56 (t,J= 7.7 Hz, 1H), 7.47 (d,J= 6.7 Hz, 2H), 7.41 (dd,J= 11.4, 4.4 Hz, 2H), 7.38 - 7.35 (m, 1H), 5.41 (s, 2H); HRMS (EI) m / z calcd for C 21 H 17 O3[M + H] 317.1178, found 317.1170.

[0785]

[0786] 10-4. Intermediate-3b: benzyl 3-(5-formylthiophen-2-yl)benzoate

[0787] The product was obtained as an off-yellow solid (1.455 g, 40.21%) through the general procedure of Example 10-2 above.

[0788] 1 H NMR (400 MHz, CDCl3) δ9.91 (s, 1H), 8.37 (t,J= 1.5 Hz, 1H), 8.09 (dd,J= 6.5, 1.3 Hz, 1H), 7.85 (ddd,J= 7.8, 1.9, 1.1 Hz, 1H), 7.76 (d,J= 3.9 Hz, 1H), 7.52 (t,J= 7.8 Hz, 1H), 7.47 (d,J= 4.0 Hz, 3H), 7.44 - 7.35 (m, 3H), 5.41 (s, 2H).

[0789]

[0790] 10-5. General Procedure for Intermediate-4a-4b

[0791] To a stirred solution of carboxylate (1.0 eq) in DCM was added 17% dimethylamine in DCM at room temperature, and the reaction mixture was stirred at ambient temperature for 1 h. Then, Na(CH3CO2)3BH (3.0 eq) was added to the reaction mixture, and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with 50 mL of sodium bicarbonate solution, extracted with DCM (3 x 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with MeOH / DCM to give intermediate-4a-4b.

[0792]

[0793] 10-6. Intermediate-4a: benzyl 3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-carboxylate

[0794] The product was obtained as an off color less liquid (1.843 g, 73.39%) through the general procedure of Example 10-5 above.

[0795] 1 H NMR (400 MHz, DMSO) δ8.20 (s, 1H), 8.00 (d,J= 8.0 Hz, 1H), 7.96 (d,J= 8.5 Hz, 1H), 7.64 (t,J= 7.8 Hz, 1H), 7.58 (d,J= 8.2 Hz, 2H), 7.49 (t,J= 6.9 Hz, 2H), 7.44 (d,J= 6.7 Hz, 1H), 7.41 (d,J= 7.4 Hz, 1H), 7.37 (d,J= 7.1 Hz, 1H), 7.33 (d,J= 7.4 Hz, 2H), 5.40 (s, 2H), 3.47 (s, 2H), 2.18 (s, 6H); HRMS (EI) m / z calcd for C 23 H 24 NO2[M + H] 346.1807, found 346.1803.

[0796]

[0797] 10-7. Intermediate-4b: benzyl 3-(5-((dimethylamino)methyl)thiophen-2-yl)benzoate

[0798] The product was obtained as an off color less liquid (1.33 g, 95.08%) through the general procedure of Example 10-5 above.

[0799] 1 H NMR (400 MHz, DMSO) δ8.13 (d,J= 1.6 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.57 (t,J= 7.8 Hz, 1H), 7.49 (d,J= 6.9 Hz, 2H), 7.44 (d,J= 2.6 Hz, 1H), 7.43 (d,J= 6.8 Hz, 1H), 7.40 (s, 1H), 7.37 (d,J= 7.1 Hz, 1H), 6.98 (d,J= 3.6 Hz, 1H), 5.39 (s, 2H), 3.61 (s, 2H), 2.20 (s, 6H).

[0800]

[0801] 10-8. General Procedure for Intermediate-5a-5b

[0802] To a stirred solution of EtOH containing carboxylate (1.0 eq) was added hydrazine (15.34 eq) at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was evaporated under reduced pressure to remove EtOH. Water was added to the mixture to form a solid, and the resulting precipitate was separated by suction filtration using hexane and dried under vacuum to obtain intermediate-5a-5b without further purification.

[0803]

[0804] 10-9. Intermediate-5a: 3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-carbohydrazide

[0805] The product was obtained as an off-white solid (1.33 g, 95.08%) through the general procedure of Example 10-8 above.

[0806] 1 H NMR (400 MHz, DMSO) δ8.10 (s, 1H), 7.81 (d,J= 7.7 Hz, 2H), 7.65 (s, 1H), 7.62 (d,J= 7.8 Hz, 1H), 7.54 (t,J= 7.7 Hz, 1H), 7.44 (t,J= 7.6 Hz, 1H), 7.32 (d,J= 4.6 Hz, 2H), 3.47 (s, 2H), 2.18 (s, 6H), 1.82 (s, 2H); HRMS (EI) m / z calcd for C 16 H 20 N3O [M + H] 270.1606, found 270.1596.

[0807]

[0808] 10-10. Intermediate-5b: 3-(5-((dimethylamino)methyl)thiophen-2-yl)benzohydrazide

[0809] The product was obtained as an off-white solid (1.01 g, 99.16%) through the general procedure of Example 10-8 above.

[0810] 1 H NMR (400 MHz, DMSO) δ9.88 (s, 2H), 8.02 (s, 1H), 7.71 (t,J= 8.5 Hz, 2H), 7.45 (t,J= 7.8 Hz, 1H), 7.39 (d,J= 3.6 Hz, 1H), 7.29 (d,J= 4.8 Hz, 1H), 6.95 (d,J= 3.3 Hz, 1H), 3.58 (s, 2H), 2.18 (s, 6H).

[0811]

[0812] 10-11. General procedure for intermediates 6a-6b

[0813] To a stirred solution of MeOH containing 3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-carbohydrazide (1.0 eq) was added cyanic bromide (1.2 eq) at room temperature, and the reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was evaporated under reduction to remove MeOH, and purified by silica gel column chromatography to obtain intermediate-6a-6b.

[0814]

[0815] 10-12. Intermediate-6a: 5-(3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-amine

[0816] The product was obtained as an off-ivory semi-solid through the general procedure of Examples 10-11 above.

[0817] 1 H NMR (400 MHz, DMSO) δ9.69 - 9.59 (m, 2H), 8.10 (s, 1H), 7.90 (s, 1H), 7.83 (d,J= 7.8 Hz, 1H), 7.79 (d,J= 8.6 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.62 - 7.57 (m, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.32 (s, 1H), 4.36 (s, 2H), 2.77 (s, 6H); HRMS (EI) m / z calcd for C 17 H 19 N4O [M + H] 295.1559, found 295.1551.

[0818]

[0819] 10-13. Intermediate-6b: 5-(3-(5-((dimethylamino)methyl)thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0820] The product was obtained as an off-yellow solid through the general procedure of Examples 10-11 above.

[0821] 1 H NMR (400 MHz, DMSO) δ8.01 (s, 1H), 7.84 (d,J= 7.8 Hz, 1H), 7.76 (d,J= 7.7 Hz, 1H), 7.62 (s, 1H), 7.38 (d,J= 3.7 Hz, 1H), 7.35 (s, 2H), 7.12 (s, 1H), 4.58 (s, 2H), 2.80 (s, 6H).

[0822]

[0823] 10-14. General Procedure for Chemical Formulas 7a-7b

[0824] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethyl benzoylchloride (4.0 eq). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with diluted water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds of formula 7a-7b.

[0825]

[0826] 10-15. Formula-7a: N-(5-(3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 56)

[0827] The product was obtained as an off-yellow solid (0.23 g, 14.51%) through the general procedure of Examples 10-14 above.

[0828] 1H NMR (400 MHz, cd3od) δ8.59 (s, 1H), 8.53 (d, J = 7.5 Hz, 1H), 8.16 (s, 1H), 7.89 (d, J = 6.5 Hz, 1H), 7.71 (s, 2H), 7.59 (s, 2H), 7.51 (s, 2H), 7.41 (s, 1H), 7.33 (d, J = 6.6 Hz, 1H), 3.63 (s, 2H), 2.33 (s, 6H);; HRMS (EI) m / z calcd for C 25 H 22 F3N4O2[M + H] 467.1695, found 467.1697.

[0829]

[0830] 10-16. Formula-7b:N-(5-(3-(5-((dimethylamino)methyl)thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 57)

[0831] The product was obtained as an off-brown solid (0.033 g, 6.18%) through the general procedure of Examples 10-14 above.

[0832] 1 H NMR (400 MHz, DMSO) δ8.43 (s, 2H), 8.15 - 8.00 (m, 2H), 7.86 (s, 3H), 7.78 - 7.70 (m, 1H), 7.66 - 7.50 (m, 2H), 7.09 (s, 1H), 3.80 (s, 2H), 2.32 (s, 6H).

[0833]

[0834] Example 11. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 11)

[0835] [Reaction Formula 11]

[0836]

[0837] Reagents and conditions: (a) NH2OH.HCl, NaOAc, methanol, room temperature, reaction time 6 hours; (b) NCS, acetonitrile, room temperature, reaction time 1 hour; methyl propiolate, Et3N, methanol, room temperature, reaction time 6 hours (c) Cs2CO3, PdCl2(dppf).DCM, dioxane, water, 100°C, reaction time 2 hours, MW; (e) 50% T3P DIPEA, THF, room temperature, reaction time 12 hours.

[0838]

[0839] 11-1. Intermediate-2: (E)-3-bromobenzaldehyde oxime

[0840] To a stirred solution of 3-bromobenzaldehyde (2 g, 1.0 eq) and NaOAc (1.77 g, 2.0 eq) in MeOH (50 mL) was added NH2OH-HCl (1.5 g, 2.0 eq) at room temperature. The reaction mixture was then stirred at room temperature for 12 h and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate-2 as an off-white solid (1.5 g, 69.44%), which was used without further purification.

[0841] 1 H NMR (400 MHz, cdcl3) δ8.09 (s, 1H), 7.74 (t,J= 1.6 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.25 (q,J= 8.0 Hz, 2H).

[0842]

[0843] 11-2. Intermediate-3: methyl 3-(3-bromophenyl)isoxazole-5-carboxylate

[0844] To a stirred solution of ACN (80 mL) containing (E)-3-bromobenzaldehyde oxime (2.5 g, 1.0 eq), Et3N (5.26 mL, 3.0 eq), and NCS (1.66 mL, 1.5 eq) was added methyl propiolate (1.52 mL, 1.5 eq) at room temperature. The reaction mixture was then stirred at 60 °C for 3 h. The reaction mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified with MPCL (0-10% ETOAc / hexane) as a solvent to obtain intermediate-3 (1.4 g, 66.30%).

[0845] 1 H NMR (400 MHz, cdcl3) δ8.00 (s, 1H), 7.76 (t,J= 6.4 Hz, 1H), 7.62 (d,J= 7.1 Hz, 1H), 7.36 (dd,J= 14.6, 6.7 Hz, 1H), 7.26 (s, 1H), 4.01 (s, 19H).

[0846]

[0847] 11-3. General procedure for intermediates 6a-6b

[0848] To a stirred solution of 1,4-dioxane containing methyl 3-(3-bromophenyl)isoxazole-5-carboxylate (1.0 eq) and 2-boronic acid (1.5 eq), K2CO3 (3.0 eq) was added to water (20 mL). The resulting reaction mixture was purged with argon gas for 3 minutes, and then Pd(dppf)Cl 2·DCM (0.33 g, 0.2 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 100 °C for 12 h, cooled to room temperature, diluted with EtOAc (20 mL), filtered through Celite, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (30% EtOAc / hexane) to obtain intermediate-6a-6b.

[0849]

[0850] 11-4. Intermediate-6a: 3-(3-(thiophen-2-yl)phenyl)isoxazole-5-carboxylic acid

[0851] The product was obtained as an off-white solid (0.55 g, 60.41%) through the general procedure of Example 11-3 above.

[0852] 1 H NMR (400 MHz, dmso) δ8.23 (s, 1H), 7.94 (s, 1H), 7.90 (d,J= 7.7 Hz, 1H), 7.81 (d,J= 7.6 Hz, 1H), 7.71 (d,J= 3.5 Hz, 1H), 7.63 (d,J= 5.0 Hz, 1H), 7.58 (t,J= 7.7 Hz, 1H), 7.19 (t,J= 4.3 Hz, 1H).

[0853]

[0854] 11-5. Intermediate-6b: 3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxylic acid

[0855] The product was obtained as an off-white solid (0.35 g, 38%) through the general procedure of Example 11-3 above.

[0856] 1H NMR (400 MHz, cdcl3) δ8.09 (s, 1H), 7.72 (d,J= 6.5 Hz, 2H), 7.53 (d,J= 8.8 Hz, 3H), 7.44 (s, 2H), 7.38 (s, 1H).

[0857]

[0858] 11-6. General procedure for chemical formulas 8c-8f

[0859] To a stirred solution of THF (30 mL) containing acid (5a-5b 1.0 eq), amine (1.2 eq), and DIPEA (3.0 eq) was added EtOAc (2.0 eq) containing 50% T3P at room temperature, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by MPLC (0-15% ETOAc / hexane) as a solvent to obtain the compound.

[0860]

[0861] 11-7. Compound-8ac: 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 58)

[0862] The product was obtained as an off-white solid (0.078 g, 49.3%) through the general procedure of Example 11-6 above.

[0863] 1 H NMR (400 MHz, cdcl3) δ8.33 (s, 1H), 8.09 (s, 1H), 7.75 (d,J= 8.4 Hz, 3H), 7.53 (t,J= 7.9 Hz, 2H), 7.47 - 7.39 (m, 3H), 7.35 (d,J= 5.1 Hz, 1H), 7.16 - 7.06 (m, 2H).

[0864]

[0865] 11-8. Chemical formula - 8ad: N-phenyl-3-(3-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 59)

[0866] The product was obtained as an off-white solid (0.031 g, 21.3%) through the general procedure of Example 11-6 above.

[0867] 1 H NMR (400 MHz, cdcl3) δ8.71 (s, 1H), 8.14 (s, 1H), 8.09 (d,J= 8.0 Hz, 1H), 8.01 (s, 1H), 7.85 (d,J= 7.8 Hz, 1H), 7.81 (s, 1H), 7.74 (dt,J= 10.2, 2.1 Hz, 2H), 7.67 (dd,J= 9.5, 6.2 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.21 (dd,J= 8.3, 2.3 Hz, 1H).

[0868]

[0869] 11-9. Chemical Formula-8ae: 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 61)

[0870] The product was obtained as an off-white solid (0.03 g, 21.2%) through the general procedure of Example 11-6 above.

[0871] 1 H NMR (400 MHz, cd3od) δ8.19 (d,J= 8.4 Hz, 2H), 7.99 (d,J= 8.6 Hz, 1H), 7.81 (dd,J= 14.0, 7.7 Hz, 2H), 7.63 (s, 1H), 7.62 - 7.42 (m, 5H), 7.17 - 7.11 (m, 1H).

[0872]

[0873] 11-10. Chemical formula-8ag: 3-(3-(thiophen-2-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 60)

[0874] The product was obtained as an off-white solid (0.064 g, 40.30%) through the general procedure of Example 11-6 above.

[0875] 1 H NMR (400 MHz, cdcl3) δ8.30 (s, 1H), 8.09 (s, 1H), 7.74 (dd,J= 7.9, 4.8 Hz, 4H), 7.52 (t,J= 7.5 Hz, 1H), 7.41 (d,J= 3.9 Hz, 2H), 7.35 (d,J= 5.0 Hz, 1H), 7.28 (d, 2H), 7.13 (t,J= 4.7 Hz, 1H).

[0876]

[0877] 11-11. Chemical formula-8be: 3-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 62)

[0878] The product was obtained as an off-white solid (0.03 g, 21.2%) through the general procedure of Example 11-6 above.

[0879] 1 H NMR (400 MHz, cdcl3) δ8.37 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.88 (d,J= 8.2 Hz, 1H), 7.75 (t,J= 6.5 Hz, 2H), 7.58 - 7.51 (m, 3H), 7.46 (dd,J= 21.5, 12.1 Hz, 4H).

[0880]

[0881] 11-12. Chemical formula-8bf: N-(3-fluorophenyl)-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 63)

[0882] The product was obtained as an off-white solid (0.025 g, 19.8%) through the general procedure of Example 11-6 above.

[0883] 1 H NMR (400 MHz, cdcl3) δ8.30 (s, 1H), 8.09 (s, 1H), 7.74 (t,J= 6.8 Hz, 2H), 7.67 (d,J= 10.9 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.45 (s, 2H), 7.40 (s, 1H), 7.34 (dd,J= 18.3, 7.9 Hz, 2H), 6.93 (t,J= 8.1 Hz, 1H).

[0884]

[0885] 11-13. Chemical formula-8bd: N-phenyl-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (compound 64)

[0886] The product was obtained as an off-white solid (0.03 g, 24.2%) through the general procedure of Example 11-6 above.

[0887] 1 H NMR (400 MHz, cdcl3) δ8.26 (s, 1H), 8.10 (s, 1H), 7.78 - 7.66 (m, 3H), 7.57 - 7.50 (m, 2H), 7.41 (dd,J= 16.5, 8.6 Hz, 4H), 7.22 (d,J= 7.4 Hz, 1H).

[0888]

[0889] Example 12. Synthesis of different types of oxydiazole derivatives (Scheme 12)

[0890] [Reaction Formula 12]

[0891]

[0892] Reagents and conditions: (a) NH2OH.HCl, NaOAc, methanol, room temperature, reaction time 6 hours; (b) NCS, acetonitrile, room temperature, reaction time 1 hour; methyl propiolate, Et3N, methanol, room temperature, reaction time 6 hours; (c) Cs2CO3, PdCl2(dppf).DCM, dioxane, water, 100°C, reaction time 2 hours, MW; (e) 50% T3P DIPEA, THF, room temperature, reaction time 12 hours.

[0893]

[0894] 12-1. Intermediate-2: (E)-6-bromopicolinaldehyde oxime

[0895] The product was obtained as an off-white solid (2.6 g, 100%) using the above reagents and conditions and was used without further purification.

[0896] 1 H NMR (400 MHz, cdcl3) δ8.19 (s, 1H), 7.74 (d,J= 7.7 Hz, 1H), 7.57 (t,J= 7.7 Hz, 1H), 7.48 (d,J= 7.8 Hz, 1H), 7.26 (s, 1H).

[0897]

[0898] 12-2. Intermediate-3: methyl 3-(6-bromopyridin-2-yl)isoxazole-5-carboxylate

[0899] The product was obtained as an off-white solid (0.8 g, 22.8%) using the above reagents and conditions.

[0900] 1 H NMR (400 MHz, cdcl3) δ8.10 (d,J= 7.6 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 7.62 - 7.55 (m, 2H), 4.01 (s, 3H).

[0901]

[0902] 12-3. Intermediate-6: 3-(6-(thiophen-2-yl)pyridin-2-yl)isoxazole-5-carboxylic acid

[0903] The product was obtained as an off-white solid (0.19 g, 60.41%) using the above reagents and conditions.

[0904] 1 H NMR (400 MHz, dmso) δ8.09 - 7.99 (m, 2H), 7.94 (d,J= 6.7 Hz, 2H), 7.72 (d,J= 5.6 Hz, 1H), 7.50 (s, 1H), 7.23 - 7.19 (m, 1H).

[0905]

[0906] 12-4. Chemical Formula 8a: 3-(6-(thiophen-2-yl)pyridin-2-yl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 65)

[0907] The product was obtained as an off-white solid (0.035 g, 28.6%) using the above reagents and conditions.

[0908] 1 H NMR (400 MHz, cdcl3) δ8.31 (s, 1H), 7.97 (d,J= 7.6 Hz, 1H), 7.82 (dd,J= 14.8, 6.9 Hz, 2H), 7.74 (d,J= 8.3 Hz, 2H), 7.67 (d,J= 3.7 Hz, 1H), 7.56 (d,J= 8.6 Hz, 1H), 7.44 (dd,J= 13.6, 6.3 Hz, 2H), 7.15 (t,J= 4.3 Hz, 1H), 7.09 (d,J= 8.5 Hz, 1H).

[0909]

[0910] 12-5. Chemical Formula-8b: N-phenyl-3-(6-(thiophen-2-yl)pyridin-2-yl)isoxazole-5-carboxamide (Compound 66)

[0911] The product was obtained as an off-white solid (0.025 g, 25.3%) using the above reagents and conditions.

[0912] 1 H NMR (400 MHz, cdcl3) δ8.25 (s, 1H), 7.97 (d,J= 7.6 Hz, 1H), 7.83 (t,J= 7.8 Hz, 1H), 7.78 (s, 1H), 7.76 - 7.65 (m, 4H), 7.43 (dd,J= 16.2, 6.5 Hz, 3H), 7.22 (d,J= 7.1 Hz, 1H), 7.17 - 7.13 (m, 1H).

[0913]

[0914] Example 13. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 13)

[0915] [Reaction Formula 13]

[0916]

[0917]

[0918] Reagents and conditions: (a) NH2OH.HCl, NaOAc, methanol, room temperature, reaction time 6 hours; (b) NCS, acetonitrile, room temperature, reaction time 1 hour; methyl propiolate, Et3N, methanol, room temperature, reaction time 6 hours; (c) Cs2CO3, PdCl2(dppf).DCM, dioxane, water, 100°C, reaction time 2 hours, MW; (d) LiOH, THF:water (9:1), room temperature, reaction time 6 hours; (e) 50% T3P DIPEA, THF, room temperature, reaction time 12 hours.

[0919]

[0920] 13-1. Intermediate-78: (E)-4-bromobenzaldehyde oxime

[0921] Intermediate-78 was obtained as an off-white solid (0.039 g, 29.44%) from 4-bromobenzaldehyde (compound-77) according to the general procedure for converting aldehyde to oxime G, and was used without further purification.

[0922] To a stirred solution of MeOH (50 mL) containing 4-bromobenzaldehyde (2 g, 1.0 eq) and NaOAc (1.77 g, 2.0 eq) was added NH2OH-HCl (1.5 g, 2.0 eq) at room temperature. The reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (3 x 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate-78 as an off-white solid (0.039 g, 29.44%), which was used without further purification.

[0923] 1 H NMR (400 MHz, CDCl3)δ8.09 (s, 1H), 7.74 (t,J= 1.6 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.25 (q,J= 8.0 Hz, 2H); HRMS (EI) m / z calcd for C7H7BrNO [M + H] + 199.9711, found 199.9707.

[0924]

[0925] 13-2. Intermediate-79: methyl 3-(4-bromophenyl)isoxazole-5-carboxylate

[0926] Intermediate-79 was obtained as an off-white solid (0.577 g, 16.36%) from (E)-4-bromobenzaldehyde oxime (Intermediate-78) according to the general procedure for converting oxime to isoxazole H.

[0927] To a stirred solution of ACN (80 mL) containing (E)-4-bromobenzaldehyde oxime (2.5 g, 1.0 eq), Et3N (5.26 mL, 3.0 eq), and NCS (1.66 mL, 1.5 eq) was added methyl propiolate (1.52 eq). The reaction mixture was then stirred at 60 °C for 3 h. The reaction mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified with MPCL (0-10% ETOAc / hexane) as a solvent to obtain intermediate-3 (0.577 g, 16.36%).

[0928] 1 H NMR (400 MHz, CDCl3)δ7.72 (d,J= 1.6 Hz, 1H), 7.71 - 7.69 (m, 1H), 7.64 (d,J= 1.7 Hz, 1H), 7.62 (d,J= 1.7 Hz, 1H), 7.24 (s, 1H), 4.01 (s, 3H); HRMS (EI) m / z calcd for C 11 H9BrNO3[M + H] + 281.9766, found 281.9762.

[0929]

[0930] 13-3. Intermediate-81: 3-(4-(Thiophen-2-yl)phenyl)isoxazole-5-carboxylic acid

[0931] Intermediate-81 was obtained as an off-white solid (0.16 g, 84.15%) from methyl 3-(4-bromophenyl)isoxazole-5-carboxylate (Intermediate-79) according to the general procedure for Suzuki coupling reaction D (Method-I).

[0932] 1H NMR (400 MHz, DMSO-d6) δ8.23 (s, 1H), 7.94 (s, 1H), 7.90 (d,J= 7.7 Hz, 1H), 7.81 (d,J= 7.6 Hz, 1H), 7.71 (d,J= 3.5 Hz, 1H), 7.63 (d,J= 5.0 Hz, 1H), 7.58 (t,J= 7.7 Hz, 1H), 7.19 (t,J= 4.3 Hz, 1H); HRMS (EI) m / z calcd for C 14 H 10 NO3S [M + H] + 272.0380, found 272.0368.

[0933]

[0934] 13-4. Chemical Formula-82: N-phenyl-3-(4-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 67)

[0935] The compound of formula-82 was obtained as an off-white solid (0.022 g, 28.74%) from 3-(4-(Thiophen-2-yl)phenyl)isoxazole-5-carboxylic acid (Intermediate-81) according to the general procedure for acid-amine coupling L.

[0936] 1 H NMR (400 MHz, CDCl3)δ9.07 (s, 1H), 7.81 (d,J= 7.7 Hz, 2H), 7.76 (d,J= 8.3 Hz, 2H), 7.45 (d,J= 3.3 Hz, 1H), 7.39 (d,J= 4.1 Hz, 1H), 7.33 (d,J= 5.9 Hz, 3H), 7.29 (d,J= 8.1 Hz, 2H), 7.14 (t,J= 5.6 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ164.56, 163.12, 154.57, 140.98, 138.18, 136.54, 130.35, 129.27, 128.82, 128.69, 127.76, 126.72, 125.57, 125.14, 124.97, 122.41, 121.19, 106.34; HRMS (EI) m / z calcd for C 20 H 15 N2O2S [M + H] + 347.0854, found 347.0842.

[0937]

[0938] Example 14. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 14)

[0939] [Reaction Formula 14]

[0940]

[0941] Reagents and conditions: (a) Hydrazine, EtOH, 80°C, reaction time 12 hours; (b&c) ethyl 2-chloro-2-oxoacetate, Et3N, DCM, room temperature, reaction time 2 hours; POCl3, 100°C, reaction time 2 hours; (d) amine, Trimethylaluminium, DCM, room temperature, reaction time 2 hours; (e) boronic acid, PdCl2(dppf)-DCM, C2CO3, DMF:water (8:2), 110°C, reaction time 2 hours.

[0942]

[0943] 14-1. General procedure for intermediates 2a-2b

[0944] Hydrazine (13.0 eq) was added to a stirred solution of EtOH containing methyl bromobenzoate (1.0 eq) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was evaporated under reduced pressure to remove EtOH, and water was added to the mixture to form a solid. The resulting precipitate was separated by suction filtration using hexane and dried under vacuum to obtain intermediate-2a-2b without further purification.

[0945]

[0946] 14-2. Intermediate-2a: 3-bromobenzohydrazide

[0947] The product was obtained as an off-white solid (4.345 g, 86.9%) through the general procedure of Example 14-1 above.

[0948] 1 H NMR (400 MHz, dmso) δ7.72 (d,J= 12.1 Hz, 1H), 7.37 (d,J= 8.8 Hz, 1H), 7.08 (d,J= 8.8 Hz, 2H), 5.41 (d,J= 12.1 Hz, 1H), 2.02 (s, 2H).

[0949]

[0950] 14-3. Intermediate-2b: 4-bromobenzohydrazide

[0951] The product was obtained as an off-white solid (1.46 g, 73.0%) through the general procedure of Example 14-1 above.

[0952] 1 H NMR (400 MHz, cdcl3) δ7.61 (m,J= 3.3 Hz, 4H), 7.32 (s, 1H), 4.09 (d,J= 3.8 Hz, 2H).

[0953]

[0954] 14-4. General procedure for intermediates 3a-3b

[0955] To a stirred solution of bromobenzohydrazide (1.0 eq) and Et3N (1.0 eq) in DCM was added ethyl 2-chloro-2-oxoacetate (1.5 eq) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with brine, diluted water containing sodium bicarbonate solution, and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate-3a-3b without further purification. This was used directly in the next step.

[0956]

[0957] 14-5. Intermediate-3a: ethyl 2-(2-(3-bromobenzoyl)hydrazinyl)-2-oxoacetate

[0958] The product was obtained as an off-white solid through the general procedure of Example 14-4 above.

[0959] 1 H NMR (400 MHz, dmso) δ8.04 (s, 1H), 7.92 - 7.86 (m, 2H), 7.82 (d,J= 8.5 Hz, 1H), 7.72 (d,J= 8.0 Hz, 1H), 7.50 (t,J= 7.8 Hz, 1H), 4.31 (dd,J= 14.7, 7.2 Hz, 2H), 1.31 (t,J= 7.3 Hz, 3H).

[0960]

[0961] 14-6. Intermediate-3b: ethyl 2-(2-(4-bromobenzoyl)hydrazinyl)-2-oxoacetate

[0962] The product was obtained as an off-white solid through the general procedure of Example 14-4 above.

[0963] 1H NMR (400 MHz, dmso) δ7.82 (d,J= 8.3 Hz, 2H), 7.78 (s, 1H), 7.75 (d,J= 8.0 Hz, 2H), 7.67 (d,J= 8.1 Hz, 1H), 4.23 (dd,J= 13.5, 6.5 Hz, 2H), 1.31 (t,J= 7.2 Hz, 3H).

[0964]

[0965] 14-7. General procedure for intermediates 4a-4b

[0966] To a stirred solution of DCE containing ethyl 2-(2-(3 or 4 -bromobenzoyl)hydrazinyl)-2-oxoacetate (1.0 eq) and Et3N (2.0 eq) was added p-toluenesulfonyl chloride (2.0 eq) at room temperature, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with diluted water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by MPLC to obtain intermediate-4a-4b.

[0967]

[0968] 14-8. Intermediate-4a: ethyl 5-(3-bromophenyl)-1,3,4-oxadiazole-2-carboxylate

[0969] The product was obtained as an off-white solid (4.11 g, 72.65%) through the general procedure of Example 14-7 above.

[0970] 1 H NMR (400 MHz, cdcl3) δ 7.37 (d,J= 7.8 Hz, 1H), 7.24 (s, 1H), 7.17 (t,J= 8.0 Hz, 1H), 7.04 (t,J= 7.8 Hz, 1H), 3.77 (dd,J= 11.9, 6.1 Hz, 2H), 2.75 (t,J= 5.9 Hz, 3H).

[0971]

[0972] 14-9. Intermediate-4b: ethyl 5-(4-bromophenyl)-1,3,4-oxadiazole-2-carboxylate

[0973] The product was obtained as an off-white solid (0.408 g) through the general procedure of Example 14-7 above.

[0974] 1 H NMR (400 MHz, cdcl3) δ8.04 (d,J= 8.5 Hz, 2H), 7.70 (d,J= 8.5 Hz, 2H), 4.56 (q,J= 7.1 Hz, 2H), 1.49 (t,J= 7.1 Hz, 3H).

[0975]

[0976] 14-10. General procedure for chemical formulas 5, 8a-8d

[0977] Trimethyl aluminum (5.0 eq) was added to a stirred solution of ethyl carboxylate (1.0 eq) and amine (1.0 eq) in DCM at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with diluted water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by MPLC to obtain compounds of formula 5 and 8a-8d.

[0978]

[0979] 14-11. Formula-5: 5-(3-bromophenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide

[0980] The product was obtained as an off-white solid (0.033 g, 32.89%) through the general procedure of Example 14-10 above.

[0981] 1H NMR (400 MHz, cdcl3) δ8.95 (s, 1H), 8.36 (s, 1H), 8.13 (d,J= 8.4 Hz, 1H), 8.02 (s, 1H), 7.90 (d,J= 8.3 Hz, 1H), 7.76 (d,J= 6.4 Hz, 1H), 7.56 (t,J= 7.7 Hz, 1H), 7.50 (d,J= 8.4 Hz, 1H), 7.45 (d,J= 8.1 Hz, 1H).

[0982]

[0983] 14-12. Chemical Formula-8a: N-phenyl-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 71)

[0984] The product was obtained as an off-white solid (0.02 g, 17.29%) through the general procedure of Example 14-10 above.

[0985] 1 H NMR (400 MHz, cdcl3) δ8.86 (s, 1H), 8.41 (d,J= 9.6 Hz, 1H), 8.11 (d,J= 8.2 Hz, 1H), 7.84 (d,J= 8.2 Hz, 1H), 7.72 (d,J= 8.1 Hz, 2H), 7.61 (d,J= 7.1 Hz, 2H), 7.50 - 7.45 (m, 2H), 7.43 (d,J= 7.8 Hz, 2H), 7.24 (d,J= 6.6 Hz, 1H).

[0986]

[0987] 14-13. Chemical Formula-8b: N-(3-fluorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 72)

[0988] The product was obtained as an off-white solid (0.01 g, 8.22%) through the general procedure of Example 14-10 above.

[0989] 1H NMR (400 MHz, cdcl3) δ8.92 (s, 1H), 8.41 (s, 1H), 8.11 (d,J= 9.2 Hz, 1H), 7.85 (d,J= 9.1 Hz, 1H), 7.68 (d,J= 11.2 Hz, 1H), 7.61 (d,J= 3.2 Hz, 2H), 7.50 - 7.45 (m, 2H), 7.40 - 7.34 (m, 2H), 6.95 (t,J= 7.4 Hz, 1H).

[0990]

[0991] 14-14. Chemical formula-8c: N-(3-chlorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 73)

[0992] The product was obtained as an off-white solid (0.037 g, 29.0%) through the general procedure of Example 14-10 above.

[0993] 1 H NMR (400 MHz, cdcl3) δ8.88 (s, 1H), 8.41 (s, 1H), 8.11 (d,J= 8.6 Hz, 1H), 7.84 (s, 2H), 7.61 (d,J= 3.8 Hz, 2H), 7.59 - 7.54 (m, 1H), 7.48 (t,J= 5.7 Hz, 2H), 7.36 (t,J= 7.8 Hz, 1H), 7.22 (d,J= 7.3 Hz, 1H).

[0994]

[0995] 14-15. Chemical Formula 8d: 5-(4-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 74)

[0996] The product was obtained as an off-yellow liquid (0.1 g, 69.08%) through the general procedure of Example 14-10 above.

[0997] 1H NMR (400 MHz, cdcl3) δ8.92 (s, 1H), 8.20 (d,J= 8.2 Hz, 2H), 7.80 (d,J= 8.0 Hz, 2H), 7.77 (s, 1H), 7.57 (d,J= 8.8 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.44 (d,J= 7.3 Hz, 1H), 7.41 (d,J= 5.8 Hz, 1H), 7.17 - 7.13 (m, 1H), 7.10 (d,J= 9.9 Hz, 1H).

[0998]

[0999] 14-16. Chemical Formula 8e: 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 68)

[1000] The product was obtained as an off-yellow liquid (0.02 g, 13.9%) through the general procedure of Example 14-10 above.

[1001] 1 H NMR (400 MHz, cdcl3) δ8.94 (s, 1H), 8.42 (s, 1H), 8.09 (d,J= 7.4 Hz, 1H), 7.85 (d,J= 7.3 Hz, 1H), 7.78 (s, 1H), 7.59 (t,J= 7.9 Hz, 2H), 7.49 - 7.43 (m, 2H), 7.38 (d,J= 4.2 Hz, 1H), 7.17 - 7.08 (m, 2H.

[1002]

[1003] 14-17. General Procedure for Chemical Formulas 6a-6d, 7a-7c

[1004] To a stirred solution of bromo (1.0 eq) and boronic acid (1.5 eq) in DMF (30 mL) was added CS2CO3 (3.0 eq). The resulting reaction mixture was purged with argon gas for 3 min, and then Pd(dppf)Cl2.DCM (0.2 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 110 °C for 2 h, cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds of formulae 7a-7b and 6a-6b.

[1005]

[1006] 14-18. Chemical Formula 6a: 5-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 69)

[1007] The product was obtained as an off-white solid (0.033 g, 32.89%) through the general procedure of the above Examples 14-17.

[1008] 1 H NMR (400 MHz, cdcl3) δ8.98 (s, 1H), 8.42 (s, 1H), 8.11 (d,J= 8.1 Hz, 1H), 8.04 (s, 1H), 7.91 (d,J= 8.0 Hz, 1H), 7.85 (d,J= 8.5 Hz, 1H), 7.61 (d,J= 6.7 Hz, 2H), 7.57 (t, 2H), 7.50 (d,J= 8.7 Hz, 1H), 7.47 (d,J= 4.2 Hz, 1H).

[1009]

[1010] 14-19. Chemical Formula 6b: 5-(3-(furan-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 70)

[1011] The product was obtained as an off-white solid (0.01 g, 10.31%) through the general procedure of Examples 14-17 above.

[1012] 1 H NMR (400 MHz, cdcl3) δ8.98 (s, 1H), 8.30 (s, 1H), 8.08 (d,J= 9.1 Hz, 1H), 8.04 (s, 1H), 7.91 (d,J= 8.4 Hz, 1H), 7.86 (s, 1H), 7.74 (d,J= 7.1 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.55 (s, 1H), 7.50 (d,J= 8.4 Hz, 1H), 6.80 (s, 1H).

[1013]

[1014] 14-20. Chemical Formula 6c: 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 75)

[1015] The product was obtained as an off-white solid (0.01 g, 8%) through the general procedure of Examples 14-17 above.

[1016] 1H NMR (400 MHz, cdcl3) δ9.04 (s, 1H), 8.42 (s, 1H), 8.09 (d,J= 7.8 Hz, 1H), 8.04 (s, 1H), 7.91 (d,J= 8.2 Hz, 1H), 7.85 (d,J= 7.6 Hz, 1H), 7.57 (dd,J= 14.8, 7.3 Hz, 2H), 7.50 (d,J= 7.8 Hz, 1H), 7.46 (d,J= 3.4 Hz, 1H), 7.38 (d,J= 5.0 Hz, 1H), 7.14 (t,J= 3.9 Hz, 1H).

[1017]

[1018] 14-21. Chemical Formula 6d: 5-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 76)

[1019] The product was obtained as an off-white solid (0.01 g, 7.8%) through the general procedure of Examples 14-17 above.

[1020] 1 H NMR (400 MHz, cdcl3) δ9.03 (s, 1H), 8.36 (s, 1H), 8.16 (d,J= 7.7 Hz, 1H), 8.04 (s, 1H), 7.91 (d,J= 8.4 Hz, 1H), 7.80 (d,J= 7.8 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.56 (t,J= 7.9 Hz, 1H), 7.50 (d,J= 7.7 Hz, 1H), 7.19 (t,J= 8.6 Hz, 2H).

[1021]

[1022] 14-22. Formula-7a: ethyl 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxylate

[1023] The product was obtained as an off-white solid through the general procedure of Examples 14-17 above.

[1024] 1 H NMR (400 MHz, cdcl3) δ8.39 (s, 1H), 8.08 (d,J= 7.9 Hz, 1H), 7.83 (d,J= 6.9 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.45 (q,J= 5.2 Hz, 2H), 4.57 (q,J= 7.1 Hz, 2H), 1.50 (t,J= 7.1 Hz, 3H).

[1025]

[1026] 14-23. Formula-7b: ethyl 5-(4-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxylate

[1027] The product was obtained as an off-white solid (0.313 g, 78.95%) through the general procedure of Examples 14-17 above.

[1028] 1 H NMR (400 MHz, cdcl3) δ8.18 (d,J= 8.5 Hz, 2H), 7.78 (d,J= 8.3 Hz, 2H), 7.47 (d,J= 4.5 Hz, 1H), 7.40 (d,J= 7.3 Hz, 1H), 7.17 - 7.12 (m, 1H), 4.57 (q,J= 7.0 Hz, 2H), 1.50 (t,J= 7.3 Hz, 3H).

[1029]

[1030] 14-24. Formula-7c: ethyl 5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazole-2-carboxylate

[1031] The product was obtained as an off-white solid (0.313 g, 78%) through the general procedure of Examples 14-17 above.

[1032] 1H NMR (400 MHz, cdcl3) δ8.40 (s, 1H), 8.07 (d,J= 7.9 Hz, 1H), 7.84 (d,J= 7.7 Hz, 1H), 7.56 (t,J= 7.6 Hz, 1H), 7.45 (d,J= 3.5 Hz, 1H), 7.37 (d,J= 5.1 Hz, 1H), 7.14 (t,J= 4.3 Hz, 1H), 4.59 - 4.52 (m, 2H), 1.50 (t,J= 7.1 Hz, 3H).

[1033]

[1034] Example 15. Synthesis of different types of oxydiazole derivatives (Reaction Scheme 15)

[1035] [Reaction Formula 15]

[1036]

[1037] Reagents and conditions: (a) Boronic acid, PdCl2(dppf)-DCM, C2CO3, DMF:water (8:2), 110°C, reaction time 2 hours; (b) Hydrazine, EtOH, 80°C, reaction time 12 hours; (c) ethyl 2-chloro-2-oxoacetate, Et3N, DCM, room temperature, reaction time 2 hours; POCl3, 100°C, reaction time 2 hours; (d) Amine, Trimethylaluminium, DCM, room temperature, reaction time 2 hours.

[1038]

[1039] 15-1. General procedure for intermediate-2

[1040] To a stirred solution of bromo (1.0 eq) and boronic acid (1.5 eq) in DMF (30 mL) was added CS2CO3 (3.0 eq). The resulting reaction mixture was purged with argon gas for 3 min, and then Pd(dppf)Cl2.DCM (0.2 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 110 °C for 2 h, cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate-2.

[1041]

[1042] 15-2. Intermediate-2: methyl 6-(thiophen-3-yl)picolinate

[1043] The product was obtained as an off-white solid (1.2 g, 82.6%) through the general procedure of Example 15-1 above.

[1044] 1 H NMR (400 MHz, cdcl3) δ8.00 (d,J= 6.0 Hz, 2H), 7.86 (t,J= 7.7 Hz, 1H), 7.79 (d,J= 7.8 Hz, 1H), 7.71 (d,J= 5.1 Hz, 1H), 7.44 - 7.38 (m, 1H), 4.02 (s, 3H).

[1045]

[1046] 15-3. General procedure for intermediate-3

[1047] Hydrazine (13.0 eq) was added to a stirred solution of EtOH containing methyl bromobenzoate (1.0 eq) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was evaporated under reduced pressure to remove EtOH, and water was added to the mixture to form a solid. The resulting precipitate was separated by suction filtration using hexane and dried under vacuum to obtain intermediate-3 without further purification.

[1048]

[1049] 15-4. Intermediate-3: 6-(thiophen-3-yl)picolinohydrazide

[1050] The product was obtained as an off-white solid (1.1 g, 100%) through the general procedure of Example 15-3 above.

[1051] 1 H NMR (400 MHz, dmso) δ10.11 (s, 1H), 8.59 (s, 1H), 8.01 (dt,J= 15.3, 6.1 Hz, 3H), 7.86 (d,J= 7.3 Hz, 1H), 7.67 (d,J= 2.9 Hz, 1H), 4.61 (s, 2H).

[1052]

[1053] 15-5. General procedure for intermediate-4

[1054] To a stirred solution of hydrazide (1.0 eq) and Et3N (1.0 eq) in DCM was added ethyl 2-chloro-2-oxoacetate (1.5 eq) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with brine, diluted water containing sodium bicarbonate solution, and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in POCl3 at room temperature, and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, basified with saturated sodium bicarbonate solution, and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by MPLC to obtain intermediate-4.

[1055]

[1056] 15-6. Intermediate-4: ethyl 5-(6-(thiophen-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate

[1057] The product was obtained as an off-white solid (0.21 g, 16.4%) through the general procedure of Example 15-5 above.

[1058] 1 H NMR (400 MHz, cdcl3) δ8.18 (d,J= 7.8 Hz, 1H), 8.09 (s, 1H), 7.93 (t,J= 7.9 Hz, 1H), 7.82 (d,J= 7.9 Hz, 1H), 7.78 (d,J= 4.6 Hz, 1H), 7.45 (d,J= 4.2 Hz, 1H), 4.58 (dd,J= 14.8, 7.4 Hz, 2H), 1.51 (t,J= 6.9 Hz, 3H).

[1059]

[1060] 15-7. General procedure for chemical formulas 5a-5b

[1061] Trimethyl aluminum (5.0 eq) was added to a stirred solution of ethyl carboxylate (1.0 eq) and amine (1.0 eq) in DCM at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with diluted water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by MPLC to obtain compounds of formula 5a-5b.

[1062]

[1063] 15-8. Chemical Formula 5a: 5-(6-(thiophen-3-yl)pyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 77)

[1064] The product was obtained as an off-white solid (0.02 g, 12.89%) through the general procedure of Example 15-7 above.

[1065] 1 H NMR (400 MHz, cdcl3) δ9.02 (s, 1H), 8.16 (d,J= 7.5 Hz, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.94 (dd,J= 13.6, 6.7 Hz, 2H), 7.84 (d,J= 7.9 Hz, 1H), 7.80 (d,J= 5.1 Hz, 1H), 7.57 (t,J= 8.0 Hz, 1H), 7.50 (d,J= 8.0 Hz, 1H), 7.45 (s, 1H).

[1066]

[1067] 15-9. Chemical Formula-5b: N-(3-fluorophenyl)-5-(6-(thiophen-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 78)

[1068] The product was obtained as an off-white solid (0.02 g, 13.6%) through the general procedure of Example 15-7 above.

[1069] 1 H NMR (400 MHz, cd3od) δ8.28 (s, 1H), 8.17 (s, 1H), 8.06 (s, 2H), 7.89 (d,J= 4.8 Hz, 1H), 7.73 (d,J= 11.3 Hz, 1H), 7.56 (s, 2H), 7.42 (d,J= 7.1 Hz, 2H), 6.97 (s, 1H). RP-HPLC purity, 99.09% at 254 nm,t R = 20.86 min.

[1070]

[1071] [Experimental Example]

[1072] Experimental Example 1. Confirmation of the MDH1 and MDH2 inhibitory effects of oxadiazole derivatives.

[1073] Inhibitory activity (IC) of MDH1 and MDH2 for the oxadiazole derivatives synthesized in Examples 1 to 15 above 50 ), inhibitory activity against cancer cells (GI 50 )(cell viability) was confirmed.

[1074] Specifically, HCT116 cells, which are colon cancer cells, and A549 cells or H460 cells, which are lung cancer cells, were seeded at 3×10 in a 96-well plate. 3After culturing for 24 hours by dispensing at a concentration of 20 μM, the prepared compound was serially diluted in a medium containing 5% fetal bovine serum. Cell growth was analyzed through SRB (Sulforhodamine B) staining after 72 hours. The plate on which the cells were cultured was fixed with 4% formalin, left at room temperature for 60 minutes, and then washed 4-5 times with water. After drying the washed plate, 100 μl / well of 0.4% SRB (Sulforhodamine B) (solution dissolved in 0.1% acetic acid; protein staining reagent) was added, left for about 30 minutes, and then washed with 0.1% acetic acid to wash away unbound staining reagent. Again, after drying the plate, 100 μl / well of 10 mM Tris base (pH 10.5) was added to dissolve the staining reagent, and the absorbance was measured at 540 nm. The measured absorbance was calculated as a percentage of the control group. As a result, as shown in Tables 1 to 8 below, it was confirmed that cell growth of lung cancer and colon cancer cell lines was inhibited, and the concentration that resulted in 50% inhibition was described.

[1075] Additionally, HCT116 cells expressing HIF1a-response element (HRE)-Luciferase 1×10 in a 96-well plate 4 After culturing for 24 hours by dispensing at a concentration of 10 μM, the prepared compound was serially diluted from a concentration of 20 μM in a medium containing 5% fetal bovine serum and treated. After pretreatment with the prepared compound for 1 hour, the cell was cultured for 6 hours under hypoxic conditions (1% O2) and the luciferase activity was measured. The measured absorbance was calculated as a percentage of the control group. As a result, as shown in Tables 1 to 8 below, it was confirmed that the prepared compound inhibited the (HRE)-Luciferase activity of HCT116 cells, and the concentration that inhibited by 50% was described.

[1076] In addition, to confirm the MDH2 inhibitory activity of the compound manufactured according to the above example, a MDH2 recombinant protein was produced. The MDH2 gene was purchased from the Korean Human Gene Bank (KUGI, NM_005918) of the Korea Research Institute of Bioscience and Biotechnology, amplified by PCR, and cloned into the pET28a vector (Merck, Germany). The plasmid vector was then introduced into E. coli Rosetta 2 (DE3) and treated with IPTG to overexpress the MDH2 recombinant protein.

[1077] The inhibitory activity of the compounds against MDH1 and the MDH2 recombinant proteins prepared above was measured. More specifically, 0.25 nM MDH1 recombinant protein (Biovision) or MDH2 recombinant protein was reacted with 200 μM oxaloacetate, nicotinamide adenine dinucleotide (NADH), the compounds prepared in the above examples, and MDH assay buffer (100 mM potassium phosphate, pH 7.4) for 30 minutes. Thereafter, the change in NADH concentration in the solution due to oxidation of NADH (NAD+) by MDH1 or MDH2 enzymes was measured at an absorbance of 340 nm.

[1078] The results are shown in Tables 1 to 8 below.

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088] Based on the above results, major compounds were selected from among the synthesized compounds and further experiments were conducted.

[1089]

[1090] Experimental Example 2. Confirmation of the anticancer effects of major oxadiazole derivatives.

[1091] 2-1. Confirmation of the anticancer effects of compounds 21 and 51

[1092] 2-1-1. Confirmation of MDH1 and MDH2 enzyme inhibition activity and lung cancer cell proliferation inhibition ability

[1093] MDH1 and MDH2 enzyme inhibitory activity (IC) of compounds 21 and 51 50 ) and proliferation inhibition ability (GI) on A549 and H460 lung cancer cells with KRAS-LKB1 co-mutation 50 ) was confirmed, as shown in Tables 9 and 10 below, it was found to have excellent MDH1 and MDH2 enzyme inhibitory activity and lung cancer cell proliferation inhibitory ability.

[1094]

[1095]

[1096]

[1097] In addition, LKB1 was expressed in A549 cells (hereinafter, "A549-EV cells"), which are KRAS-LKB1 co-mutation cells, and the cells with normal LKB1 function (hereinafter, "A549-LKB1 cells") were treated with compound 21 to confirm the inhibition of lung cancer cell proliferation. As a result, as shown in Fig. 1a, it was confirmed that the inhibition of cancer cell proliferation of compound 21 was reduced in A549-LKB1 cells.

[1098] Accordingly, it was found that compound 21 had a better proliferation inhibition ability against KRAS-LKB1 co-mutation lung cancer cells (A549-EV cells), a cancer type for which no suitable treatment has been developed.

[1099] In addition, the relationship between compound 51's antiproliferative effect and LKB1-expressing cells was evaluated. To confirm this, the antiproliferative effect of FM702 on KRAS-LKB1 co-mutation cells and KRAS single mutant cells was compared in A549 cells, CT26 cells, and MC38 cells.

[1100] First, compound 51 was treated on A549-LKB1 cells that had LKB1 expressed in A549-EV cells, and then GI 50 were compared. As a result, as shown in Fig. 1b, the GI of A549-EV cells 50 is 1.96 μM, and the GI of A549-LKB1 cells 50 was 3.96 μM, GI in A549-EV cells 50 Since the value was reduced by approximately 2-fold, it was confirmed that compound 51 had a better proliferation inhibitory effect in KRAS-LKB1 co-mutation cells than in KRAS single mutant cells.

[1101] In addition, the proliferation inhibitory efficacy of compound 51 on KRAS mutant CT26 colon cancer cells (hereinafter, "CT26-Neg") and KRAS-LKB1 double mutant cells with LKB1 knockout (hereinafter, "CT26-sgLKB1") was compared, and as shown in Fig. 1b, the GI of CT26-sgLKB1 50 Compared to the values, GI of CT26-Neg cells 50 has increased fourfold.

[1102] On the other hand, in MC38 cells without KRAS or LKB1 mutation (hereinafter, "MC38-Neg"), in which LKB1 was knocked out (hereinafter, "MC38-sgLKB1"), the proliferation inhibitory efficacy of compound 51 on both cells was not changed if there was no KRAS mutation.

[1103] Therefore, it was found that compound 51 is a drug that effectively exhibits proliferation inhibition efficacy in mouse KRAS-LKB1 co-mutation cancer cells.

[1104]

[1105] 2-1-2. Confirmation of ATP production through mitochondrial respiration and real-time ATP production through glycolysis

[1106] After treatment of the A549-EV cells and A549-LKB1 cells with compound 21, the production of respiration-derived ATP (hereinafter, "mito-ATP") by changes in mitochondrial respiratory activity through oxygen consumption rates (OCR) analysis and glycolysis-derived ATP (hereinafter, "glyco-ATP") through proton efflux rate (PER) analysis were compared. As a result, as shown in Fig. 2, there was no significant change in the production of glyco-ATP in A549-EV and A549-LKB1 cells, but it was confirmed that the production of mito-ATP decreased. In addition, when A549-EV cells were treated with compound 21, the amount of glyco-ATP increased relatively more than that of A549-LKB1 cells due to the absence of the glycolysis regulatory function by LKB1, and it was confirmed that the total amount of ATP in the cells increased by regulating various energy metabolisms in the cells by LKB1 expression. However, when treated with compound 21, mito-ATP was significantly It was confirmed that the total amount of ATP in the cell decreased.

[1107]

[1108] 2-1-3. Confirmation of anti-tumor effect

[1109] To confirm the antitumor effect, changes in tumor size in mice following administration of Compound 21 and Compound 51 were examined. Mice implanted with A549 tumor cells were treated with 20, 40, and 80 mg / kg of Compound 21 and Compound 51, respectively, and changes in tumor size and weight were measured up to 25 days. No drug was administered to the negative control group (vehicle), and 2 mg / kg of the anticancer drug cisplatin was administered to the positive control group.

[1110] As a result, as shown in Figures 3a to 3c, the increase in tumor size was dose-dependently reduced when treated with compound 21, and it was confirmed that the tumor weight was reduced by 26.7%, 30.8%, and 47.8% in the groups treated with 20, 40, and 80 mg / kg of compound 21, respectively, compared to the negative control group.

[1111] In addition, as shown in Figures 3a to 3b, the tumor size increased in all groups, but the amount of increase in tumor size decreased in a dose-dependent manner, and compared to the negative control group, the tumor weights decreased by 22.9%, 35.7%, and 45.0% in the groups treated with 20, 40, and 80 mg / kg of compound 51, respectively.

[1112] Therefore, it was found that when compounds 21 and 51 were treated, antitumor efficacy was observed in a dose-dependent manner.

[1113]

[1114] 2-1-4. Confirmation of the efficacy of combination therapy with compound 21 and anti-PD-1 antibodies.

[1115] We examined whether a synergistic effect was observed when compound 21 was combined with an anti-PD-1 antibody, an immune checkpoint inhibitor. Since this experiment was conducted to determine the antitumor efficacy through the regulation of immune responses occurring in the cancer cell microenvironment, we performed a syngeneic mouse model experiment using CT26-sgLKB1 (KRAS-LKB1 KO), a mouse-derived colon cancer cell line in which the LKB1 gene of the CT26 mouse colon cancer cell line with a KRAS mutation was deleted (knockout, KO).

[1116] During the experimental period, no general symptoms or specific symptoms were observed during long-term observation, and no abnormalities were observed in major organs in the final autopsy. In addition, as shown in Figures 4a to 4c, no statistically significant weight loss was observed (Figure 4a), and when treated with compound 21, the tumor size (Figure 4b) and tumor weight (Figure 4c) were reduced compared to the control group. Compared to the negative control group, the tumor size was reduced by 19.6% and 36.7% when compound 21 was treated alone at 40 mg / kg and 80 mg / kg, respectively, and by 26.8% when treated with anti-PD-1 antibody. In particular, when compound 21 and anti-PD-1 antibody were co-administered, the antitumor efficacy was 47.8% when compound 21 was treated at 40 mg / kg, and 58.1% when treated at 80 mg / kg.

[1117]

[1118] 2-1-5. Confirmation of the efficacy of combination therapy with compound 51 and anti-PD-1 antibodies.

[1119] To conduct a combined efficacy experiment with Compound 51 and an anti-PD-1 antibody, KRAS-LKB1 KO double mutant colon cancer cells were used. Specifically, the synergistic effect was examined when Compound 51 and an anti-PD-1 antibody, an immune checkpoint inhibitor, were combined to treat tumors derived from KRAS-LKB1 KO double mutant cells.

[1120] As a result, as shown in Figures 5a to 5c, no statistically significant body weight loss was observed (Figure 5a), and when compound 51 or compound 51 and anti-PD-1 antibody were administered in combination, the increase in tumor size (Figure 5b) and tumor weight (Figure 5c) was reduced. In the case of tumor weight, when compound 51 was administered alone at 40 mg / kg and 80 mg / kg, it was reduced by 18.9% and 37.8%, respectively, and when anti-PD-1 antibody was treated, it was reduced by 30.6%. In addition, among the cases of combined administration of compound 51 and anti-PD-1 antibody, it was confirmed that when compound 51 was administered at 40 mg / kg, the tumor weight was reduced by 49%, and when 80 mg / kg was treated, it was reduced by 60.7%.

[1121] Therefore, it was found that the combined administration of compound 51 and anti-PD-1 antibody was effective in KRAS-LKB1 KO colon cancer cell lines.

[1122]

[1123] 2-1-6. Confirmation of the efficacy of combination with compound 51 and gefitinib.

[1124] When gefitinib 10 mg / kg, a drug designed to block the growth of tumor cells by targeting EGFR, was administered in combination with compound 51 60 mg / kg 5 times / week, we examined whether there was a synergistic effect in the antitumor effect.

[1125] As a result, as shown in Figures 6a to 6c, no statistically significant weight loss was observed (Figure 6a), and when compound 51 or compound 51 and gefitinib were administered together, the increase in tumor size (Figure 6b) and tumor weight (Figure 6c) was reduced, and compared to the negative control group, when gefitinib and compound 51 were administered alone, the tumor weight was reduced by 28.8% and 35.5%, respectively, and when compound 51 and gefitinib were administered together, the tumor weight was reduced by 57.9%.

[1126] Therefore, it was found that there was a synergistic effect when compound 51 and gefitinib were administered together.

[1127]

[1128] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[1129] The oxadiazole derivative compound according to the present invention exhibits MDH1 and MDH2 enzyme inhibitory activity, anti-proliferation and tumor suppression activity against cancer cells, and effectively exhibits anti-proliferation efficacy against KRAS-LKB1 co-mutation cancer cells. In addition, it exhibits a more excellent anti-cancer effect when administered in combination with an anti-PD-1 inhibitor or an anti-cancer agent such as gefitinib. Therefore, the oxadiazole derivative compound according to the present invention is expected to be useful as a therapeutic agent for various cancers, and thus has industrial applicability.

Claims

1. An oxadiazole derivative or a salt thereof represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, W is carbon (C) or nitrogen (N), R1 is hydrogen (H), a hydroxyl group (OH), a halogen element, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aryl group, a C1-C6 alkyl group, a C1-C6 alkenyl group, or a C1-C6 alkoxy group, R2 is hydrogen (H), a hydroxyl group (OH), a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, or a heteroaryl group, At this time, when R1 and R2 are each independently a C1-C6 alkyl group or a C1-C6 alkenyl group, Cy is formed by being fused and connected to each other, and forms an unsaturated ring having 4 to 6 carbon atoms including one or more double bonds, including R1 and R2. R3 is hydrogen (H), a hydroxyl group (OH), or a substituted or unsubstituted C1-C6 alkoxy group, R4 is hydrogen (H), hydroxyl group (OH), C1-C6 alkoxy group, or And, R5 is a heteroaryl group or And, At this time, the above R4 and R5 When, N of R4 and R5 are connected to each other to form a heterocycle, X is N-R6, -C=O-NH-, or -NH-C=O-, R6 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, The above 'substituted or unsubstituted' means substituted or unsubstituted with one or more substituents selected from the group consisting of one or more halogen elements, C1-C6 alkyl groups, C1-C6 alkyl ester groups, C1-C6 alkoxy groups, C1-C6 alkyl groups substituted with one or more halogen elements or C1-C6 alkoxy groups, cyano groups (C≡N), aryl groups, C≡CH, and CH2N(CH3)2.

2. In paragraph 1, The above heteroaryl group is a 5-membered or 6-membered heteroaryl group containing one or more heteroatoms selected from the group consisting of oxygen (O), nitrogen (N), and sulfur (S), The aryl group is a phenyl group or a benzyl group, C1-C6 alkyl group is a methyl group, ethyl group, propyl group, or butyl group, The C1-C6 alkenyl group is an ethenyl group, a propenyl group, or a butenyl group, An oxadiazole derivative or a salt thereof, characterized in that the C1-C6 alkoxy group is a methoxy group.

3. In paragraph 1, An oxadiazole derivative or a salt thereof, characterized in that the halogen element is at least one selected from the group consisting of F, Cl, Br, and I.

4. In paragraph 1, An oxadiazole derivative or salt thereof, characterized in that the compound represented by the above chemical formula 1 is at least one selected from the group consisting of the following compounds: (1)N-(5-(2'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 1) (2)N-(5-([1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 2) (3)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 3) (4)N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 4) (5)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 5) (6)N-(5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 6) (7)N-(5-(3'-methoxy-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 7) (8) 3-cyano-N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 8) (9) 3-cyano-N-(5-(3-(thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 9) (10)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 10) (11)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-carboxamide (Compound 11) (12)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-carboxamide (Compound 12) (13)N-(5-(3-(furan-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 13) (14) 3-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 14) (15) 4-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 15) (16)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzamide (Compound 16) (17) 2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (2-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide) (Compound 17) (18) 2,3-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 18) (19) 3-cyano-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 19) (20) 3-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 20) (21)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 21) (22) 2,6-difluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 22) (23)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 23) (24) 3-methyl-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 24) (25) 4-fluoro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 25) (26) 2-chloro-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 26) (27)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethoxy)benzamide (Compound 27) (28) Methyl 3-((5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)carbamoyl)benzoate (Compound 28) (29)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)isonicotinamide (Compound 29) (30)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)picolinamide (Compound 30) (31) 5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-amine (Compound 31) (32)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)benzamide (Compound 32) (33) 4-iodo-N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 33) (34)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 34) (35)N-(5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 35) (36) 5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine (5-(3-(thiophen-2-yl)phenyl)-N,N-bis(3-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-amine) (Compound 36) (37)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-6-(trifluoromethyl)picolinamide (Compound 37) (38)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)nicotinamide (Compound 38) (39)N-(5-(3-(furan-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 39) (40) 3-cyano-N-(5-(naphthalen-2-yl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 40) (41)N-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 41) (42)N-(1-(3-hydroxyphenyl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide (Compound 42) (43)N-(3-(3-bromophenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 43) (44)N-(3-(3-(thiophen-2-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 44) (45)N-(3-(3-(thiophen-3-yl)phenyl)isoxazol-5-yl)-3-(trifluoromethyl)benzamide (Compound 45) (46) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 46) (47) 3-(trifluoromethyl)-N-(5-(3-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide (Compound 47) (48)N-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 48) (49)N-(5-(4-methoxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 49) (50)N-(5-(3-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 50) (51)N-(5-(2-methoxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 51) (52)N-(5-(4-hydroxy-3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 52) (53)N-(5-(3-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 53) (54)N-(5-(2-hydroxy-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 54) (55)N-(5-(3-(prop-2-yn-1-yloxy)-5-(thiophen-3-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 55) (56)N-(5-(3'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 56) (57)N-(5-(3-(5-((dimethylamino)methyl)thiophen-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 57) (58) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 58) (59)N-phenyl-3-(3-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 59) (60) 3-(3-(thiophen-2-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 60) (61) 3-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 61) (62) 3-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)isoxazole-5-carboxamide (Compound 62) (63)N-(3-fluorophenyl)-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 63) (64)N-phenyl-3-(3-(thiophen-3-yl)phenyl)isoxazole-5-carboxamide (Compound 64) (65) 3-(6-(thiophen-2-yl)pyridin-2-yl)-N-(3-(trifluoromethoxy)phenyl)isoxazole-5-carboxamide (Compound 65) (66)N-phenyl-3-(6-(thiophen-2-yl)pyridin-2-yl)isoxazole-5-carboxamide (Compound 66) (67)N-phenyl-3-(4-(thiophen-2-yl)phenyl)isoxazole-5-carboxamide (Compound 67) (68) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 68) (69) 5-(3-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 69) (70) 5-(3-(furan-3-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 70) (71)N-phenyl-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 71) (72)N-(3-fluorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 72) (73)N-(3-chlorophenyl)-5-(3-(thiophen-3-yl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 73) (74) 5-(4-(thiophen-3-yl)phenyl)-N-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 74) (75) 5-(3-(thiophen-2-yl)phenyl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 75) (76) 5-(4'-fluoro-[1,1'-biphenyl]-3-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 76) (77) 5-(6-(thiophen-3-yl)pyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole-2-carboxamide (Compound 77) (78)N-(3-fluorophenyl)-5-(6-(thiophen-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 78).

5. A pharmaceutical composition for preventing or treating cancer, comprising a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. In paragraph 5, A pharmaceutical composition for preventing or treating cancer, characterized in that the composition inhibits the activity of at least one of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2).

7. In paragraph 5, The cancers include lung cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, colorectal cancer, colon cancer, rectal cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, endometrial or uterine carcinoma, salivary gland carcinoma, and kidney cancer. and renal cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, biliary tract cancer, head and neck cancer, carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma,A pharmaceutical composition for preventing or treating cancer, characterized in that it comprises at least one selected from the group consisting of schwanoma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancy, squamous cell cancer, and epithelial squamous cell cancer.

8. In paragraph 5, A pharmaceutical composition for preventing or treating cancer, characterized in that the composition is administered in combination with an anticancer agent.

9. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the anticancer agent is an immune checkpoint inhibitor or a chemotherapy agent.

10. In paragraph 9, A pharmaceutical composition for preventing or treating cancer, characterized in that the immune checkpoint inhibitor is at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

11. In paragraph 9, The above chemotherapeutic agents include gefitinib, docetaxel, paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, imatinib, carboplatin, oxaliplatin, tegafur, irinotecan, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, camptothecin, Danuorubicin, chlorambucil, bryostatin-1, calicheamicin, mayatansine, levamisole, DNA recombinant interferon alfa-2a, mitoxantrone, nimustine, interferon alfa-2a, doxifluridine, formestane, leuprolide acetate, megestrol acetate, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, Anastrozole, estramustine, capecitabine,A pharmaceutical composition for preventing or treating cancer, characterized in that it comprises at least one selected from the group consisting of goserelin acetate, polysaccharide potassium, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, and actinomycin D.

12. A method for preventing or treating cancer, comprising administering a pharmaceutically effective amount of a composition containing a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

13. Use of a composition comprising a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

14. Use of a composition comprising a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a preparation for preventing or treating cancer.

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