Novel oxazole derivative and composition for preventing or treating cancer, comprising same

Abstract

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

Description

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

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

[0002] This invention claims priority to Republic of Korea Patent Application No. 10-2024-0042133, 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 and is reoxidized to oxalate by mitochondrial MDH2, generating NADH. The generated NADH generates ATP through 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 oxazole 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 oxazole 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 oxazole 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 oxazole 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] To achieve the above purpose, the present invention provides an oxazole derivative or a salt thereof represented by the following chemical formula 1:

[0014] [Chemical Formula 1]

[0015]

[0016] (In the above chemical formula 1,

[0017] X1, X2, and X3 are each independently carbon (C) or nitrogen (N),

[0018] Y1 is N=C-, CR6=N-, CH=C-, or NH-C=O-R8,

[0019] Y2 is absent, hydrogen (H), oxygen (O), nitrogen (N), sulfur (S), CH=C-, N=C-, or NR7,

[0020] R6 and R7 are each independently hydrogen (H) or a C1-C6 alkyl group,

[0021] R8 is a substituted or unsubstituted aryl group,

[0022] The above Cy is formed by Y1 and Y2 being fused and connected to each other, and forms a 5-membered or 6-membered unsaturated ring including one or more double bonds including Y1 and Y2, and the unsaturated ring contains at least one or more selected from the group consisting of C, N, O, and S,

[0023] Z is absent, NH-C=O-, NH-SO2-, or NR 10 -and,

[0024] R 10 is hydrogen (H), a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group,

[0025] R1 is absent, a substituted or unsubstituted aryl group, a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group,

[0026] R2 is hydrogen (H), a halogen element, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polycyclic heteroaryl group, a C1-C6 alkoxy group, an amino group (NH2), a nitro group (NO2), or NH-R9,

[0027] R9 is a heteroaryl group, a polycyclic heteroaryl group, a cycloalkyl group, a C1-C6 alkyl group, or a C1-C6 acyl group,

[0028] R3 is hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, a halogen element, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,

[0029] R4 is absent, hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, or a halogen element,

[0030] R5 is absent, hydrogen (H), or a C1-C6 alkoxy group,

[0031] 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 alkoxy groups, C1-C6 alkyl groups or C1-C6 alkoxy groups substituted with one or more halogen elements, cyano groups (C≡N), aryl groups, and nitro groups (NO2).

[0032] 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).

[0033] The aryl group is a phenyl group or a benzyl group,

[0034] C1-C6 alkyl group is a methyl group, an ethyl group, an i-propyl group, an n-propyl group, an n-butyl group, or an i-butyl 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) 3-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 1)

[0039] (2)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-trifluoromethyl)benzamide; (Compound 2)

[0040] (3) 3-chloro-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 3)

[0041] (4)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 4)

[0042] (5)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 5)

[0043] (6) 3-Cyano-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 6)

[0044] (7) 3-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 7)

[0045] (8)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (Compound 8)

[0046] (9) 4-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 9)

[0047] (10) 4-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 10)

[0048] (11)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-trifluoromethyl)benzamide; (화합물 11)

[0049] (12)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethoxy)benzamide; (화합물 12)

[0050] (13) 2-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)isonicotinamide; (Compound 13)

[0051] (14) 2-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 14)

[0052] (15) 2-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 15)

[0053] (16) 2-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 16)

[0054] (17)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(trifluoromethyl)benzamide; (화합물 17)

[0055] (18)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (화합물 18)

[0056] (19) 5-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (Compound 19)

[0057] (20)N-(4-Methoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine; (화합물 20)

[0058] (21)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 21)

[0059] (22) 3-Fluoro-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 22)

[0060] (23)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 23)

[0061] (24)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 24)

[0062] (25)N-(5-Fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 25)

[0063] (26)N-(5-Methoxybenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 26)

[0064] (27)N-(5-Chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 27)

[0065] (28) 5-(Thiophen-3-yl)benzo[d]thiazol-2-amine; (화합물 28)

[0066] (29)N-(5-bromobenzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 29)

[0067] (30)N-(5-Bromo-1-methyl-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 30)

[0068] (31)N-(5-(Thiophen-3-yl)benzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 31)

[0069] (32)N-(5-(Thiophen-3-yl)benzo[d]isoxazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 32)

[0070] (33)N-(1-Methyl-5-(thiophen-3-yl)-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 33)

[0071] (34) 3-Methoxy-N-(5-(thiophen-2-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 34)

[0072] (35)N-(5-(4-Cyano-3-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 35)

[0073] (36)N-(5-(4-Cyanophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 36)

[0074] (37)N-(5-(Furan-2-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 37)

[0075] (38) 3-Methoxy-N-(5-(3-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 38)

[0076] (39) 3-Methoxy-N-(5-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 39)

[0077] (40) 3-Methoxy-N-(5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 40)

[0078] (41) 3-Methoxy-N-(5-phenylbenzo[d]oxazol-2-yl)benzamide; (화합물 41)

[0079] (42) 3-Methoxy-N-(5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 42)

[0080] (43)N-(5-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 43)

[0081] (44) 3-Methoxy-N-(5-(2-methylfuran-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 44)

[0082] (45)N-(5-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 45)

[0083] (46)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 46)

[0084] (47)N-(5-Bromo-7-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 47)

[0085] (48)N-(5-Bromo-6-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 48)

[0086] (49)N-(5-Bromo-6-fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 49)

[0087] (50)N-(5-Bromo-6-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 50)

[0088] (51)N-(7-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 51)

[0089] (52) 3-Methoxy-N-(7-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 52)

[0090] (53)N-(6-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 53)

[0091] (54)N-(6-Fluoro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 54)

[0092] (55) 3-Methoxy-N-(6-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 55)

[0093] (56)N-(5-(Thiophen-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 56)

[0094] (57)N-(6-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 57)

[0095] (58)N-(6-Bromooxazolo[5,4-b]pyridin-2-yl)-3-methoxybenzamide; (화합물 58)

[0096] (59) 3-Methoxy-N-(6-(thiophen-3-yl)oxazolo[5,4-b]pyridin-2-yl)benzamide; (화합물 59)

[0097] (60)N-(5-(Thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)-3-(trifluoromethyl)benzamide; (화합물 60)

[0098] (61) 3-Methoxy-N-(5-(thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)benzamide; (화합물 61)

[0099] (62) 3-Methoxy-N-(5-((thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 62)

[0100] (63)N-(5-((Furan-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 63)

[0101] (64)N-(5-(Cyclohexylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 64)

[0102] (65) 3-Methoxy-N-(5-((pyridin-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 65)

[0103] (66)N-(5-((Benzo[b]thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 66)

[0104] (67)N-(5-(Isopropylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 67)

[0105] (68) 3-Methoxy-N-(5-(3-methylbutanamido)benzo[d]oxazol-2-yl)benzamide; (화합물 68)

[0106] (69) 3-Methoxy-N-(5-propionamidobenzo[d]oxazol-2-yl)benzamide; (화합물 69)

[0107] (70) 3-Methoxy-N-(5-nitrobenzo[d]oxazol-2-yl)benzamide; (화합물 70)

[0108] (71)N-(5-Aminobenzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 71)

[0109] (72) 2-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)acetamide; (화합물 72)

[0110] (73) 3-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)propanamide; (화합물 73)

[0111] (74)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide; (화합물 74)

[0112] (75)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)propanamide; (화합물 75)

[0113] (76)N-(5-Bromobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 76)

[0114] (77) 1-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea; (화합물 77)

[0115] (78) 3-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzenesulfonamide; (화합물 78)

[0116] (79)N-(6-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 79)

[0117] (80) 3-Methoxy-N-(6-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 80)

[0118] (81) 3-Methoxy-N-(6-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 81)

[0119] (82)N-(6-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 82)

[0120] (83) 3-methoxy-N-(6-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 83)

[0121] (84) 3-(Trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 84)

[0122] (85) 3-Fluoro-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 85)

[0123] (86)N-(4-Methoxybenzyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-amine; (화합물 86)

[0124] (87)N-(4-Methoxybenzyl)-3-(trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)benzamide (화합물 87)

[0125] (88)N-(4-Methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 88)

[0126] (89)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-chlorobenzamide; (화합물 89)

[0127] (90)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 90)

[0128] (91)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-nitrobenzamide; (화합물 91)

[0129] (92)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)thiophene-2-carboxamide; (화합물 92)

[0130] (93)N-(7-Bromonaphthalen-2-yl)-3-(trifluoromethyl)benzamide; (화합물 93)

[0131] (94)N-(7-Bromoquinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (Compound 94)

[0132] (95)N-(7-(Thiophen-3-yl)naphthalen-2-yl)-3-(trifluoromethyl)benzamide; (Compound 95)

[0133] (96)N-(7-(Thiophen-3-yl)quinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (Compound 96)

[0134] (97)N-(5-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 97)

[0135] (98)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 98)

[0136] (99)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 99) and

[0137] (100)N-(3-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 100).

[0138] As another embodiment of the present invention, the compound represented by the above chemical formula 1 is a compound wherein X1, X2, and X3 are each independently carbon (C),

[0139] Y1 is N=C-, Y2 is oxygen (O),

[0140] Z is NH-C=O-,

[0141] R1 may be a substituted or unsubstituted aryl group, R2 may be a heteroaryl group or a halogen element, R3 and R4 may each independently be hydrogen (H) or a halogen element, and R5 may be hydrogen (H), but is not limited thereto.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] As another embodiment of the present invention, the composition may be administered in combination with an anticancer agent, but is not limited thereto.

[0146] 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.

[0147] As 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] The oxazole 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 oxazole derivative compound according to the present invention is expected to be useful as a therapeutic agent for various cancers.

[0153] FIG. 1 is a diagram showing the results of comparing the total ATP amount, mito-ATP (OCR), and glyco-ATP (PER) production when treating cancer cells with compounds 49 and 37 according to one embodiment of the present invention.

[0154] Figure 2a is a drawing confirming the change in body weight when treating a cancer animal model with compounds 49 and 37 according to one embodiment of the present invention.

[0155] Figure 2b is a drawing confirming the change in body weight when compound 51 is treated in a cancer animal model according to one embodiment of the present invention.

[0156] Figure 3a is a drawing showing the tumor weight when treating a cancer animal model with compounds 49 and 37 according to one embodiment of the present invention.

[0157] Figure 3b is a drawing showing the tumor weight when compound 51 is treated in a cancer animal model according to one embodiment of the present invention.

[0158] Figure 4a is a drawing confirming the tumor size when treating a cancer animal model with compounds 49 and 37 according to one embodiment of the present invention.

[0159] Figure 4b is a drawing confirming the tumor size when compound 51 is treated in a cancer animal model according to one embodiment of the present invention.

[0160] FIG. 5a is a drawing confirming the change in body weight of CT26 sgNeg mice when combined treatment with compound 51 and an anti-PD-1 antibody in a cancer animal model according to one embodiment of the present invention.

[0161] FIG. 5b is a drawing showing the tumor weight of CT26 sgNeg mice 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.

[0162] FIG. 5c is a drawing confirming the tumor size of CT26 sgNeg mice when combined treatment with compound 51 and an anti-PD-1 antibody in a cancer animal model according to one embodiment of the present invention.

[0163] FIG. 6a is a drawing confirming the change in body weight of CT26 sgLKB1 mice when combined treatment with compound 51 and anti-PD-1 antibody in a cancer animal model according to one embodiment of the present invention.

[0164] FIG. 6b is a drawing showing the tumor weight of CT26 sgLKB1 mice 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.

[0165] FIG. 6c is a drawing confirming the tumor size of CT26 sgLKB1 mice when combined treatment with compound 51 and anti-PD-1 antibody in a cancer animal model according to one embodiment of the present invention.

[0166] Figure 7a is a drawing confirming the change in body weight of a mouse when compound 51 and gefitinib are combined and treated in a cancer animal model according to one embodiment of the present invention.

[0167] Figure 7b is a drawing showing the tumor weight of a mouse when a cancer animal model was treated with compound 51 and gefitinib in combination according to one embodiment of the present invention.

[0168] Figure 7c is a drawing confirming the tumor size of a mouse when compound 51 and gefitinib are combined and treated in a cancer animal model according to one embodiment of the present invention.

[0169] The present invention provides an oxazole derivative or a salt thereof represented by the following chemical formula 1:

[0170] [Chemical Formula 1]

[0171]

[0172] (In the above chemical formula 1,

[0173] X1, X2, and X3 are each independently carbon (C) or nitrogen (N),

[0174] Y1 is N=C-, CR6=N-, CH=C-, or NH-C=O-R8,

[0175] Y2 is absent, hydrogen (H), oxygen (O), nitrogen (N), sulfur (S), CH=C-, N=C-, or NR7,

[0176] R6 and R7 are each independently hydrogen (H) or a C1-C6 alkyl group,

[0177] R8 is a substituted or unsubstituted aryl group,

[0178] The above Cy is formed by Y1 and Y2 being fused and connected to each other, and forms a 5-membered or 6-membered unsaturated ring including one or more double bonds including Y1 and Y2, and the unsaturated ring contains at least one or more selected from the group consisting of C, N, O, and S,

[0179] Z is absent, NH-C=O-, NH-SO2-, or NR 10 -and,

[0180] R 10 is hydrogen (H), a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group,

[0181] R1 is absent, a substituted or unsubstituted aryl group, a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group,

[0182] R2 is hydrogen (H), a halogen element, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polycyclic heteroaryl group, a C1-C6 alkoxy group, an amino group (NH2), a nitro group (NO2), or NH-R9,

[0183] R9 is a heteroaryl group, a polycyclic heteroaryl group, a cycloalkyl group, a C1-C6 alkyl group, or a C1-C6 acyl group,

[0184] R3 is hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, a halogen element, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group,

[0185] R4 is absent, hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, or a halogen element,

[0186] R5 is absent, hydrogen (H), or a C1-C6 alkoxy group,

[0187] 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 alkoxy groups, C1-C6 alkyl groups or C1-C6 alkoxy groups substituted with one or more halogen elements, cyano groups (C≡N), aryl groups, and nitro groups (NO2).

[0188]

[0189] 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).

[0190] 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, an i-propyl group, an n-propyl group, an n-butyl group, or an i-butyl group, but is not limited thereto.

[0191] 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.

[0192] In the present invention, “polycyclic heteroaryl group” means a ring structure in which two or more heteroaryl groups are fused.

[0193] 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 methyl group, a trifluoromethyl group (CF3), and a heteroaryl group, but is not limited thereto.

[0194] 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.

[0195] 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, a trifluoromethyl group (CF3), a cyano group (C≡N), OCF3, a methyl group, and a methoxy group, but is not limited thereto.

[0196] In the present invention, “substitution” includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0197] 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.

[0198] 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 OCF3, but is not limited thereto.

[0199] In the present invention, “heteroarylcarbonyl group” means a 5-membered or 6-membered monocyclic heteroaryl ring or condensed cyclic heteroaryl ring containing at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, bonded to a carbonyl group.

[0200]

[0201] 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.

[0202] (1) 3-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 1)

[0203] (2)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-trifluoromethyl)benzamide; (화합물 2)

[0204] (3) 3-chloro-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 3)

[0205] (4)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 4)

[0206] (5)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 5)

[0207] (6) 3-Cyano-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 6)

[0208] (7) 3-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 7)

[0209] (8)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (Compound 8)

[0210] (9) 4-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 9)

[0211] (10) 4-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 10)

[0212] (11)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-trifluoromethyl)benzamide; (화합물 11)

[0213] (12)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethoxy)benzamide; (화합물 12)

[0214] (13) 2-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)isonicotinamide; (Compound 13)

[0215] (14) 2-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 14)

[0216] (15) 2-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 15)

[0217] (16) 2-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 16)

[0218] (17)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(trifluoromethyl)benzamide; (화합물 17)

[0219] (18)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (화합물 18)

[0220] (19) 5-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (Compound 19)

[0221] (20)N-(4-Methoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine; (화합물 20)

[0222] (21)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 21)

[0223] (22) 3-Fluoro-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 22)

[0224] (23)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 23)

[0225] (24)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 24)

[0226] (25)N-(5-Fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 25)

[0227] (26)N-(5-Methoxybenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 26)

[0228] (27)N-(5-Chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 27)

[0229] (28) 5-(Thiophen-3-yl)benzo[d]thiazol-2-amine; (화합물 28)

[0230] (29)N-(5-bromobenzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 29)

[0231] (30)N-(5-Bromo-1-methyl-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 30)

[0232] (31)N-(5-(Thiophen-3-yl)benzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 31)

[0233] (32)N-(5-(Thiophen-3-yl)benzo[d]isoxazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 32)

[0234] (33)N-(1-Methyl-5-(thiophen-3-yl)-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 33)

[0235] (34) 3-Methoxy-N-(5-(thiophen-2-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 34)

[0236] (35)N-(5-(4-Cyano-3-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 35)

[0237] (36)N-(5-(4-Cyanophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 36)

[0238] (37)N-(5-(Furan-2-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 37)

[0239] (38) 3-Methoxy-N-(5-(3-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 38)

[0240] (39) 3-Methoxy-N-(5-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 39)

[0241] (40) 3-Methoxy-N-(5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 40)

[0242] (41) 3-Methoxy-N-(5-phenylbenzo[d]oxazol-2-yl)benzamide; (화합물 41)

[0243] (42) 3-Methoxy-N-(5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 42)

[0244] (43)N-(5-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 43)

[0245] (44) 3-Methoxy-N-(5-(2-methylfuran-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 44)

[0246] (45)N-(5-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 45)

[0247] (46)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 46)

[0248] (47)N-(5-Bromo-7-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 47)

[0249] (48)N-(5-Bromo-6-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 48)

[0250] (49)N-(5-Bromo-6-fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 49)

[0251] (50)N-(5-Bromo-6-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 50)

[0252] (51)N-(7-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 51)

[0253] (52) 3-Methoxy-N-(7-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 52)

[0254] (53)N-(6-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 53)

[0255] (54)N-(6-Fluoro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 54)

[0256] (55) 3-Methoxy-N-(6-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 55)

[0257] (56)N-(5-(Thiophen-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 56)

[0258] (57)N-(6-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 57)

[0259] (58)N-(6-Bromooxazolo[5,4-b]pyridin-2-yl)-3-methoxybenzamide; (화합물 58)

[0260] (59) 3-Methoxy-N-(6-(thiophen-3-yl)oxazolo[5,4-b]pyridin-2-yl)benzamide; (화합물 59)

[0261] (60)N-(5-(Thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)-3-(trifluoromethyl)benzamide; (화합물 60)

[0262] (61) 3-Methoxy-N-(5-(thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)benzamide; (화합물 61)

[0263] (62) 3-Methoxy-N-(5-((thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 62)

[0264] (63)N-(5-((Furan-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 63)

[0265] (64)N-(5-(Cyclohexylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 64)

[0266] (65) 3-Methoxy-N-(5-((pyridin-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 65)

[0267] (66)N-(5-((Benzo[b]thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 66)

[0268] (67)N-(5-(Isopropylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 67)

[0269] (68) 3-Methoxy-N-(5-(3-methylbutanamido)benzo[d]oxazol-2-yl)benzamide; (화합물 68)

[0270] (69) 3-Methoxy-N-(5-propionamidobenzo[d]oxazol-2-yl)benzamide; (화합물 69)

[0271] (70) 3-Methoxy-N-(5-nitrobenzo[d]oxazol-2-yl)benzamide; (화합물 70)

[0272] (71)N-(5-Aminobenzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 71)

[0273] (72) 2-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)acetamide; (화합물 72)

[0274] (73) 3-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)propanamide; (화합물 73)

[0275] (74)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide; (화합물 74)

[0276] (75)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)propanamide; (화합물 75)

[0277] (76)N-(5-Bromobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 76)

[0278] (77) 1-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea; (화합물 77)

[0279] (78) 3-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzenesulfonamide; (화합물 78)

[0280] (79)N-(6-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 79)

[0281] (80) 3-Methoxy-N-(6-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 80)

[0282] (81) 3-Methoxy-N-(6-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 81)

[0283] (82)N-(6-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 82)

[0284] (83) 3-methoxy-N-(6-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 83)

[0285] (84) 3-(Trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 84)

[0286] (85) 3-Fluoro-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 85)

[0287] (86)N-(4-Methoxybenzyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-amine; (화합물 86)

[0288] (87)N-(4-Methoxybenzyl)-3-(trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)benzamide (화합물 87)

[0289] (88)N-(4-Methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 88)

[0290] (89)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-chlorobenzamide; (화합물 89)

[0291] (90)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 90)

[0292] (91)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-nitrobenzamide; (화합물 91)

[0293] (92)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)thiophene-2-carboxamide; (화합물 92)

[0294] (93)N-(7-Bromonaphthalen-2-yl)-3-(trifluoromethyl)benzamide; (화합물 93)

[0295] (94)N-(7-Bromoquinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (화합물 94)

[0296] (95)N-(7-(Thiophen-3-yl)naphthalen-2-yl)-3-(trifluoromethyl)benzamide; (화합물 95)

[0297] (96)N-(7-(Thiophen-3-yl)quinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (화합물 96)

[0298] (97)N-(5-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (화합물 97)

[0299] (98)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)-3-(trifluoromethyl)benzamide; (화합물 98)

[0300] (99)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (화합물 99) 및

[0301] (100)N-(3-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)phenyl)-3-(trifluoromethyl)benzamide (화합물 100).

[0302] In the present invention, the compound represented by the chemical formula 1 is wherein X1, X2, and X3 are each independently carbon (C),

[0303] Y1 is N=C-, Y2 is oxygen (O),

[0304] Z is NH-C=O-,

[0305] R1 may be a substituted or unsubstituted aryl group, R2 may be a heteroaryl group or a halogen element, R3 and R4 may each independently be hydrogen (H) or a halogen element, and R5 may be hydrogen (H), but is not limited thereto.

[0306]

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] In the present invention, the anticancer agent may be an immune checkpoint inhibitor or a chemotherapy agent, but is not limited thereto.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] In the present invention, “pharmaceutically acceptable salt” includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.

[0321] 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.

[0322] 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).

[0323] 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.

[0324] 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.

[0325] 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.

[0326] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0327] 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.

[0328] 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.

[0329] 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 modifier, and the like, as needed.

[0330] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340]

[0341] In addition, the present invention provides a food composition for preventing or improving cancer, comprising an oxazole derivative or a food-related acceptable salt thereof as an active ingredient.

[0342] In the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0343] In the present invention, “food-wise acceptable salt” includes a salt derived from a food-wise acceptable organic acid, inorganic acid, or base.

[0344] When the oxazole derivative of the present invention or its food-related acceptable salt is used as a food additive, the oxazole derivative or its food-related acceptable salt can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the oxazole derivative of the present invention or its food-related acceptable salt can 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 can be below the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount above the above range.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354]

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359]

[0360] [Example] Synthesis process of oxazole derivatives

[0361] Example 1. Synthesis of different types of oxazole derivatives (Scheme 1)

[0362] [Reaction Formula 1]

[0363]

[0364] Reagents and conditions: (a) Et3N, DCM, room temperature (RT), 3 h reaction; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O (9:1), 100 ℃, 2 h reaction; (c) 6a-m: Et3N, DMAP, DCM, room temperature, 12 h reaction; 6n-s: KHMDS, THF, room temperature, 2 h reaction; (d) (i) TFA, DCE, 60 ℃, 2 h reaction; (ii) TFA, DCM, room temperature, 2 h reaction.

[0365]

[0366] 1-1. Intermediate-3a: 5-Bromo-N-(4-methoxybenzyl)benzo[d]oxazol-2-amine

[0367] To a stirred solution of 5-bromo-2-chlorobenzo[d]oxazole (10.0 g, 1.0 eq) and triethylamine (18.01 mL, 3.0 eq) in DCM (200 mL) was added 4-methoxybenzylamine (11.24 g, 2.0 eq) at room temperature, and the solution was stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of water and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was then dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 50 mL of diethyl ether, and dried in air to give intermediate 3a as an off pale yellow solid (13.04 g, 90.98%).

[0368] 1H NMR (400MHz, DMSO-d6) δ8.60(s, 1H), 7.39(d,J= 1.9Hz, 1H), 7.28(t,J= 7.8Hz, 3H), 7.10(dd,J= 8.4, 2.0Hz, 1H), 6.88(d,J= 8.6Hz, 2H), 4.42(s, 2H), 3.70(s, 3H).

[0369]

[0370] 1-2. Intermediate-3b: 5-Bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine

[0371] To a stirred solution of 5-bromo-2-chlorobenzo[d]oxazole (2.00 g, 1.0 eq) and triethylamine (3.60 mL, 3.0 eq) in DCM (100 mL) was added 2,4-dimethoxybenzylamine (2.59 mL, 2.0 eq) at room temperature, and the solution was stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of water and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was then dissolved in ether, and the resulting solid was isolated by suction filtration, washed with 50 mL of diethyl ether, and dried in air to give intermediate 3b as an off pale-yellow solid (2.89 g, 92.38%).

[0372] 1H NMR (400 MHz, DMSO-d6) δ8.45 (t,J= 6.0 Hz, 1H), 7.40 (d,J= 2.0 Hz, 1H), 7.31 (d,J= 8.4 Hz, 1H), 7.19 (d,J= 8.3 Hz, 1H), 7.11 (dd,J= 8.4, 2.1 Hz, 1H), 6.57 (d,J= 2.4 Hz, 1H), 6.48 (dd,J= 8.4, 2.4 Hz, 1H), 4.40 (d,J= 4.8 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[0373]

[0374] 1-3. Intermediate-4a: N-(4-Methoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine (Compound 20)

[0375] Cs2CO3 (12.22 g, 2.5 eq) was added to a stirred solution of a 1,4-dioxane:H2O (9:1) mixture containing halide (5.00 g, 1.0 eq) and boronic acid (2.27 g, 1.2 eq). The resulting reaction mixture was purged with argon for 10 min and then Pd(dppf)Cl 2· DCM (1.23 g, 0.1 eq) was added to the reaction mixture. The resulting reaction mixture was then stirred 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 then purified with EtOAc / hexane to give intermediate 4a as an off-brown solid (4.27 g, 84.65%).

[0376] 1H NMR (400 MHz, DMSO-d6) δ8.45 (t,J= 5.9 Hz, 1H), 7.79 (d,J= 1.7 Hz, 1H), 7.60 (dd,J= 5.0, 2.9 Hz, 2H), 7.54 (d,J= 5.1 Hz, 1H), 7.36 - 7.29 (m, 4H), 6.91 (d,J= 8.6 Hz, 2H), 4.45 (d,J= 6.0 Hz, 2H), 3.73 (s, 3H).

[0377]

[0378] 1-4. Intermediate-4b:N-(2,4-Dimethoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0379] To a stirred solution of a mixture of 1,4-dioxane:H2O (9:1) containing 5-bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine (8.00 g, 1.0 eq) and 3-thiopheneboronic acid (3.92 g, 1.2 eq) was added Cs2CO3 (8.25 g, 2.5 eq), and the resulting reaction mixture was purged with argon for 10 min, followed by Pd(dppf)Cl 2· DCM (2.09 g, 0.1 eq) was added to the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 2 h, 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 to give intermediate 4b as an off-brown solid (4.27 g, 84.65%).

[0380] 1H NMR (400 MHz, DMSO-d6)δ8.26 (t,J= 6.0 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.60 (dd,J= 5.0, 2.9 Hz, 1H), 7.58 (s, 1H), 7.55 - 7.52 (m, 1H), 7.37 - 7.30 (m, 2H), 7.21 (d,J= 8.3 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.4, 2.5 Hz, 1H), 4.41 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[0381]

[0382] 1-5. General procedure for acid chloride coupling reaction (intermediates 6a-6m)

[0383] Acyl chloride (5.0 eq) was added to a stirred solution of amine (1.0 eq), triethylamine (3.0 eq), and DMAP (0.5 eq) in DCM (20 mL) at room temperature, and the reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was then diluted with 50 mL of water and extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane containing 0-70% EtOAc).

[0384]

[0385] 1-6. General procedure for acid chloride coupling reaction (intermediate 6n-6s)

[0386] To a stirred solution of intermediate 4b (1.0 eq) in THF (20 mL) was added THF (3.0 eq) containing 1 M KHMDS at room temperature. After 10 min, 3-methoxybenzoyl chloride (3.0 eq) was added at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then 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 purified by silica gel column chromatography (hexane containing 0–70% EtOAc).

[0387]

[0388] 1-7. Intermediate-6a: 3-Fluoro-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 22)

[0389] Intermediate 6a was obtained as an off white solid (1.6 g, 78.21%) through the general procedure of Example 1-5 above.

[0390] 1 H NMR (400 MHz, DMSO-d6) δ7.93 (d,J= 1.5 Hz, 1H), 7.89 (d,J= 1.5 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.58 (d,J= 3.9 Hz, 1H), 7.50 (d,J= 8.6 Hz, 1H), 7.41 (d,J= 7.9 Hz, 2H), 7.37 (d,J= 8.5 Hz, 3H), 7.28 (d,J= 7.5 Hz, 1H), 6.90 (d,J= 8.7 Hz, 2H), 5.21 (s, 2H), 3.71 (s, 3H).

[0391]

[0392] 1-8. Intermediate-6b:N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 21)

[0393] Intermediate 6b was obtained as an off white solid (0.15 g, 49.6%) through the general procedure of Example 1-5 above.

[0394] 1 H NMR (400 MHz, DMSO-d6) δ7.89 (dd,J= 14.3, 10.0 Hz, 4H), 7.78 (d,J= 7.8 Hz, 1H), 7.63 (dd,J= 11.2, 6.2 Hz, 3H), 7.58 (d,J= 4.9 Hz, 1H), 7.49 (d,J= 8.5 Hz, 1H), 7.38 (d,J= 8.7 Hz, 2H), 6.90 (d,J= 8.6 Hz, 2H), 5.24 (s, 2H), 3.71 (s, 3H).

[0395]

[0396] 1-9. Intermediate-6c: 3-Chloro-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0397] Intermediate 6c was obtained as an off white solid (1.6 g, 69.85%) through the general procedure of Example 1-5 above.

[0398] 1 H NMR (400 MHz, DMSO-d6) δ7.93 (s, 1H), 7.88 (s, 1H), 7.67 - 7.60 (m, 3H), 7.58 (d,J= 4.4 Hz, 2H), 7.51 (d,J= 8.6 Hz, 1H), 7.38 (dd,J= 11.4, 6.8 Hz, 4H), 6.90 (d,J= 8.6 Hz, 2H), 5.21 (s, 2H), 3.71 (s, 3H).

[0399]

[0400] 1-10. Intermediate-6d:N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0401] Intermediate 6d was obtained as an off-white solid (0.17 g, 43.3%) through the general procedure of the above Example 1-5.

[0402] 1 H NMR (400 MHz, DMSO-d6) δ7.93 (d,J= 1.6 Hz, 1H), 7.88 (d,J= 1.6 Hz, 1H), 7.62 (dd,J= 5.2, 3.0 Hz, 2H), 7.57 (d,J= 5.1 Hz, 1H), 7.50 (t,J= 6.2 Hz, 3H), 7.45 (d,J= 8.5 Hz, 1H), 7.39 (t,J= 7.7 Hz, 4H), 6.90 (d,J= 8.6 Hz, 2H), 5.21 (s, 2H), 3.71 (s, 3H).

[0403]

[0404] 1-11. Intermediate-6e:N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide (Compound 24)

[0405] Intermediate 6e was obtained as an off white solid (0.16 g, 34.3%) through the general procedure of the above Example 1-5.

[0406] 1 H NMR (400 MHz, DMSO-d6) δ7.92 (s, 1H), 7.88 (s, 1H), 7.63 (dd,J= 11.9, 6.7 Hz, 2H), 7.56 (dd,J= 9.6, 5.2 Hz, 4H), 7.47 (d,J= 8.4 Hz, 2H), 7.37 (d,J= 8.7 Hz, 2H), 6.90 (d,J= 8.7 Hz, 2H), 5.22 (s, 2H), 3.712 (s, 3H).

[0407]

[0408] 1-12. Intermediate-6f: 3-Cyano-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0409] Intermediate 6f was obtained as an off white solid (0.24 g, 21.68%) through the general procedure of the above Example 1-5.

[0410] 1 H NMR (400 MHz, DMSO-d6) δ8.09 (s, 1H), 7.99 (d,J= 7.8 Hz, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.79 (d,J= 8.2 Hz, 1H), 7.62 (d,J= 5.6 Hz, 2H), 7.60 - 7.55 (m, 2H), 7.51 (d,J= 8.5 Hz, 1H), 7.38 (d,J= 8.6 Hz, 2H), 6.90 (d,J= 8.7 Hz, 2H), 5.23 (s, 2H), 3.71 (s, 3H).

[0411]

[0412] 1-13. Intermediate-6g:N-(3,5-Dimethoxybenzyl)-3-methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0413] Through the general procedure of Example 1-5 above, 6 g of the intermediate was obtained as an off white solid (1.66 g, 69.73%).

[0414] 1H NMR (400 MHz, DMSO-d6) δ7.95 (d,J= 1.5 Hz, 1H), 7.89 (dd,J= 2.8, 1.3 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.58 (dd,J= 5.0, 1.2 Hz, 1H), 7.49 (d,J= 8.5 Hz, 1H), 7.37 (d,J= 8.7 Hz, 2H), 7.27 (t,J= 8.1 Hz, 1H), 7.09 - 7.04 (m, 2H), 7.00 (d,J= 7.7 Hz, 1H), 6.90 (d,J= 8.7 Hz, 2H), 5.19 (s, 2H), 3.71 (s, 3H), 3.68 (s, 3H).

[0415]

[0416] 1-14. Intermediate-6h:N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide (Compound 23)

[0417] Intermediate 6h was obtained as an off-white solid (1.05 g, 80.20%) through the general procedure of Example 1-5 above.

[0418] 1 H NMR (400 MHz, DMSO-d6) δ8.73 - 8.65 (m, 2H), 7.95 - 7.86 (m, 3H), 7.67 - 7.56 (m, 3H), 7.52 (d,J= 8.5 Hz, 1H), 7.44 (dd,J= 7.8, 4.8 Hz, 1H), 7.38 (d,J= 8.6 Hz, 2H), 6.90 (d,J= 8.6 Hz, 2H), 5.24 (s, 2H), 3.71 (s, 3H).

[0419]

[0420] 1-15. Intermediate-6i: 4-Chloro-N-(3,5-dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0421] Intermediate 6i was obtained as an off pale yellow solid (0.31 g, 63.79%) through the general procedure of Example 1-5 above.

[0422] 1 H NMR (400 MHz, DMSO-d6) δ8.14 (d,J= 8.1 Hz, 3H), 7.88 (d,J= 8.4 Hz, 4H), 7.77 (d,J= 8.5 Hz, 2H), 7.63 - 7.61 (m, 1H), 7.58 (d,J= 7.7 Hz, 2H), 7.32 (d,J= 8.0 Hz, 1H), 5.15 (s, 2H), 3.73 (s, 3H), 3.48 (s, 3H).

[0423]

[0424] 1-16. Intermediate-6j:N-(3,5-Dimethoxybenzyl)-4-fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0425] Intermediate 6j was obtained as an off pale yellow solid (0.16 g, 34.76%) through the general procedure of the above Example 1-5.

[0426] 1 H NMR (400 MHz, DMSO-d6) δ7.92 (d,J= 1.4 Hz, 1H), 7.90 - 7.88 (m, 1H), 7.66 (dd,J= 8.5, 1.8 Hz, 1H), 7.62 (dd,J= 5.0, 2.9 Hz, 1H), 7.60 - 7.55 (m, 3H), 7.54 (s, 1H), 7.30 (d,J= 8.1 Hz, 1H), 7.22 (t,J= 8.8 Hz, 2H), 6.54 - 6.48 (m, 2H), 5.12 (s, 2H), 3.72 (s, 3H), 3.49 (s, 3H).

[0427]

[0428] 1-17. Intermediate-6k:N-(3,5-Dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethyl)benzamide

[0429] Intermediate 6k was obtained as an off-white solid (0.60 g, 49.30%) through the general procedure of Example 1-5 above.

[0430] 1 H NMR (400 MHz, DMSO-d6) δ8.14 (d,J= 8.1 Hz, 3H), 7.88 (d,J= 8.4 Hz, 4H), 7.77 (d,J= 8.5 Hz, 2H), 7.63 - 7.61 (m, 1H), 7.58 (d,J= 7.7 Hz, 2H), 7.32 (d,J= 8.0 Hz, 1H), 5.15 (s, 2H), 3.73 (s, 3H), 3.48 (s, 3H).

[0431]

[0432] 1-18. Intermediate-6l:N-(3,5-Dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethoxy)benzamide

[0433] Intermediate 6l was obtained as an off white solid (0.60 g, 49.30%) through the general procedure of the above Example 1-5.

[0434] 1 H NMR (400 MHz, DMSO-d6) δ8.14 (d,J= 8.1 Hz, 3H), 7.88 (d,J= 8.4 Hz, 4H), 7.77 (d,J= 8.5 Hz, 2H), 7.63 - 7.61 (m, 1H), 7.58 (d,J= 7.7 Hz, 2H), 7.32 (d,J= 8.0 Hz, 1H), 5.15 (s, 2H), 3.73 (s, 3H), 3.48 (s, 3H).

[0435]

[0436] 1-19. Intermediate-6m: 5-Chloro-N-(2,4-dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide

[0437] Intermediate 6m was obtained as an off-white solid (0.080 g, 65.2%) through the general procedure of the above Example 1-5.

[0438] 1 H NMR (400 MHz, DMSO-d6) δ8.10 (d, J= 2.4 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.68 - 7.58 (m, 3H), 7.54 (d,J= 8.4 Hz, 1H), 7.34 (d,J= 9.2 Hz, 1H), 6.51 (d,J= 6.8 Hz, 2H), 5.14 (s, 2H), 3.72 (s, 3H), 3.50 (s, 3H).

[0439]

[0440] 1-20. Intermediate-6n: 2-Chloro-N-(3,5-dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0441] Intermediate 6n was obtained as an off white solid (0.080 g, 7.26%) through the general procedure of the above Example 1-6.

[0442] 1H NMR (400 MHz, DMSO-d6) δ7.87 (dd,J= 2.9, 1.4 Hz, 1H), 7.84 (d,J= 1.4 Hz, 1H), 7.63 - 7.61 (m, 1H), 7.61 - 7.59 (m, 1H), 7.56 (dd,J= 5.1, 1.4 Hz, 1H), 7.50 (s, 1H), 7.47 (dd,J= 3.6, 1.7 Hz, 2H), 7.43 (d,J= 8.0 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.26 (d,J= 8.2 Hz, 1H), 6.53 - 6.47 (m, 2H), 5.18 (s, 2H), 3.72 (s, 3H), 3.58 (s, 3H).

[0443]

[0444] 1-21. Intermediate-6o:N-(3,5-Dimethoxybenzyl)-2-fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0445] Intermediate 6o was obtained as an off pale yellow solid (0.22 g, 20.63%) through the general procedure of the above Example 1-6.

[0446] 1 H NMR (400 MHz, DMSO-d6) δ7.87 (dd,J= 2.9, 1.4 Hz, 1H), 7.84 (d,J= 1.4 Hz, 1H), 7.63 - 7.61 (m, 1H), 7.61 - 7.59 (m, 1H), 7.56 (dd,J= 5.1, 1.4 Hz, 1H), 7.50 (s, 1H), 7.47 (dd,J= 3.6, 1.7 Hz, 2H), 7.43 (d,J= 8.0 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.26 (d,J= 8.2 Hz, 1H), 6.53 - 6.47 (m, 2H), 5.18 (s, 2H), 3.72 (s, 3H), 3.58 (s, 3H).

[0447]

[0448] 1-22. Intermediate-6p:N-(2,4-Dimethoxybenzyl)-2-methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0449] Intermediate 6p was obtained as an off-white solid (0.50 g, 72.5%) through the general procedure of the above Example 1-6.

[0450] 1 H NMR (400 MHz, DMSO-d6) δ7.86 (d,J= 4.3 Hz, 2H), 7.64 - 7.60 (m, 2H), 7.57 (d,J= 3.7 Hz, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 7.43 (d,J= 7.6 Hz, 1H), 7.27 (d,J= 8.0 Hz, 1H), 7.03 (t,J= 7.5 Hz, 1H), 6.94 (d,J= 8.0 Hz, 1H), 6.50 (d,J= 8.2 Hz, 2H), 5.13 (s, 2H), 3.73 (s, 3H), 3.60 (s, 3H), 3.42 (s, 3H).

[0451]

[0452] 1-23. Intermediate-6q:N-(2,4-Dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(trifluoromethyl)benzamide

[0453] Intermediate 6q was obtained as an off-white solid (0.54 g, 73.3%) through the general procedure of Example 1-6 above.

[0454] 1H NMR (400 MHz, DMSO-d6)δ7.84 (dd,J= 13.7, 6.2 Hz, 3H), 7.66 - 7.58 (m, 4H), 7.56 - 7.54 (m, 1H), 7.50 (d,J= 4.7 Hz, 1H), 7.45 (d,J= 8.9 Hz, 1H), 7.21 (d,J= 8.5 Hz, 1H), 6.52 - 6.47 (m, 2H), 5.19 (s, 2H), 3.72 (s, 3H), 3.58 (s, 3H).

[0455]

[0456] 1-24. Intermediate-6r:N-(2,4-Dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide

[0457] Intermediate 6r was obtained as a pale-yellow solid (0.080 g, 73.3%) through the general procedure of the above Example 1-6.

[0458] 1 H NMR (400 MHz, DMSO-d6)δ8.24 (d,J= 4.6 Hz, 1H), 8.01 (ddd,J= 16.4, 14.8, 7.6 Hz, 3H), 7.91 - 7.88 (m, 2H), 7.66 - 7.64 (m, 1H), 7.63 - 7.58 (m, 2H), 7.49 (d,J= 8.5 Hz, 1H), 7.36 (d,J= 9.0 Hz, 1H), 6.53 - 6.50 (m, 2H), 5.14 (s, 2H), 3.73 (s, 3H), 3.52 (s, 3H).

[0459]

[0460] 1-25. Intermediate-6s: 5-Chloro-N-(2,4-dimethoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide

[0461] Intermediate 6s was obtained as an off-white solid (0.080 g, 65.2%) through the general procedure of the above Example 1-6.

[0462] 1 H NMR (400 MHz, DMSO-d6) δ8.10 (d, J= 2.4 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.68 - 7.58 (m, 3H), 7.54 (d,J= 8.4 Hz, 1H), 7.34 (d,J= 9.2 Hz, 1H), 6.51 (d,J= 6.8 Hz, 2H), 5.14 (s, 2H), 3.72 (s, 3H), 3.50 (s, 3H).

[0463]

[0464] 1-26. General procedure for 4-methoxy benzyl or 2,4-methoxy benzyl deprotection

[0465] Trifluoroacetic acid (10 mL) was added to a stirred solution of DCE (20 mL) containing amide (1.0 eq) at room temperature, and the reaction mixture was stirred at room temperature or 60 °C. The reaction mixture was diluted with 50 mL of water and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with hexane containing EtOAc.

[0466]

[0467] 1-27. Chemical Formula 7a: 3-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 1)

[0468] Through the above general procedure, the compound of formula 7a was obtained as an off gray solid (0.36 g, 32.59%).

[0469] 1H NMR (400 MHz, Chloroform-d)δ12.22 - 12.07 (s, 1H), 7.97 (d, 2H), 7.54 - 7.41 (m, 5H), 7.36 (s, 1H), 7.24 - 7.21 (m, 1H), 7.07 (d,J= 8.5 Hz, 1H).

[0470]

[0471] 1-28. Chemical Formula-7b: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-trifluoromethyl)benzamide (Compound 2)

[0472] Through the above general procedure, the compound of chemical formula 7b was obtained as an off white solid (0.025 g, 16.00%).

[0473] 1 H NMR (400 MHz, Chloroform-d)δ8.61 (d,J= 47.5 Hz, 2H), 7.78 (s, 1H), 7.53 (br s, 3H), 7.34 (d,J= 36.9 Hz, 1H), 7.16 (d,J= 28.4 Hz, 2H), 6.81 (s, 1H).

[0474]

[0475] 1-29. Chemical Formula 7c: 3-chloro-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 3)

[0476] Through the above general procedure, the compound of chemical formula 7c was obtained as an off gray solid (0.27 g, 25.67%).

[0477] 1H NMR (400 MHz, cd3od)δ8.09 (s, 1H), 8.01 (d,J= 8.0 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.63 (d,J= 7.9 Hz, 2H), 7.56 - 7.48 (m, 3H), 7.31 (dd,J= 13.2, 6.6 Hz, 1H), 7.10 - 7.02 (m, 1H).

[0478]

[0479] 1-30. Chemical formula - 7d:N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (compound 4)

[0480] Through the above general procedure, the compound of chemical formula 7d was obtained as an off white solid (0.025 g, 23.5%).

[0481] 1 H NMR (400 MHz, DMSO-d6)δ12.07 (s, 1H), 8.23 ​​(d,J= 29.9 Hz, 2H), 7.99 (dd,J= 29.1, 16.7 Hz, 3H), 7.74 - 7.52 (m, 6H), 7.46 - 7.23 (m, 4H), 7.19 - 7.06 (m, 2H), 6.93 - 6.83 (m, 2H), 6.73 (d,J= 7.8 Hz, 1H).

[0482]

[0483] 1-31. Chemical formula -7e: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide (Compound 5)

[0484] Through the above general procedure, the compound of chemical formula 7e was obtained as an off white solid (0.025 g, 22.1%).

[0485] 1H NMR (400 MHz, Chloroform-d)δ8.25 (d,J=13.8 Hz, 2H), 7.57 - 7.32 (m, 5H), 7.20 - 6.99 (m, 2H), 6.88 - 6.74 (m, 1H).

[0486]

[0487] 1-32. Formula-7f: 3-Cyano-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 6)

[0488] Through the above general procedure, the compound of chemical formula 7f was obtained as an off gray solid (0.14 g, 50.60%).

[0489] 1 H NMR (400 MHz, Chloroform-d)δ8.25 (d,J=13.8 Hz, 2H), 7.57 - 7.32 (m, 5H), 7.20 - 6.99 (m, 2H), 6.88 - 6.74 (m, 1H).

[0490]

[0491] 1-33. Chemical Formula-7g: 3-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 7)

[0492] Through the above general procedure, the compound of chemical formula 7g was obtained as an off white solid (0.14 g, 50.60%).

[0493] 1 H NMR (400 MHz, DMSO-d6) δ12.07 (s, 1H), 7.92 (s, 1H), 7.67 (d,J= 7.4 Hz, 2H), 7.62 (s, 3H), 7.46 (dd,J= 15.1, 6.6 Hz, 2H), 7.22 (d,J= 8.0 Hz, 1H), 7.10 (d,J= 8.5 Hz, 1H), 6.86 (d,J= 8.6 Hz, 1H), 3.85 (s, 3H).

[0494]

[0495] 1-34. Chemical formula - 7h:N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide (Compound 8)

[0496] Through the above general procedure, the compound of chemical formula 7h was obtained as an off yellow solid (0.16 g, 21.44%).

[0497] 1 H NMR (400 MHz, DMSO-d6)δ12.59 (s, 1H), 9.21 (s, 1H), 8.80 (d,J= 4.6 Hz, 1H), 8.40 (d,J= 7.3 Hz, 1H), 7.91 (s, 1H), 7.74 - 7.63 (m, 2H), 7.58 (d,J= 11.3 Hz, 2H), 7.08 (dd,J= 18.4, 7.3 Hz, 1H), 6.86 (d,J= 8.7 Hz, 1H).

[0498]

[0499] 1-35. Chemical Formula-7i: 4-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 9)

[0500] Through the above general procedure, the compound of chemical formula 7i was obtained as an off white solid (0.079 g, 45.70%).

[0501] 1 H NMR (400 MHz, DMSO-d6) δ12.23 (s, 1H), 8.09 (d,J= 5.7 Hz, 2H), 7.91 (s, 2H), 7.68 (s, 3H), 7.63 (d,J= 8.5 Hz, 3H).

[0502]

[0503] 1-36. Chemical Formula-7j: 4-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 10)

[0504] Through the above general procedure, the compound of chemical formula 7j was obtained as an off white solid (0.11 g, 52.94%).

[0505] 1 H NMR (400 MHz, DMSO-d6) δ12.11 (s, 1H), 8.11 (s, 2H), 7.92 (s, 2H), 7.68 (s, 4H), 7.41 (s, 2H).

[0506]

[0507] 1-37. Chemical formula - 7k: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-trifluoromethyl)benzamide (Compound 11)

[0508] Through the above general procedure, the compound of chemical formula 7k was obtained as a gray solid (0.023 g, 2.50%).

[0509] 1 H NMR (400 MHz, DMSO-d6) δ12.57 (s, 1H), 8.25 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 8.6 Hz, 3H), 7.66 (s, 2H), 7.58 (d, J = 5.2 Hz, 1H), 7.08 (d,J= 8.5 Hz, 1H), 6.84 (d,J= 8.4 Hz, 1H).

[0510]

[0511] 1-38. Chemical formula - 7l: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethoxy)benzamide (Compound 12)

[0512] Through the above general procedure, the compound of chemical formula 7l was obtained as an off white solid (0.015 g, 6.86%).

[0513] 1H NMR (400 MHz, Methanol-d4)δ8.19 (d,J= 6.5 Hz, 2H), 7.84 (s, 1H), 7.64 (d,J= 9.0 Hz, 2H), 7.55 (d,J= 8.9 Hz, 1H), 7.50 (s, 2H), 7.44 (d,J= 7.4 Hz, 2H).

[0514]

[0515] 1-39. Chemical Formula-7m: 2-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)isonicotinamide (Compound 13)

[0516] Through the above general procedure, the compound of chemical formula 7m was obtained as a white solid (0.021 g, 11.3%).

[0517] 1 H NMR (400 MHz, DMSO-d6) δ8.85 (d,J= 6.0 Hz, 2H), 8.03 (d,J= 2.5 Hz, 2H), 7.91 (d,J= 5.6 Hz, 2H), 7.70 (s, 2H), 7.69 - 7.66 (m, 1H), 7.60 (d,J= 4.8 Hz, 1H).

[0518]

[0519] 1-40. Chemical formula-7n: 2-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 14)

[0520] Through the above general procedure, the compound of chemical formula 7n was obtained as an off white solid (0.010 g, 25.88%).

[0521] 1 H NMR (400 MHz, DMSO-d6) δ12.34 (s, 1H), 7.94 (d, J= 16.0 Hz, 2H), 7.68 (s, 3H), 7.59 (s, 1H), 7.56 (s, 2H), 7.50 (d, J= 7.9 Hz, 2H).

[0522]

[0523] 1-41. Chemical Formula-7o: 2-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 15)

[0524] Through the above general procedure, the compound of chemical formula 7o was obtained as an off white solid (0.072 g, 5.84%).

[0525] 1 H NMR (400 MHz, DMSO-d6) δ12.26 (s, 1H), 7.93 (s, 2H), 7.66 (d, J= 15.5 Hz, 6H), 7.37 (s, 2H).

[0526]

[0527] 1-42. Chemical Formula-7p: 2-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 16)

[0528] Through the above general procedure, the compound of chemical formula 7p was obtained as a white solid (0.035 g, 10.4%).

[0529] 1 H NMR (400 MHz, DMSO-d6)δ11.62 (s, 1H), 7.93 (d,J= 14.7 Hz, 2H), 7.66 (s, 3H), 7.64 (s, 2H), 7.59 - 7.54 (m, 1H), 7.20 (d,J= 8.5 Hz, 1H), 7.09 (t,J= 7.4 Hz, 1H), 3.88 (s, 3H).

[0530]

[0531] 1-43. Chemical formula -7q:N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(trifluoromethyl)benzamide (Compound 17)

[0532] Through the above general procedure, the compound of chemical formula 7q was obtained as a white solid (0.071 g, 13.4%).

[0533] 1 H NMR (400 MHz, DMSO-d6) δ12.34 (s, 1H), 7.94 (d, J= 16.0 Hz, 2H), 7.68 (s, 3H), 7.59 (s, 1H), 7.56 (s, 2H), 7.50 (d, J= 7.9 Hz, 2H).

[0534]

[0535] 1-44. Chemical formula -7r:N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide (Compound 18)

[0536] Through the above general procedure, the compound of chemical formula 7r was obtained as a white solid (0.034 g, 11.1%).

[0537] 1 H NMR (400 MHz, DMSO-d6) δ12.34 (s, 1H), 7.94 (d, J= 16.0 Hz, 2H), 7.68 (s, 3H), 7.59 (s, 1H), 7.56 (s, 2H), 7.50 (d, J= 7.9 Hz, 2H).

[0538]

[0539] 1-45. Chemical Formula-7s: 5-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide (Compound 19)

[0540] Through the above general procedure, the compound of chemical formula 7s was obtained as a white solid (0.035 g, 11.3%).

[0541] 1 H NMR (400 MHz, DMSO-d6)δ12.03 (s, 1H), 8.84 (s, 1H), 8.25 (d,J= 9.2 Hz, 1H), 8.19 (d,J= 8.4 Hz, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.70 (s, 2H), 7.65 (t,J= 5.0 Hz, 2H).

[0542]

[0543] Example 2. Synthesis of different types of oxazole derivatives (Reaction Scheme 2)

[0544] [Reaction Formula 2]

[0545]

[0546] Reagents and conditions: (a) zinc, EtOH:AcOH (7:3), 80 °C, 2 h reaction; (b) cyanogen bromide, MeOH, 40 °C, 12 h reaction; (c) pyridine, room temperature, 2 h reaction.

[0547]

[0548] 2-1. Intermediate-9: 2-Amino-4-fluorophenol

[0549] To a stirred solution of EtOH:AcOH (7:3, 100 mL) containing 4-fluoro-2-nitrophenol (1.50 g, 1.0 eq) was added zinc powder (6.24 g, 10.0 eq) at room temperature, and the solution was stirred at 80 °C for 2 h. The reaction mixture was then filtered and evaporated. The crude product was washed with pentane to give intermediate 9 as a brown solid (2.0 g, quantitative).

[0550] 1 H NMR (400 MHz, DMSO-d6) δ8.90 (s, 1H), 6.55 (dd,J= 8.5, 5.6 Hz, 1H), 6.36 (dd,J= 10.8, 3.1 Hz, 1H), 6.12 (td,J= 8.6, 3.0 Hz, 1H), 4.78 (s, 2H).

[0551]

[0552] 2-2. General procedure for intermediates 10 and 12

[0553] To a stirred solution of substituted intermediate 2a / b (1.0 eq) in MeOH (200 mL) was added cyanogen bromide (3.0 eq) at room temperature, and the solution was stirred at 40 °C for 12 h. The reaction mixture was quenched by the addition of saturated Na2CO3 solution, and the pH was adjusted to 7–8. The reaction mixture was then evaporated under reduced pressure, and the residue was washed with pentane.

[0554]

[0555] 2-3. Intermediate-10: 5-Fluorobenzo[d]oxazol-2-amine

[0556] Intermediate 10 was obtained as a brown solid (0.15 g, 6.3%) through the general procedure of Example 2-2 above.

[0557] 1 H NMR (400 MHz, DMSO-d6) δ7.53 (s, 2H), 7.30 (dd,J= 8.6, 4.5 Hz, 1H), 7.01 (dd,J= 9.4, 2.6 Hz, 1H), 6.78 - 6.72 (m, 1H).

[0558]

[0559] 2-4. Intermediate-12: 5-Methoxybenzo[d]oxazol-2-amine

[0560] Intermediate 12 was obtained as a black solid (0.42 g, 35.6%) through the general procedure of Example 2-2 above.

[0561] 1 H NMR (400 MHz, DMSO-d6) δ7.32 (s, 2H), 7.18 (d,J= 8.6 Hz, 1H), 6.78 (d,J= 2.5 Hz, 1H), 6.51 (dd,J= 8.6, 2.5 Hz, 1H), 3.73 (s, 3H).

[0562]

[0563] 2-5. General procedure for chemical formulas 14, 15, and 16

[0564] To a stirred solution of pyridine (20 mL) containing intermediates 10, 12, and 13 (1.0 eq) was added 3-(trifluoromethyl)benzoyl chloride (2.0 eq) dropwise at room temperature, and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then diluted with 50 mL of water and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude product was washed with ether.

[0565]

[0566] 2-6. Chemical Formula-14: N-(5-Fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 25)

[0567] Through the general procedure of Example 2-5 above, the compound of chemical formula 14 was obtained as a pale brown solid (14.0 mg, 2.3%).

[0568] 1 H NMR (400 MHz, DMSO-d6) δ12.45 (s, 1H), 8.39 (s, 1H), 8.34 (d,J= 7.6 Hz, 1H), 8.03 (d,J= 8.0 Hz, 1H), 7.81 (t,J= 7.8 Hz, 1H), 7.71 (d,J= 8.7 Hz, 2H), 7.37 (dd,J= 8.6, 2.1 Hz, 1H).

[0569]

[0570] 2-7. Chemical Formula-15: N-(5-Methoxybenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 26)

[0571] Through the general procedure of Example 2-5 above, the compound of chemical formula 15 was obtained as a white solid (0.27 g, 33.0%).

[0572] 1H NMR (400 MHz, DMSO-d6) δ12.22 (s, 1H), 8.40 (s, 1H), 8.36 (d,J= 7.4 Hz, 1H), 8.01 (d,J= 7.8 Hz, 1H), 7.80 (t,J= 7.8 Hz, 1H), 7.55 (d,J= 8.9 Hz, 1H), 7.15 (s, 1H), 6.89 (dd,J= 8.9, 2.6 Hz, 1H), 3.81 (s, 3H).

[0573]

[0574] 2-8. Chemical Formula-16: N-(5-Chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 27)

[0575] Through the general procedure of Example 2-5 above, the compound of chemical formula 16 was obtained as a gray solid (8.2 mg, 2.6%).

[0576] 1 H NMR (400 MHz, DMSO-d6) δ8.39 (s, 1H), 8.34 (d,J= 7.9 Hz, 1H), 8.03 (d,J= 7.5 Hz, 1H), 7.81 (t,J= 7.8 Hz, 1H), 7.70 (dd,J= 8.9, 4.3 Hz, 1H), 7.47 (d,J= 8.3 Hz, 1H), 7.20 - 7.15 (m, 1H).

[0577]

[0578] Example 3. Synthesis of different types of oxazole derivatives (Scheme 3)

[0579] [Reaction Formula 3]

[0580]

[0581] Reagents and conditions: (a) 3-trifluoromethylbenzoyl chloride, pyridine, room temperature, reaction time 2 hours; (b) 3-thiopheneboronic acid, PdCl2(dppf)·DCM, Et3N, EtOH, 80 ℃, reaction time 2 hours.

[0582]

[0583] 3-1. General procedures for chemical formulas and intermediates 18a-18d

[0584] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethylbenzoyl chloride (4.0 eq), and the reaction mixture was 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 then purified by silica gel column chromatography to obtain the chemical formula and intermediates 18a-18d.

[0585]

[0586] 3-2. Chemical Formula-18a: 5-(Thiophen-3-yl)benzo[d]thiazol-2-amine (Compound 28)

[0587] Through the general procedure of Example 3-1 above, a compound of chemical formula 18a was obtained as an off-white solid (0.47 g, 53.41%).

[0588] 1 H NMR (400 MHz, Chloroform-d)δ12.41 (s, 1H), 8.62 (s, 1H), 8.50 (d,J= 8.0 Hz, 1H), 7.75 (d,J= 7.7 Hz, 1H), 7.57 (t,J= 7.7 Hz, 1H), 7.49 (d,J= 1.7 Hz, 1H), 7.42 (dd,J= 8.5, 1.8 Hz, 1H), 7.15 (d,J= 8.5 Hz, 1H), 3.77 (s, 3H).

[0589]

[0590] 3-3. Chemical formula-18b: N-(5-bromobenzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 29)

[0591] Through the general procedure of Example 3-1 above, a compound of chemical formula 18b was obtained as an off-white solid (1.2 g, 34.26%).

[0592] 1 H NMR (400 MHz, Chloroform-d)δ11.48 (s, 1H), 8.24 (s, 1H), 8.18 (d,J= 7.7 Hz, 1H), 7.88 (d,J= 7.9 Hz, 1H), 7.72 (d,J= 8.5 Hz, 1H), 7.65 (t,J= 7.8 Hz, 1H), 7.43 (dd,J= 8.5, 1.8 Hz, 1H), 7.34 (d,J= 1.7 Hz, 1H).

[0593]

[0594] 3-4. Intermediate-18c:N-(5-Bromobenzo[d]isoxazol-3-yl)-3-(trifluoromethyl)benzamide

[0595] Intermediate 18c was obtained as an off-white solid (0.8 g, 88.39%) through the general procedure of Example 3-1 above.

[0596] 1 H NMR (400 MHz, Chloroform-d)δ8.42 (s, 1H), 8.33 (s, 1H), 8.22 (d,J= 7.3 Hz, 1H), 7.88 (d,J= 8.0 Hz, 1H), 7.67 (d,J= 8.3 Hz, 2H), 7.40 (d,J= 9.0 Hz, 1H).

[0597]

[0598] 3-5. Chemical formula - 18d: N-(5-Bromo-1-methyl-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide (Compound 30)

[0599] Through the general procedure of Example 3-1 above, a compound of chemical formula 18d was obtained as an off-white solid (0.705 g, 80.12%).

[0600] 1 H NMR (400 MHz, DMSO-d6) δ11.18 (s, 1H), 8.40 (s, 1H), 8.34 (d,J= 8.1 Hz, 1H), 8.01 (d,J= 1.6 Hz, 1H), 7.98 (d,J= 8.0 Hz, 1H), 7.78 (t,J= 7.9 Hz, 1H), 7.62 (d,J= 8.9 Hz, 1H), 7.54 - 7.49 (m, 1H).

[0601]

[0602] 3-6. General procedure for chemical formulas 19b-19d

[0603] Et3N (3.0 eq) was added to a stirred solution of EtOH containing a bromo compound (1.0 eq) and 3-thiopheneboronic 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, and the reaction mixture was stirred in a sealed tube at 80 °C for 2 h. The reaction mixture was then 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 chemical formula 19b-19d.

[0604]

[0605] 3-7. Chemical Formula-19b: N-(5-(Thiophen-3-yl)benzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 31)

[0606] Through the general procedure of Example 3-6 above, the compound of chemical formula 19b was obtained as an off white solid (0.023 g, 3.21%).

[0607] 1H NMR (400 MHz, Chloroform-d)δ8.30 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.91 - 7.85 (m, 2H), 7.75 (s, 1H), 7.70 (s, 1H), 7.61 (d,J= 9.9 Hz, 1H), 7.51 (dd,J= 4.6, 2.5 Hz, 1H), 7.43 (d,J= 2.2 Hz, 1H).

[0608]

[0609] 3-8. Chemical Formula-19c: N-(5-(Thiophen-3-yl)benzo[d]isoxazol-3-yl)-3-(trifluoromethyl)benzamide (Compound 32)

[0610] Through the general procedure of Example 3-6 above, a compound of chemical formula 19c was obtained as an off orange solid (0.168 g, 16.64%).

[0611] 1 H NMR (400 MHz, DMSO-d6)δ10.71 (s, 1H), 8.42 (d,J= 1.9 Hz, 1H), 8.31 (d,J= 7.8 Hz, 1H), 8.28 (s, 1H), 8.03 (d,J= 8.0 Hz, 1H), 7.88 (d,J= 10.7 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.66 (d,J= 2.1 Hz, 2H), 7.01 (d,J= 8.6 Hz, 1H).

[0612]

[0613] 3-9. Chemical Formula-19d: N-(1-Methyl-5-(thiophen-3-yl)-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide (Compound 33)

[0614] Through the general procedure of Example 3-6 above, a compound of chemical formula 19d was obtained as an off-white solid (0.159 g, 31.44%).

[0615] 1H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 8.44 (s, 1H), 8.38 (d,J= 8.2 Hz, 1H), 8.04 (s, 1H), 8.01 (d,J= 7.8 Hz, 1H), 7.95 (s, 1H), 7.81 (d,J= 4.4 Hz, 2H), 7.67 (d,J= 8.9 Hz, 1H), 7.63 (dd,J= 5.0, 2.9 Hz, 1H), 7.58 - 7.55 (m, 1H), 4.04 (s, 3H).

[0616]

[0617] Example 4. Synthesis of different types of oxazole derivatives (Reaction Scheme 4)

[0618] [Reaction Formula 4]

[0619]

[0620] Reagents and conditions: (b) corresponding boronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 100 ℃, 2 h reaction; (c) KHMDS, THF, room temperature, 2 h reaction; (d) TFA, DCM, room temperature, 30 min reaction.

[0621]

[0622] 4-1. Intermediate-3b: 5-Bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine

[0623] To a stirred solution of 5-bromo-2-chlorobenzo[d]oxazole (2.00 g, 1.0 eq) and triethylamine (3.60 mL, 3.0 eq) in DCM (100 mL) was added 2,4-dimethoxybenzylamine (2.59 mL, 2.0 eq) at room temperature, and the solution was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (3 x 100 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 air dried to give intermediate 3a as an off pale-yellow solid (2.89 g, 92.38%).

[0624] 1 H NMR (400 MHz, DMSO-d6) δ8.45 (t,J= 6.0 Hz, 1H), 7.40 (d,J= 2.0 Hz, 1H), 7.31 (d,J= 8.4 Hz, 1H), 7.19 (d,J= 8.3 Hz, 1H), 7.11 (dd,J= 8.4, 2.1 Hz, 1H), 6.57 (d,J= 2.4 Hz, 1H), 6.48 (dd,J= 8.4, 2.4 Hz, 1H), 4.40 (d,J= 4.8 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[0625]

[0626] 4-2. General procedure for chemical formulas 20a-20l

[0627] Cs2CO3 (2.5 eq) was added to a stirred solution of a mixture of 1,4-dioxane:H2O (9:1) containing 5-bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine (1.0 eq) and boronic acids (1.2 eq). The resulting reaction mixture was purged with argon for 10 min, and then Pd(dppf)Cl 2· DCM (0.1 eq) was added to the reaction mixture, and the resulting reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was then 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 hexane containing EtOAc.

[0628]

[0629] 4-3. Intermediate-20a:N-(2,4-Dimethoxybenzyl)-5-(thiophen-2-yl)benzo[d]oxazol-2-amine

[0630] Intermediate 20a was obtained as an off-white solid (0.25 g, 42.7%) through the general procedure of Example 4-2 above.

[0631] 1 H NMR (400 MHz, DMSO-d6) δ8.33 (t,J= 5.9 Hz, 1H), 7.50 (d,J= 1.6 Hz, 1H), 7.48 (dd,J= 5.1, 1.0 Hz, 1H), 7.43 (dd,J= 3.6, 1.1 Hz, 1H), 7.36 (d,J= 8.2 Hz, 1H), 7.25 (dd,J= 8.2, 1.9 Hz, 1H), 7.21 (d,J= 8.3 Hz, 1H), 7.10 (dd,J= 5.0, 3.6 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.3, 2.4 Hz, 1H), 4.41 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[0632]

[0633] 4-4. Intermediate-20b: 4-(2-((2,4-Dimethoxybenzyl)amino)benzo[d]oxazol-5-yl)-2-fluorobenzonitrile

[0634] Intermediate 20b was obtained as a yellow solid (0.40 g, 44.4%) through the general procedure of Example 4-2 above.

[0635] 1 H NMR (400 MHz, DMSO-d6)δ8.41 (t,J= 5.9 Hz, 1H), 7.99 - 7.93 (m, 1H), 7.87 (dd,J= 11.3, 1.3 Hz, 1H), 7.74 (dd,J= 8.1, 1.5 Hz, 1H), 7.68 (d,J= 1.6 Hz, 1H), 7.47 (d,J= 8.3 Hz, 1H), 7.42 (dd,J= 8.3, 1.8 Hz, 1H), 7.21 (d,J= 8.3 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J=8.4, 2.2 Hz, 1H), 4.43 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[0636]

[0637] 4-5. Intermediate-20c: 4-(2-((2,4-Dimethoxybenzyl)amino)benzo[d]oxazol-5-yl)benzonitrile

[0638] Intermediate 20c was obtained as an orange solid (0.40 g, 46.4%) through the general procedure of Example 4-2 above.

[0639] 1H NMR (400 MHz, DMSO-d6) δ8.37 (t,J= 5.9 Hz, 1H), 7.88 (d,J= 4.3 Hz, 3H), 7.60 (d,J= 1.8 Hz, 1H), 7.46 (d,J= 8.3 Hz, 1H), 7.35 (dd,J= 8.3, 1.9 Hz, 1H), 7.21 (d,J= 8.3 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.3, 2.4 Hz, 1H), 4.43 (d,J= 6.0 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[0640]

[0641] 4-6. Intermediate-20d:N-(2,4-Dimethoxybenzyl)-5-(furan-2-yl)benzo[d]oxazol-2-amine

[0642] Intermediate 20d was obtained as an orange solid (0.45 g, 50.3%) through the general procedure of Example 4-2 above.

[0643] 1 H NMR (400 MHz, Chloroform-d)δ7.66 (d,J= 1.7 Hz, 1H), 7.45 (d,J= 1.8 Hz, 1H), 7.37 (dd,J= 8.3, 1.8 Hz, 1H), 7.29 (d,J= 8.2 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 6.58 (d,J= 3.3 Hz, 1H), 6.49 - 6.43 (m, 3H), 4.58 (d,J= 6.0 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H).

[0644]

[0645] 4-7. Intermediate-20e:N-(2,4-Dimethoxybenzyl)-5-(3-methoxyphenyl)benzo[d]oxazol-2-amine

[0646] Intermediate 20e was obtained as a yellow solid (0.46 g, 52.7%) through the general procedure of Example 4-2 above.

[0647] 1 H NMR (400 MHz, DMSO-d6) δ8.30 (t,J= 5.9 Hz, 1H), 7.50 (d,J= 1.5 Hz, 1H), 7.40 (d,J= 8.3 Hz, 1H), 7.34 (t,J= 7.9 Hz, 1H), 7.25 (dd,J= 8.2, 1.7 Hz, 1H), 7.20 (dd,J= 8.0, 4.7 Hz, 2H), 7.15 (s, 1H), 6.90 (dd,J= 8.1, 2.0 Hz, 1H), 6.58 (d,J= 2.2 Hz, 1H), 6.49 (dd,J= 8.3, 2.3 Hz, 1H), 4.42 (d,J= 5.9 Hz, 2H), 3.81 (s, 6H), 3.74 (s, 3H).

[0648]

[0649] 4-8. Intermediate-20f:N-(2,4-Dimethoxybenzyl)-5-(2-methoxyphenyl)benzo[d]oxazol-2-amine

[0650] Intermediate 20f was obtained as an orange solid (0.67 g, 76.8%) through the general procedure of Example 4-2 above.

[0651] 1H NMR (400 MHz, DMSO-d6) δ8.24 (t,J= 5.9 Hz, 1H), 7.34 (t,J= 8.1 Hz, 2H), 7.30 - 7.26 (m, 2H), 7.20 (d,J= 8.4 Hz, 1H), 7.09 (d,J= 8.1 Hz, 1H), 7.03 (dd,J= 8.1, 1.5 Hz, 1H), 7.00 (d,J= 7.4 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.3, 2.3 Hz, 1H), 4.41 (d,J= 5.9 Hz, 2H), 3.81 (s, 3H), 3.74 (d,J= 3.0 Hz, 6H).

[0652]

[0653] 4-9. Intermediate-20g: N-(2,4-Dimethoxybenzyl)-5-(4-methoxyphenyl)benzo[d]oxazol-2-amine

[0654] Through the general procedure of Example 4-2 above, 20 g of the intermediate was obtained as an orange solid (0.67 g, 76.8%).

[0655] 1 H NMR (400 MHz, Chloroform-d)δ7.61 (d,J= 1.8 Hz, 1H), 7.51 (d,J= 8.7 Hz, 2H), 7.28 (d,J= 8.3 Hz, 1H), 7.25 - 7.16 (m, 2H), 6.97 (d,J= 8.8 Hz, 2H), 6.49 - 6.42 (m, 2H), 4.59 (d,J= 6.0 Hz, 2H), 3.85 (d,J= 5.4 Hz, 6H), 3.80 (s, 3H).

[0656]

[0657] 4-10. Intermediate-20h:N-(2,4-Dimethoxybenzyl)-5-phenylbenzo[d]oxazol-2-amine

[0658] Intermediate 20h was obtained as a white solid (0.63 g, 78.2%) through the general procedure of Example 4-2 above.

[0659] 1 H NMR (400 MHz, DMSO-d6) δ8.28 (t,J= 5.9 Hz, 1H), 7.63 (d,J= 7.0 Hz, 2H), 7.49 (d,J= 1.8 Hz, 1H), 7.43 (dd,J= 16.4, 8.6 Hz, 3H), 7.35 - 7.31 (m, 1H), 7.26 - 7.20 (m, 2H), 6.58 (d,J= 2.4 Hz, 1H), 6.49 (dd,J= 8.3, 2.4 Hz, 1H), 4.43 (d,J= 5.9 Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H).

[0660]

[0661] 4-11. Intermediate-20i:N-(2,4-Dimethoxybenzyl)-5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-amine

[0662] Intermediate 20i was obtained as an orange solid (0.48 g, 78.8%) through the general procedure of Example 4-2 above.

[0663] 1 H NMR (400 MHz, Chloroform-d)δ7.55 (s, 1H), 7.29 (d,J= 8.2 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.13 (d,J= 1.5 Hz, 1H), 7.04 (t,J= 1.3 Hz, 1H), 6.49 - 6.43 (m, 2H), 4.58 (d,J= 5.9 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.53 (d,J= 1.1 Hz, 3H).

[0664]

[0665] 4-12. Intermediate-20j: 5-(2-((2,4-Dimethoxybenzyl)amino)benzo[d]oxazol-5-yl)-2-fluorobenzonitrile

[0666] Intermediate 20j was obtained as a pale brown solid (0.44 g, 68.3%) through the general procedure of Example 4-2 above.

[0667] 1 H NMR (400 MHz, DMSO-d6) δ8.33 (t,J= 6.0 Hz, 1H), 8.19 (dd,J= 6.3, 2.4 Hz, 1H), 8.06 - 8.02 (m, 1H), 7.59 - 7.53 (m, 2H), 7.42 (d,J= 8.3 Hz, 1H), 7.29 (dd,J= 8.3, 1.9 Hz, 1H), 7.19 (d,J= 8.3 Hz, 1H), 6.56 (d,J= 2.4 Hz, 1H), 6.47 (dd,J= 8.3, 2.4 Hz, 1H), 4.40 (d,J= 5.9 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H).

[0668]

[0669] 4-13. Intermediate-20k:N-(2,4-Dimethoxybenzyl)-5-(2-methylfuran-3-yl)benzo[d]oxazol-2-amine

[0670] Intermediate 20k was obtained as a white solid (0.062 g, 26.8%) through the general procedure of Example 4-2 above.

[0671] 1H NMR (400 MHz, DMSO-d6) δ8.27 (t,J= 5.9 Hz, 1H), 7.54 (d,J= 1.9 Hz, 1H), 7.36 (d,J= 8.2 Hz, 1H), 7.27 (t,J= 1.2 Hz, 1H), 7.20 (d,J= 8.3 Hz, 1H), 7.02 (dd,J= 8.3, 1.8 Hz, 1H), 6.67 (d,J= 1.9 Hz, 1H), 6.58 (d,J= 2.4 Hz, 1H), 6.49 (dd,J= 8.3, 2.4 Hz, 1H), 4.41 (d,J=5.9 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.41 (s, 3H).

[0672]

[0673] 4-14. Intermediate-20l:N-(3,5-Dimethoxybenzyl)-5-(furan-3-yl)benzo[d]oxazol-2-amine

[0674] Intermediate 20l was obtained as an off brown solid (0.20 g, 51.75%) through the general procedure of Example 4-2 above.

[0675] 1 H NMR (400 MHz, DMSO-d6) δ7.62 (d,J= 1.7 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.36 (dd,J= 8.5, 1.7 Hz, 1H), 7.29 (d,J= 7.9 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.06 - 7.02 (m, 2H), 6.99 (dt,J= 7.6, 1.3 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.49 (s, 3H).

[0676]

[0677] 4-15. General procedure for intermediates 21a-21l

[0678] To a stirred solution of intermediate 20a-l (1.0 eq) in THF (20 mL) was added KHMDS (3.0 eq) at room temperature. After 10 min, 3-methoxybenzoyl chloride (3.0 eq) was added at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then 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, and the crude product was purified with hexane containing EtOAc.

[0679]

[0680] 4-16. Intermediate-21a:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(thiophen-2-yl)benzo[d]oxazol-2-yl)benzamide

[0681] Intermediate 21a was obtained as a yellow solid (0.39 g, quant.) through the general procedure of Example 4-15 above.

[0682] 1 H NMR (400 MHz, Chloroform-d)δ7.77 (dd,J= 1.8, 0.7 Hz, 1H), 7.49 (dd,J= 8.6, 1.8 Hz, 1H), 7.44 (d,J= 8.4 Hz, 1H), 7.29 - 7.26 (m, 3H), 7.14 - 7.09 (m, 2H), 7.08 - 7.06 (m, 1H), 6.99 (dt,J= 7.7, 1.3 Hz, 1H), 6.93 - 6.90 (m, 1H), 6.46 (dd,J= 8.4, 2.4 Hz, 1H), 6.34 (d,J= 2.4 Hz, 1H), 5.23 (s, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.45 (s, 3H).

[0683]

[0684] 4-17. Intermediate-21b:N-(5-(4-Cyano-3-fluorophenyl)benzo[d]oxazol-2-yl)-N-(2,4-dimethoxybenzyl)-3-methoxybenzamide

[0685] Intermediate 21b was obtained as a yellow oil (0.13 g, 25.3%) through the general procedure of Example 4-15 above.

[0686] 1 H NMR (400 MHz, DMSO-d6) δ8.08 - 8.05 (m, 1H), 7.99 (dd,J= 8.2, 7.0 Hz, 1H), 7.94 (dd,J= 11.2, 1.6 Hz, 1H), 7.79 (dd,J= 8.2, 1.7 Hz, 1H), 7.75 (dd,J= 8.6, 1.9 Hz, 1H), 7.67 (d,J= 8.6 Hz, 1H), 7.30 (d,J= 8.3 Hz, 1H), 7.26 (td,J= 7.6, 1.1 Hz, 1H), 7.04 (dq,J= 8.9, 1.4 Hz, 2H), 6.99 (dt,J= 7.7, 1.1 Hz, 1H), 6.53 - 6.49 (m, 2H), 5.12 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.47 (s, 3H).

[0687]

[0688] 4-18. Intermediate-21c:N-(5-(4-Cyanophenyl)benzo[d]oxazol-2-yl)-N-(2,4-dimethoxybenzyl)-3-methoxybenzamide

[0689] Intermediate 21c was obtained as a yellow oil (0.65 g, quant.) through the general procedure of Example 4-15 above.

[0690] 1H NMR (400 MHz, Chloroform-d)δ7.75 - 7.70 (m, 3H), 7.66 (d,J= 8.1 Hz, 2H), 7.46 - 7.42 (m, 2H), 7.37 (d,J= 8.4 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.99 (d,J= 8.0 Hz, 1H), 6.93 (dd,J= 7.9, 2.1 Hz, 1H), 6.46 (dd,J= 8.4, 2.3 Hz, 1H), 6.35 (d,J= 2.4 Hz, 1H), 5.24 (s, 2H), 3.77 (s, 3H), 3.72 (s, 3H), 3.48 (s, 3H).

[0691]

[0692] 4-19. Intermediate-21d:N-(2,4-Dimethoxybenzyl)-N-(5-(furan-2-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide

[0693] Intermediate 21d was obtained as a yellow solid (0.30 g, 47.7%) through the general procedure of Example 4-15 above.

[0694] 1 H NMR (400 MHz, DMSO-d6) δ7.88 (d,J= 1.3 Hz, 1H), 7.74 (d,J= 1.1 Hz, 1H), 7.66 (dd,J= 8.5, 1.7 Hz, 1H), 7.58 (d,J= 8.6 Hz, 1H), 7.31 (d,J= 8.3 Hz, 1H), 7.25 (t,J= 8.1 Hz, 1H), 7.05 - 7.01 (m, 2H), 7.00 - 6.97 (m, 2H), 6.59 (dd,J= 3.4, 1.8 Hz, 1H), 6.52 (dd,J= 8.3, 2.4 Hz, 1H), 6.48 (d,J= 2.3 Hz, 1H), 5.10 (s, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 3.45 (s, 3H).

[0695]

[0696] 4-20. Intermediate-21e:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(3-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide

[0697] Intermediate 21e was obtained as a white solid (0.41 g, 67.5%) through the general procedure of Example 4-15 above.

[0698] 1 H NMR (400 MHz, DMSO-d6) δ7.88 (t,J= 1.2 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.36 (t,J= 7.9 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.25 (dd,J= 7.5, 1.2 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.04 (dq,J= 9.1, 1.3, 0.9 Hz, 2H), 6.99 (dt,J= 7.7, 1.2 Hz, 1H), 6.94 - 6.91 (m, 1H), 6.53 - 6.49 (m, 2H), 5.12 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H), 3.48 (s, 3H).

[0699]

[0700] 4-21. Intermediate-21f:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide

[0701] Intermediate 21f was obtained as a yellow oil (0.58 g, 64.9%) through the general procedure of Example 4-15 above.

[0702] 1H NMR (400 MHz, DMSO-d6) δ7.64 - 7.62 (m, 1H), 7.53 - 7.50 (m, 1H), 7.38 - 7.35 (m, 1H), 7.35 - 7.31 (m, 1H), 7.30 - 7.26 (m, 3H), 7.11 (dd,J= 8.4, 1.1 Hz, 1H), 7.08 - 7.04 (m, 2H), 7.01 (dt,J= 7.4, 1.3 Hz, 2H), 6.52 (d,J= 7.0 Hz, 2H), 5.12 (s, 2H), 3.74 (d,J= 6.4 Hz, 6H), 3.69 (s, 3H), 3.53 (s, 3H).

[0703]

[0704] 4-22. Intermediate-21g:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide

[0705] Through the general procedure of Example 4-15 above, 21 g of intermediate was obtained as a yellow solid (0.29 g, 32.4%).

[0706] 1 H NMR (400 MHz, DMSO-d6) δ7.63 - 7.59 (m, 2H), 7.55 (dd,J= 5.1, 1.2 Hz, 2H), 7.42 - 7.39 (m, 2H), 7.28 (ddd,J= 9.6, 6.2, 3.4 Hz, 3H), 7.00 (dd,J= 8.2, 6.3 Hz, 3H), 6.53 - 6.49 (m, 2H), 5.11 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H), 3.48 (s, 3H).

[0707]

[0708] 4-23. Intermediate-21h:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-phenylbenzo[d]oxazol-2-yl)benzamide

[0709] Intermediate 21h was obtained as an orange solid (0.20 g, 24.4%) through the general procedure of Example 4-15 above.

[0710] 1 H NMR (400 MHz, DMSO-d6) δ7.60 (t,J= 1.4 Hz, 2H), 7.47 - 7.42 (m, 3H), 7.40 - 7.24 (m, 5H), 7.04 (d,J= 7.7 Hz, 2H), 7.00 (dt,J= 7.7, 1.3 Hz, 1H), 6.53 - 6.49 (m, 2H), 5.12 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.48 (s, 3H).

[0711]

[0712] 4-24. Intermediate-21i:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[0713] Intermediate 21i was obtained as a yellow solid (0.40 g, 61.8%) through the general procedure of Example 4-15 above.

[0714] 1 H NMR (400 MHz, Chloroform-d)δ7.46 - 7.42 (m, 2H), 7.27 (s, 1H), 7.19 - 7.13 (m, 2H), 7.13 - 7.09 (m, 2H), 7.03 - 6.98 (m, 2H), 6.91 (dd,J= 8.3, 1.6 Hz, 1H), 6.46 (dd,J= 8.4, 2.4 Hz, 1H), 6.34 (d,J= 2.4 Hz, 1H), 5.22 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.43 (s, 3H), 2.52 (d,J= 1.1 Hz, 3H).

[0715]

[0716] 4-25. Intermediate-21j:N-(5-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-N-(2,4-dimethoxybenzyl)-3-methoxybenzamide

[0717] Intermediate 21j was obtained as a yellow solid (0.15 g, 26.2%) through the general procedure of Example 4-15 above.

[0718] 1 H NMR (400 MHz, Chloroform-d)δ7.79 - 7.75 (m, 2H), 7.66 (t,J= 1.2 Hz, 1H), 7.43 (d,J= 8.3 Hz, 1H), 7.36 (d,J= 1.2 Hz, 2H), 7.28 (s, 1H), 7.15 - 7.12 (m, 2H), 6.99 (dt,J= 7.6, 1.2 Hz, 1H), 6.95 - 6.92 (m, 1H), 6.46 (dd,J= 8.4, 2.4 Hz, 1H), 6.36 (d,J= 2.3 Hz, 1H), 5.24 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.48 (s, 3H).

[0719]

[0720] 4-26. Intermediate-21k:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(5-(2-methylfuran-3-yl)benzo[d]oxazol-2-yl)benzamide

[0721] Intermediate 21k was obtained as a yellow solid (0.060 g, 79.3%) through the general procedure of Example 4-15 above.

[0722] 1H NMR (400 MHz, DMSO-d6) δ7.62 (d,J= 1.7 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.36 (dd,J= 8.5, 1.7 Hz, 1H), 7.29 (d,J= 7.9 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.06 - 7.02 (m, 2H), 6.99 (dt,J= 7.6, 1.3 Hz, 1H), 6.73 (d,J= 1.9 Hz, 1H), 6.53 - 6.49 (m, 2H), 5.11 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.49 (s, 3H), 2.41 (s, 3H).

[0723]

[0724] 4-27. Intermediate-21l:N-(3,5-Dimethoxybenzyl)-N-(5-(furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide

[0725] Intermediate 21l was obtained as a yellow oil (0.13 g, 49.67%) through the general procedure of Example 4-15 above.

[0726] 1 H NMR (400 MHz, DMSO-d6) δ7.62 (d,J= 1.7 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.36 (dd,J= 8.5, 1.7 Hz, 1H), 7.29 (d,J= 7.9 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.06 - 7.02 (m, 2H), 6.99 (dt,J= 7.6, 1.3 Hz, 1H), 6.73 (d,J= 1.9 Hz, 1H), 6.53 - 6.49 (m, 2H), 5.11 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.49 (s, 3H).

[0727]

[0728] 4-28. General procedure for chemical formulas 22a-22k

[0729] To a stirred solution of intermediate 21a-k (1.0 eq) in DCM (20 mL) was added a solution of diluted trifluoroacetic acid (5 mL) in DCM (15 mL), and the reaction mixture was stirred at room temperature. The reaction mixture was then quenched with 5 mL of MeOH, extracted with DCM (3 x 10 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with ether and filtered.

[0730]

[0731] 4-29. Chemical Formula 22a: 3-Methoxy-N-(5-(thiophen-2-yl)benzo[d]oxazol-2-yl)benzamide (Compound 34)

[0732] Through the general procedure of Example 4-28 above, the compound of chemical formula 22a was obtained as a white solid (0.041 g, 15.4%).

[0733] 1 H NMR (400 MHz, DMSO-d6)δ12.10 (s, 1H), 7.79 (d,J= 92.3 Hz, 3H), 7.60 (d,J= 7.2 Hz, 2H), 7.56 (d,J= 4.9 Hz, 2H), 7.49 - 7.43 (m, 1H), 7.21 (s, 1H), 7.18 - 7.13 (m, 1H), 3.85 (s, 3H).

[0734]

[0735] 4-30. Chemical Formula-22b: N-(5-(4-Cyano-3-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 35)

[0736] Through the general procedure of Example 4-28 above, the compound of chemical formula 22b was obtained as a white solid (0.012 g, 13.9%).

[0737] 1H NMR (400 MHz, DMSO-d6)δ12.16 (s, 1H), 8.10 (s, 1H), 8.02 (t,J= 7.6 Hz, 1H), 7.98 (d,J= 10.9 Hz, 1H), 7.85 - 7.74 (m, 3H), 7.66 - 7.58 (m, 2H), 7.48 (t,J= 7.9 Hz, 1H), 7.23 (dd,J= 8.2, 2.4 Hz, 1H), 3.86 (s, 3H).

[0738]

[0739] 4-31. Chemical Formula-22c: N-(5-(4-Cyanophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 36)

[0740] Through the general procedure of Example 4-28 above, a compound of chemical formula 22c was obtained as a white solid (0.085 g, 17.8%).

[0741] 1 H NMR (400 MHz, DMSO-d6) δ12.14 (s, 1H), 8.03 (s, 1H), 7.95 (s, 4H), 7.80 (d,J= 8.5 Hz, 1H), 7.70 (dd,J= 8.4, 1.9 Hz, 1H), 7.61 (s, 2H), 7.48 (t,J= 8.0 Hz, 1H), 7.23 (d,J= 7.5 Hz, 1H), 3.86 (s, 3H).

[0742]

[0743] 4-32. Chemical formula - 22d: N-(5-(Furan-2-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 37)

[0744] Through the general procedure of Example 4-28 above, a compound of chemical formula 22d was obtained as a purple solid (0.022 g, 11.1%).

[0745] 1H NMR (400 MHz, DMSO-d6) δ12.13 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.71 (dd,J= 18.7, 8.4 Hz, 2H), 7.59 (d,J= 6.7 Hz, 2H), 7.51 - 7.46 (m, 1H), 7.23 (d,J= 8.2 Hz, 1H), 7.03 (d,J= 2.3 Hz, 1H), 6.62 (s, 1H), 3.86 (s, 3H).

[0746]

[0747] 4-33. Chemical Formula 22e: 3-Methoxy-N-(5-(3-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide (Compound 38)

[0748] Through the general procedure of Example 4-28 above, a compound of chemical formula 22e was obtained as a white solid (0.048 g, 16.7%).

[0749] 1 H NMR (400 MHz, DMSO-d6)δ11.20 (s, 1H), 8.47 (d,J= 2.3 Hz, 1H), 7.62 (ddd,J= 7.8, 5.2, 1.5 Hz, 2H), 7.46 (t,J= 7.9 Hz, 1H), 7.36 (t,J= 7.9 Hz, 1H), 7.22 (td,J= 8.4, 2.4 Hz, 2H), 7.13 (dt,J= 7.6, 1.2 Hz, 1H), 7.07 (t,J= 2.1 Hz, 1H), 6.99 (d,J= 8.3 Hz, 1H), 6.89 (dd,J=8.1, 2.3 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H).

[0750]

[0751] 4-34. Chemical Formula-22f: 3-Methoxy-N-(5-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide (Compound 39)

[0752] Through the general procedure of Example 4-28 above, a compound of chemical formula 22f was obtained as a white solid (0.030 g, 7.35%).

[0753] 1 H NMR (400 MHz, DMSO-d6) δ8.19 (s, 1H), 7.30 (t,J= 8.0 Hz, 2H), 7.23 (d,J= 9.0 Hz, 2H), 7.16 (d,J= 8.6 Hz, 1H), 7.05 (d,J= 8.1 Hz, 1H), 6.97 (d,J= 8.6 Hz, 2H), 6.54 (s, 1H), 6.45 (d,J= 7.9 Hz, 1H), 3.74 (d,J= 28.2 Hz, 6H).

[0754]

[0755] 4-35. Chemical Formula - 22g: 3-Methoxy-N-(5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide (Compound 40)

[0756] Through the general procedure of Example 4-28 above, a compound of chemical formula 22g was obtained as a pale brown solid (0.028 g, 14.0%).

[0757] 1 H NMR (400 MHz, DMSO-d6)δ12.08 (s, 1H), 7.85 (s, 1H), 7.72 (d,J= 8.0 Hz, 1H), 7.67 (d,J= 8.0 Hz, 2H), 7.63 - 7.54 (m, 3H), 7.51 - 7.46 (m, 1H), 7.23 (d,J= 9.1 Hz, 1H), 7.05 (d,J= 7.8 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H).

[0758]

[0759] 4-36. Chemical Formula-22h: 3-Methoxy-N-(5-phenylbenzo[d]oxazol-2-yl)benzamide (Compound 41)

[0760] Through the general procedure of Example 4-28 above, a compound of chemical formula 22h was obtained as a white solid (0.015 g, 11.3%).

[0761] 1 H NMR (400 MHz, Chloroform-d)δ8.00 - 7.89 (m, 1H), 7.68 (q,J= 15.7, 11.7 Hz, 2H), 7.50 (s, 2H), 7.31 (s, 2H), 7.06 (s, 1H), 7.00 (d,J= 7.7 Hz, 1H), 3.63 (s, 3H).

[0762]

[0763] 4-37. Chemical Formula-22i: 3-Methoxy-N-(5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 42)

[0764] Through the general procedure of Example 4-28 above, a compound of chemical formula 22i was obtained as a yellow solid (0.025 g, 9.1%).

[0765] 1 H NMR (400 MHz, Chloroform-d)δ12.16 (d,J= 5.7 Hz, 1H), 7.81 (s, 2H), 7.51 (d,J= 11.3 Hz, 1H), 7.47 (s, 2H), 7.40 (t,J= 7.9 Hz, 1H), 7.18 (s, 1H), 7.13 (d,J= 9.2 Hz, 1H), 7.03 (s, 1H), 3.89 (s, 3H), 2.55 (s, 3H).

[0766]

[0767] 4-38. Chemical Formula-22j: N-(5-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 43)

[0768] Through the general procedure of Example 4-28 above, a compound of chemical formula 22j was obtained as a pale-yellow solid (0.011 g, 10.1%).

[0769] 1 H NMR (400 MHz, DMSO-d6) δ12.11 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.76 (d,J= 8.8 Hz, 1H), 7.63 (dd,J= 17.7, 8.7 Hz, 3H), 7.59 (s, 1H), 7.46 (t,J= 7.7 Hz, 1H), 7.21 (d,J= 8.6 Hz, 1H), 3.84 (s, 3H).

[0770]

[0771] 4-39. Chemical Formula-22k: 3-Methoxy-N-(5-(2-methylfuran-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 44)

[0772] Through the general procedure of Example 4-28 above, a compound of chemical formula 22k was obtained as a gray solid (0.004 g, 13.5%).

[0773] 1 H NMR (400 MHz, DMSO-d6)δ12.05 (s, 1H), 7.74 - 7.66 (m, 2H), 7.60 (t,J= 7.6 Hz, 3H), 7.47 (d,J= 8.0 Hz, 1H), 7.38 (d,J= 8.5 Hz, 1H), 7.23 (d,J= 10.3 Hz, 1H), 6.77 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H).

[0774]

[0775] 4-40. Chemical formula - 22l: N-(5-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 45)

[0776] Through the general procedure of Example 4-28 above, a compound of chemical formula 22l was obtained as an off white solid (0.0077 g, 9.54%).

[0777] 1 H NMR (400 MHz, DMSO-d6) δ12.12 - 12.06 (m, 1H), 8.24 (s, 1H), 7.76 (t,J= 1.6 Hz, 1H), 7.65 (t,J= 8.7 Hz, 2H), 7.47 (t,J= 7.9 Hz, 2H), 7.22 (d,J= 8.2 Hz, 2H), 7.04 (s, 2H), 3.85 (s, 3H).

[0778]

[0779] Example 5. Synthesis of different types of oxazole derivatives (Scheme 5)

[0780] [Reaction Formula 5]

[0781]

[0782] Reagents and conditions: (a) cyanogen bromide, MeOH, 40°C, 12 h reaction; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 100 ℃, 2 h reaction; (c) pyridine, room temperature, 2 h reaction.

[0783]

[0784] 5-1. General procedure for intermediates 24a-24f

[0785] To a stirred solution of 2-amino-4-bromophenol (1.0 eq) in MeOH (100 mL) was added cyanogen bromide (3.0 eq) at room temperature, and the resulting mixture was stirred at 40 °C for 12 h. The reaction mixture was then quenched with saturated Na2CO3 solution, and the pH was adjusted to 7–8. The reaction mass was quenched with aqueous sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure, and the crude product was purified with hexane containing EtOAc.

[0786]

[0787] 5-2. Intermediate-24a: 5-Bromo-7-chlorobenzo[d]oxazol-2-amine

[0788] Intermediate 24a was obtained as a brown solid (0.12 g, 3.6%) through the general procedure of Example 5-1 above.

[0789] 1 H NMR (400 MHz, DMSO-d6) δ7.92 (s, 2H), 7.36 (s, 1H), 7.27 (s, 1H).

[0790]

[0791] 5-3. Intermediate-24b: 5-Bromo-7-methylbenzo[d]oxazol-2-amine

[0792] Intermediate 24b was obtained as an off red solid (1.37 g, 60.95%) through the general procedure of Example 5-1 above.

[0793] 1 H NMR (400 MHz, DMSO-d6) δ7.56 (s, 2H), 7.17 (d, J= 1.8 Hz, 1H), 6.98 (s, 1H), 2.32 (s, 3H).

[0794]

[0795] 5-4. Intermediate-24c: 5-Bromo-6-chlorobenzo[d]oxazol-2-amine

[0796] Intermediate 24c was obtained as a brown solid (0.4 g, 12.0%) through the general procedure of Example 5-1 above.

[0797] 1 H NMR (400 MHz, DMSO-d6) δ7.76 (s, 2H), 7.71 (s, 1H), 7.54 (s, 1H).

[0798]

[0799] 5-5. Intermediate-24d: 5-Bromo-6-fluorobenzo[d]oxazol-2-amine

[0800] Intermediate 24d was obtained as an off orange solid (1.21 g, 53.94%) through the general procedure of Example 5-1 above.

[0801] 1 H NMR (400 MHz, DMSO-d6) δ7.62 (s, 2H), 7.57 (d,J= 8.4 Hz, 1H), 7.46 (d,J= 6.4 Hz, 1H).

[0802]

[0803] 5-6. Intermediate-24e: 5-Bromo-6-methylbenzo[d]oxazol-2-amine

[0804] Intermediate 24e was obtained as an off yellow solid (1.73 g, 61.59%) through the general procedure of Example 5-1 above.

[0805] 1 H NMR (400 MHz, DMSO-d6) δ7.50 (s, 2H), 7.37 (d, J= 3.9 Hz, 2H), 2.34 (s, 3H).

[0806]

[0807] 5-7. Intermediate-24f: 5-Bromo-6-(trifluoromethyl)benzo[d]oxazol-2-amine

[0808] Intermediate 24f was obtained as a brown solid (0.3 g, 13.7%) through the general procedure of Example 5-1 above.

[0809] 1 H NMR (400 MHz, DMSO-d6) δ8.06 (s, 2H), 7.85 (s, 1H), 7.63 (s, 1H).

[0810]

[0811] 5-8. General procedure for intermediates 25a-25f

[0812] Cs2CO3 (2.5 eq) was added to a stirred solution of a 1,4-dioxane:H2O (9:1) mixture containing intermediates 24a-f (1.0 eq) and 3-thiopheneboronic acid (1.2 eq). The resulting reaction mixture was purged with argon for 10 min and then Pd(dppf)Cl 2· DCM (0.1 eq) was added to the reaction mixture, and the resulting reaction mixture was stirred 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 then purified with hexane containing EtOAc.

[0813]

[0814] 5-9. Intermediate-25a: 7-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0815] Intermediate 25a was obtained as a brown solid (0.63 g, 62.2%) through the general procedure of the above Example 5-8.

[0816] 1H NMR (400 MHz, DMSO-d6) δ7.91 (dd,J= 2.8, 1.4 Hz, 1H), 7.75 (s, 2H), 7.61 (ddd,J= 6.5, 5.1, 2.2 Hz, 2H), 7.53 (d,J= 1.5 Hz, 1H), 7.42 (d,J= 1.5 Hz, 1H).

[0817]

[0818] 5-10. Intermediate-25b: 7-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0819] Intermediate 25b was obtained as an off ivory solid (0.68 g, 69.15%) through the general procedure of Example 5-8 above.

[0820] 1 H NMR (400 MHz, DMSO-d6) δ7.77 - 7.75 (m, 1H), 7.59 (dd, J = 5.0, 2.9 Hz, 1H), 7.53 (dd, J = 5.0, 1.0 Hz, 1H), 7.40 (s, 2H), 7.36 (s, 1H), 7.17 (s, 1H), 2.38 (s, 3H).

[0821]

[0822] 5-11. Intermediate-25c: 6-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0823] Intermediate 25c was obtained as a brown solid (0.28 g, 55.3%) through the general procedure of the above Example 5-8.

[0824] 1 H NMR (400 MHz, DMSO-d6) δ7.65 - 7.63 (m, 1H), 7.63 - 7.59 (m, 3H), 7.58 (s, 1H), 7.31 (dd,J= 4.9, 1.3 Hz, 1H), 7.24 (s, 1H).

[0825]

[0826] 5-12. Intermediate-25d: 6-Fluoro-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0827] Intermediate 25d was obtained as an off pink solid (0.14 g, 15.32%) through the general procedure of the above Example 5-8.

[0828] 1 H NMR (400 MHz, DMSO-d6) δ7.79 - 7.76 (m, 1H), 7.64 (dd, J = 5.0, 3.0 Hz, 1H), 7.48 (s, 2H), 7.44 (t, J = 8.7 Hz, 3H).

[0829]

[0830] 5-13. Intermediate-25e: 6-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[0831] Intermediate 25e was obtained as an off yellow solid (1.08 g, 98.69%) through the general procedure of the above Example 5-8.

[0832] 1 H NMR (400 MHz, DMSO-d6) δ7.59 (dd, J = 4.9, 3.0 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.33 (s, 2H), 7.24 (s, 1H), 7.22 (dd, J = 4.9, 1.2 Hz, 1H), 7.07 (s, 1H), 2.29 (s, 3H).

[0833]

[0834] 5-14. Intermediate-25f: 5-(Thiophen-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-2-amine

[0835] Intermediate 25f was obtained as a brown solid (0.12 g, 59.5%) through the general procedure of the above Example 5-8.

[0836] 1H NMR (400 MHz, DMSO-d6) δ7.88 (s, 2H), 7.78 (s, 1H), 7.59 (dd,J= 4.9, 3.0 Hz, 1H), 7.49 (d,J= 1.7 Hz, 1H), 7.17 - 7.13 (m, 2H).

[0837]

[0838] 5-15. General Procedure for Chemical Formulas 26a-26e and 27a-27g

[0839] To a stirred solution of pyridine (20 mL) containing amine (1.0 eq) was added 3-(trifluoromethyl)benzoyl chloride (2.0 eq) dropwise at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then diluted with 50 mL of water, extracted with EtOAc (3 x 40 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude product was washed with ether.

[0840]

[0841] 5-16. Chemical Formula-26a: N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 46)

[0842] Through the general procedure of Example 5-15 above, the compound of chemical formula 26a was obtained as a pink solid (28.6 mg, 16.9%).

[0843] 1 H NMR (400 MHz, DMSO-d6)δ12.68 (s, 1H), 8.40 (s, 1H), 8.33 (d,J= 6.6 Hz, 1H), 8.04 (d,J= 8.0 Hz, 1H), 7.89 - 7.78 (m, 2H), 7.69 (s, 1H).

[0844]

[0845] 5-17. Chemical Formula-26b: N-(5-Bromo-7-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 47)

[0846] Through the general procedure of Example 5-15 above, the compound of chemical formula 26b was obtained as an off ivory solid (0.03 g, 5.25%).

[0847] 1 H NMR (400 MHz, DMSO-d6) δ12.73 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.02 (d,J= 7.4 Hz, 1H), 7.80 (t,J= 7.7 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 2.46 (s, 3H).

[0848]

[0849] 5-18. Formula-26c:N-(5-Bromo-6-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 48)

[0850] Through the general procedure of Example 5-15 above, the compound of chemical formula 26c was obtained as a pink solid (9.5 mg, 1.4%).

[0851] 1 H NMR (400 MHz, DMSO-d6) δ12.60 (s, 1H), 8.38 (s, 1H), 8.32 (d,J= 7.9 Hz, 1H), 8.14 (s, 1H), 8.03 (d,J= 7.6 Hz, 2H), 7.81 (t,J= 7.7 Hz, 1H).

[0852]

[0853] 5-19. Chemical formula -26d:N-(5-Bromo-6-fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 49)

[0854] Through the general procedure of Example 5-15 above, a compound of chemical formula 26d was obtained as a pink solid (0.025 g, 7.16%).

[0855] 1 H NMR (400 MHz, DMSO-d6) δ8.41 - 8.33 (m, 1H), 8.21 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H).

[0856]

[0857] 5-20. Chemical Formula-26e: N-(5-Bromo-6-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 50)

[0858] Through the general procedure of Example 5-15 above, a compound of chemical formula 26e was obtained as an off white solid (0.43 g, 61.15%).

[0859] 1 H NMR (400 MHz, DMSO-d6) δ8.39 (s, 1H), 8.33 (s, 1H), 8.02 (d,J= 8.6 Hz, 1H), 7.81 (d,J= 7.9 Hz, 2H), 7.74 (s, 1H), 2.45 (s, 3H).

[0860]

[0861] 5-21. Formula-27a:N-(7-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 51)

[0862] Through the general procedure of Example 5-15 above, the compound of chemical formula 27a was obtained as a brown solid (34 mg, 23.7%).

[0863] 1H NMR (400 MHz, DMSO-d6)δ12.61 (s, 1H), 8.55 (d,J= 19.4 Hz, 1H), 8.42 (s, 1H), 8.35 (d,J= 7.5 Hz, 1H), 8.03 (s, 1H), 7.94 (d,J= 12.8 Hz, 1H), 7.82 (t,J= 7.8 Hz, 2H), 7.68 (s, 2H).

[0864]

[0865] 5-22. Chemical Formula-27b: 3-Methoxy-N-(7-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 52)

[0866] Through the general procedure of Example 5-15 above, the compound of chemical formula 27b was obtained as an off ivory solid (0.26 g, 54.88%).

[0867] 1 H NMR (400 MHz, DMSO-d6) δ7.88 (s, 1H), 7.77 - 7.72 (m, 1H), 7.67 - 7.64 (m, 2H), 7.61 (s, 2H), 7.53 (s, 1H), 7.47 (t, J= 7.9 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 3.86 (s, 3H).

[0868]

[0869] 5-23. Chemical Formula-27c: N-(6-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 53)

[0870] Through the general procedure of Example 5-15 above, a compound of chemical formula 27c was obtained as a white solid (7 mg, 1.0%).

[0871] 1H NMR (400 MHz, DMSO-d6)δ12.51 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.06 - 7.97 (m, 2H), 7.84 - 7.79 (m, 1H), 7.73 (d,J= 1.6 Hz, 1H), 7.67 (dd,J= 4.9, 3.0 Hz, 2H), 7.36 (d,J= 4.3 Hz, 1H).

[0872]

[0873] 5-24. Chemical formula -27d:N-(6-Fluoro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 54)

[0874] Through the general procedure of Example 5-15 above, the compound of chemical formula 27d was obtained as an off pink solid (0.081 g, 73.54%).

[0875] 1 H NMR (400 MHz, DMSO-d6)δ12.23 - 12.16 (m, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.80 (d,J= 10.4 Hz, 1H), 7.69 (dd,J= 5.0, 3.0 Hz, 1H), 7.62 (d,J= 7.9 Hz, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.47 (t,J= 8.0 Hz, 1H), 7.22 (d,J= 8.5 Hz, 1H), 3.85 (s, 3H).

[0876]

[0877] 5-25. Chemical Formula 27e: 3-Methoxy-N-(6-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 55)

[0878] Through the general procedure of Example 5-15 above, a compound of chemical formula 27e was obtained as an off purple liquid (0.077 g, 60.82%).

[0879] 1 H NMR (400 MHz, DMSO-d6) δ12.14 - 11.91 (m, 1H), 7.65 (dd,J= 4.6, 2.8 Hz, 1H), 7.61 (d,J= 2.6 Hz, 1H), 7.58 (dd,J= 5.5, 4.4 Hz, 2H), 7.46 (dd,J= 14.0, 5.9 Hz, 2H), 7.41 (d,J= 7.7 Hz, 1H), 7.28 (d,J= 4.7 Hz, 1H), 7.23 - 7.18 (m, 1H), 3.85 (s, 3H), 2.39 (s, 3H).

[0880]

[0881] 5-26. Chemical Formula-27f: N-(5-(Thiophen-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 56)

[0882] Through the general procedure of Example 5-15 above, a compound of chemical formula 27f was obtained as a brown solid (40 mg, 23.3%).

[0883] 1 H NMR (400 MHz, DMSO-d6) δ12.71 (s, 1H), 8.42 (s, 1H), 8.37 (d,J= 6.1 Hz, 1H), 8.19 (s, 1H), 8.04 (d,J= 8.0 Hz, 1H), 7.82 (t,J= 7.6 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.59 (s, 2H), 7.20 (d,J= 4.7 Hz, 1H).

[0884]

[0885] 5-27. Formula-27g:N-(6-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 57)

[0886] Through the general procedure of Example 5-15 above, a compound of chemical formula 27g was obtained as an off white solid (0.36 g, 51.99%).

[0887] 1 H NMR (400 MHz, DMSO-d6) δ12.33 (s, 1H), 8.41 (s, 2H), 8.02 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.58 (s, 2H), 7.54 - 7.43 (m, 1H), 7.27 (s, 1H), 2.38 (s, 3H).

[0888]

[0889] Example 6. Synthesis of different types of oxazole derivatives (Scheme 6)

[0890] [Reaction Formula 6]

[0891]

[0892] Reagents and conditions: (a) cyanogen bromide, MeOH, 40°C, 12 h reaction; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 80 ℃, 2 h reaction; (c) pyridine, room temperature, 2 h reaction.

[0893]

[0894] 6-1. General Procedure for Cyclization

[0895] To a stirred solution of MeOH containing 2-aminophenol (1.0 eq) was added cyanogen bromide (1.2 eq), and the reaction mixture was stirred at 40 °C for 6 h. The reaction mixture was then cooled to room temperature, quenched with a solution of Na2CO3 in 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, which was purified with hexane containing EtOAc to obtain intermediate 29b.

[0896]

[0897] 6-2. Intermediate-29b: 5-Bromooxazolo[4,5-b]pyridin-2-amine

[0898] Intermediate 29b was obtained as an off yellow solid (1.8 g, 79.49%) through the general procedure of Example 6-1 above.

[0899] 1 H NMR (400 MHz, DMSO-d6) δ8.18 (s, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H).

[0900]

[0901] 6-3. General procedure for intermediates 30a-30b

[0902] Cs2CO3 (3.0 eq) was added to a stirred solution of 1,4-dioxane containing bromo compound (1.0 eq) and 3-thiopheneboronic acid (1.5 eq), and the resulting reaction mixture was purged with argon gas for 3 minutes, followed by 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 80 °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 with hexane containing EtOAc to obtain intermediates 30a-30b.

[0903]

[0904] 6-4. Intermediate-30a: 6-(Thiophen-3-yl)oxazolo[5,4-b]pyridin-2-amine

[0905] Intermediate-30a was obtained as a black solid (0.2 g, 66.6%) through the general procedure of Example 6-3 above.

[0906] 1 H NMR (400 MHz, DMSO-d6) δ8.20 (s, 1H), 7.89 (d,J= 22.0 Hz, 2H), 7.77 (s, 2H), 7.62 (d,J= 15.4 Hz, 2H).

[0907]

[0908] 6-5. Intermediate-30b: 5-(Thiophen-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0909] Intermediate-30b was obtained as an off-white solid (0.42 g, 34.46%) through the general procedure of Example 6-3 above.

[0910] 1 H NMR (400 MHz, DMSO-d6) δ8.03 (dd,J= 2.9, 1.1 Hz, 1H), 7.94 (s, 2H), 7.70 (dd,J= 5.1, 1.1 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.60 (dd,J= 5.0, 3.0 Hz, 1H), 7.45 (d,J= 8.1 Hz, 1H).

[0911]

[0912] 6-6. General procedure for chemical formulas 31 and 32a-32c

[0913] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethyl or 3-methoxybenzoyl chloride (4.0 eq), and the reaction mixture was 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 with hexane containing EtOAc to obtain compounds of formula 31 and 32a-32c.

[0914]

[0915] 6-7. Chemical Formula-31: N-(6-Bromooxazolo[5,4-b]pyridin-2-yl)-3-methoxybenzamide (Compound 58)

[0916] Through the general procedure of Example 6-6, the compound of chemical formula 31 was obtained as an off white solid (0.209 g, 62.57%).

[0917] 1 H NMR (400 MHz, DMSO-d6) δ8.31 (s, 2H), 7.57 (d, J= 11.4 Hz, 2H), 7.46 (s, 1H), 7.22 (s, 1H), 3.83 (s, 3H). Purity 97.00% (as determined by RP-HPLC, method A,t R = 20.70 min).

[0918]

[0919] 6-8. Chemical Formula-32a: 3-Methoxy-N-(6-(thiophen-3-yl)oxazolo[5,4-b]pyridin-2-yl)benzamide (Compound 59)

[0920] Through the general procedure of Example 6-6, a compound of chemical formula 32a was obtained as an off-white solid (0.035 g, 21.7%).

[0921] 1 H NMR (400 MHz, DMSO-d6)δ12.28 - 12.20 (m, 1H), 8.63 (s, 1H), 8.07 (s, 1H), 7.71 (s, 2H), 7.60 (s, 2H), 7.47 (d,J= 7.8 Hz, 2H), 7.24 (s, 1H), 3.86 (s, 3H).

[0922]

[0923] 6-9. Chemical Formula-32b: N-(5-(Thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)-3-(trifluoromethyl)benzamide (Compound 60)

[0924] Through the general procedure of Example 6-6, a compound of chemical formula 32b was obtained as an off-white solid (0.109 g, 40.57%).

[0925] 1 H NMR (400 MHz, DMSO-d6) δ8.46 (s, 1H), 8.42 (d, J= 7.6 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.75 - 7.65 (m, 4H), 7.57 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H),J= 4.9, 1.2 Hz, 1H), 7.07 (s, 1H), 2.29 (s, 3H).

[0926]

[0927] 6-10. Chemical Formula-32c: 3-Methoxy-N-(5-(thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)benzamide (Compound 61)

[0928] Through the general procedure of Example 6-6, a compound of chemical formula 32c was obtained as an off yellow solid (0.04 g, 16.5%).

[0929] 1 H NMR (400 MHz, DMSO-d6) δ8.04 (s, 1H), 7.76 (d,J= 7.5 Hz, 1H), 7.72 (d,J= 4.4 Hz, 3H), 7.56 (d,J= 7.9 Hz, 2H), 7.38 (t,J= 7.9 Hz, 1H), 7.10 (d,J= 10.1 Hz, 1H), 3.82 (s, 3H).

[0930]

[0931] Example 7. Synthesis of different types of oxazole derivatives (Scheme 7)

[0932] [Reaction Formula 7]

[0933]

[0934] Reagents and conditions: (a) cyanogen bromide, MeOH, 40 ℃, reaction time 12 hours; (b) pyridine, room temperature, reaction time 2 hours; (c) Pd / C, H2balloon, MeOH, room temperature, reaction time 12 hours; (d) aldehydes / ketones, Na(OAc)3BH, DCM, room temperature, reaction time 12 hours.

[0935]

[0936] 7-1. Intermediate-34: 5-Nitrobenzo[d]oxazol-2-amine)

[0937] To a stirred solution of 2-amino-4-nitrophenol (7.00 g, 1.0 eq) in MeOH (200 mL) was added cyanogen bromide (7.21 g, 1.5 eq) at room temperature, and the solution was stirred at 40 °C for 12 h. Then, the reaction mixture was quenched by adding saturated Na2CO3 solution, and the pH was adjusted to 7–8. The reaction mixture was evaporated under reduced pressure, and the residue was washed with pentane to give intermediate 34 as a brown solid (13.5 g, quant.).

[0938] 1 H NMR (400 MHz, DMSO-d6) δ7.98 (d,J= 2.3 Hz, 1H), 7.95 (d,J= 2.4 Hz, 1H), 7.93 (d,J= 2.4 Hz, 1H), 7.57 (d,J= 8.7 Hz, 2H).

[0939]

[0940] 7-2. Intermediate-35: 3-Methoxy-N-(5-nitrobenzo[d]oxazol-2-yl)benzamide (Compound 70)

[0941] To a stirred solution of pyridine (100 mL) containing 5-nitrobenzo[d]oxazol-2-amine (7.00 g, 1.0 eq) was added 3-methoxybenzoyl chloride (8.24 mL, 2.0 eq) dropwise at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then diluted with 50 mL of water and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude product was washed with ether to give intermediate 35 as a brown solid (2.5 g, 30.7%).

[0942] 1H NMR (400 MHz, DMSO-d6) δ12.41 (s, 1H), 8.47 (s, 1H), 8.25 (d,J= 8.6 Hz, 1H), 7.93 (d,J= 9.0 Hz, 1H), 7.61 (d,J= 8.6 Hz, 2H), 7.49 (t,J= 7.7 Hz, 1H), 7.24 (d,J= 8.0 Hz, 1H), 3.86 (s, 3H).

[0943]

[0944] 7-3. Intermediate-36: N-(5-Aminobenzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 71)

[0945] To a stirred solution of 3-methoxy-N-(5-nitrobenzo[d]oxazol-2-yl)benzamide (6.2 g, 1.0 eq) in MeOH was added 10% Pd / C (0.30 g, 0.2 eq), and the resulting reaction mixture was stirred at room temperature under H2 gas for 12 h. The reaction mixture was then filtered and evaporated. The resulting crude product was washed with ether to give intermediate 36 as a brown solid (3.1 g, 78.8%).

[0946] 1 H NMR (400 MHz, DMSO-d6) δ11.84 (s, 1H), 7.63 (d,J= 15.5 Hz, 2H), 7.43 (t,J= 7.9 Hz, 1H), 7.25 (d,J= 8.6 Hz, 1H), 7.18 (d,J= 7.9 Hz, 1H), 6.72 (s, 1H), 6.51 (d,J= 8.8 Hz, 1H), 5.14 (s, 2H), 3.84 (s, 3H).

[0947]

[0948] 7-4. General Procedure for Chemical Formulas 37a-37h

[0949] To a stirred solution of N-(5-aminobenzo[d]oxazol-2-yl)-3-methoxybenzamide (1.0 eq) and Na(OAc)3BH in DCM (20 mL) was added the aldehyde / ketone at room temperature, and the reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was then diluted with water (20 mL), and the aqueous phase was extracted with DCM (3 x 30 mL). The combined organic layers were washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified with hexane containing EtOAc.

[0950]

[0951] 7-5. Chemical Formula 37a: 3-Methoxy-N-(5-((thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide (Compound 62)

[0952] Through the general procedure of Example 7-4, the compound of chemical formula 37a was obtained as a green solid (37.5 mg, 23.3%).

[0953] 1 H NMR (400 MHz, DMSO-d6)δ12.78 (s, 1H), 11.79 (s, 1H), 7.56 (s, 1H), 7.49 (dd,J= 4.6, 3.0 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 7.19 (s, 1H), 7.12 (d,J= 4.7 Hz, 1H), 6.76 (s, 1H), 6.63 (s, 1H), 6.10 (s, 1H), 4.27 (d,J= 4.3 Hz, 2H), 3.83 (s, 3H).

[0954]

[0955] 7-6. Chemical Formula-37b: N-(5-((Furan-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 63)

[0956] Through the general procedure of Example 7-4, the compound of chemical formula 37b was obtained as a yellow solid (15.3 mg, 9.9%).

[0957] 1 H NMR (400 MHz, DMSO-d6) δ12.80 (s, 1H), 11.80 (s, 1H), 7.72 (d,J= 26.2 Hz, 1H), 7.61 (d,J= 9.7 Hz, 2H), 7.55 (s, 1H), 7.46 (s, 1H), 7.35 (d,J= 8.2 Hz, 1H), 7.21 (d,J= 8.0 Hz, 1H), 6.79 (s, 1H), 6.64 (d,J= 8.0 Hz, 1H), 6.50 (s, 1H), 4.10 (s, 2H), 3.84 (s, 3H).

[0958]

[0959] 7-7. Chemical Formula-37c: N-(5-(Cyclohexylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 64)

[0960] Through the general procedure of Example 7-4 above, a compound of chemical formula 37c was obtained as a yellow solid (0.11 g, 27.4%).

[0961] 1 H NMR (400 MHz, DMSO-d6) δ12.75 (s, 1H), 11.79 (s, 1H), 7.72 (d,J= 30.1 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.25 (d,J= 41.4 Hz, 2H), 6.71 (s, 1H), 6.56 (s, 1H), 3.84 (s, 3H), 3.18 (s, 1H), 1.95 (d,J= 12.2 Hz, 2H), 1.77 - 1.68 (m, 2H), 1.64 - 1.57 (m, 1H), 1.33 (t,J=12.5 Hz, 2H), 1.24 - 1.11 (m, 3H).

[0962]

[0963] 7-8. Chemical Formula-37d: 3-Methoxy-N-(5-((pyridin-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide (Compound 65)

[0964] Through the general procedure of Example 7-4 above, a compound of chemical formula 37d was obtained as a yellow solid (0.11 g, 28.3%).

[0965] 1 H NMR (400 MHz, DMSO-d6)δ12.79 (s, 1H), 11.80 (s, 1H), 8.64 - 8.58 (m, 1H), 8.45 (dd,J= 4.9, 1.7 Hz, 1H), 7.78 (d,J= 7.9 Hz, 1H), 7.62 (d,J= 45.0 Hz, 2H), 7.44 (s, 1H), 7.36 (dd,J= 7.9, 4.8 Hz, 2H), 7.19 (s, 1H), 6.68 (d,J= 50.4 Hz, 2H), 4.33 (s, 2H), 3.83 (s, 3H).

[0966]

[0967] 7-9. Chemical Formula-37e: N-(5-((Benzo[b]thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 66)

[0968] Through the general procedure of Example 7-4 above, a compound of chemical formula 37e was obtained as a yellow solid (0.17 g, 37.6%).

[0969] 1 H NMR (400 MHz, DMSO-d6) δ12.77 (s, 1H), 11.80 (s, 1H), 7.99 (d,J= 8.5 Hz, 2H), 7.60 (d,J= 20.9 Hz, 3H), 7.47 - 7.37 (m, 3H), 7.33 (s, 1H), 7.19 (s, 1H), 6.84 (s, 1H), 6.67 (s, 1H), 4.53 (d,J= 4.8 Hz, 2H), 3.83 (s, 3H).

[0970]

[0971] 7-10. Chemical formula - 37f: N-(5-(Isopropylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 67)

[0972] Through the general procedure of Example 7-4 above, a compound of chemical formula 37f was obtained as a yellow solid (0.15 g, 34.6%).

[0973] 1 H NMR (400 MHz, DMSO-d6) δ7.61 (s, 2H), 7.44 (t,J= 8.0 Hz, 1H), 7.28 (s, 1H), 7.17 (d,J= 10.7 Hz, 1H), 6.68 (s, 1H), 6.52 (d,J= 7.6 Hz, 1H), 3.84 (s, 3H), 3.53 (s, 1H), 1.15 (d, J = 6.3 Hz, 6H).

[0974]

[0975] 7-11. Chemical Formula - 37g: 3-Methoxy-N-(5-(3-methylbutanamido)benzo[d]oxazol-2-yl)benzamide (Compound 68)

[0976] Through the general procedure of Example 7-4 above, a compound of chemical formula 37g was obtained as a yellow solid (0.12 g, 46.6%).

[0977] 1 H NMR (400 MHz, DMSO-d6) δ9.97 (s, 1H), 7.97 (s, 1H), 7.61 (s, 2H), 7.55 (d,J= 8.5 Hz, 1H), 7.46 (d,J= 7.7 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.20 (d,J= 8.1 Hz, 1H), 3.84 (s, 3H), 2.21 (d,J= 7.0 Hz, 2H), 2.13 - 2.06 (m, 1H), 0.95 (d,J= 6.5 Hz, 6H).

[0978]

[0979] 7-12. Chemical Formula-37h: 3-Methoxy-N-(5-propionamidobenzo[d]oxazol-2-yl)benzamide (Compound 69)

[0980] Through the general procedure of Example 7-4 above, a compound of chemical formula 37h was obtained as a yellow solid (0.12 g, 46.4%).

[0981] 1 H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 7.97 (s, 1H), 7.60 (s, 2H), 7.55 (d,J= 7.6 Hz, 1H), 7.45 (t,J= 7.8 Hz, 1H), 7.40 (d,J= 10.7 Hz, 1H), 7.21 (s, 1H), 3.84 (s, 3H), 2.34 (q,J= 7.6 Hz, 2H), 1.10 (t,J= 7.6 Hz, 3H).

[0982]

[0983] Example 8. Synthesis of different types of oxazole derivatives (Scheme 8)

[0984] [Reaction Formula 8]

[0985]

[0986] Reagents and conditions: (a) cyanogen bromide, MeOH, 40°C, 12 h reaction; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 100 ℃, 2 h reaction; (c) pyridine, room temperature, 2 h reaction; (d) DMAP, THF, room temperature, 2 h reaction.

[0987]

[0988] 8-1. Intermediate-39: 5-Bromobenzo[d]oxazol-2-amine

[0989] To a stirred solution of 2-amino-4-bromophenol (5.00 g, 1.0 eq) in MeOH (200 mL) was added cyanogen bromide (14.08 g, 5.0 eq) at room temperature, and the solution was stirred at 40 °C for 12 h. The reaction mixture was quenched by adding saturated Na2CO3 solution, the pH was adjusted to 7–8, and the reaction mixture was evaporated under reduced pressure. The residue was washed with pentane to give intermediate 39 as a blue solid (4.5 g, 79.4%).

[0990] 1 H NMR (400 MHz, DMSO-d6) δ7.60 (s, 2H), 7.35 (d,J= 1.9 Hz, 1H), 7.29 (d,J= 8.4 Hz, 1H), 7.10 (dd,J= 8.3, 2.0 Hz, 1H).

[0991]

[0992] 8-2. Intermediate-40: 5-(Thiophen-3-yl)benzo[d]oxazol-2-amine

[0993] To a stirred solution of a mixture of 1,4-dioxane:H2O (9:1) containing 5-bromobenzo[d]oxazol-2-amine (4.4 g, 1.0 eq) and 3-thiopheneboronic acid (3.17 g, 1.2 eq) was added Cs2CO3 (6.67 g, 2.5 eq), and the resulting reaction mixture was purged with argon for 10 min, followed by Pd(dppf)Cl 2· DCM (1.69 g, 0.1 eq) was added to the reaction mixture. The resulting reaction mixture was then stirred 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 to give intermediate 40 as a pink solid (2.0 g, 44.8%).

[0994] 1H NMR (400 MHz, DMSO-d6) δ7.79 (dd,J= 2.7, 1.1 Hz, 1H), 7.60 (dd,J= 5.0, 2.9 Hz, 1H), 7.54 (d,J= 4.9 Hz, 2H), 7.42 (s, 2H), 7.32 (s, 2H).

[0995]

[0996] 8-3. General Procedure for Chemical Formulas 41a-41d

[0997] To a stirred solution of pyridine (20 mL) containing intermediate 40 (1.0 eq) was added acid chloride (2.0 eq) dropwise at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then diluted with 50 mL of water and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude product was washed with ether.

[0998]

[0999] 8-4. Chemical Formula-41a: 2-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)acetamide (Compound 72)

[1000] Through the general procedure of Example 8-3, the compound of chemical formula 41a was obtained as a pink solid (22.9 mg, 5.9%).

[1001] 1 H NMR (400 MHz, DMSO-d6)δ11.92 (s, 1H), 7.93 (s, 1H), 7.90 (dd,J= 2.7, 1.3 Hz, 1H), 7.65 - 7.60 (m, 4H), 7.35 (d,J= 4.4 Hz, 4H), 7.28 (dd,J= 8.9, 4.5 Hz, 1H), 3.85 (s, 2H).

[1002]

[1003] 8-5. Chemical Formula-41b: 3-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)propanamide (Compound 73)

[1004] Through the general procedure of Example 8-3, the compound of chemical formula 41b was obtained as a pale blue solid (85.4 mg, 21.2%).

[1005] 1 H NMR (400 MHz, DMSO-d6)δ11.73 (s, 1H), 7.92 (s, 1H), 7.90 (dd,J= 2.8, 1.4 Hz, 1H), 7.67 - 7.59 (m, 4H), 7.33 - 7.25 (m, 4H), 7.20 (t,J= 6.7 Hz, 1H), 2.95 - 2.91 (m, 2H), 2.89 - 2.82 (m, 2H).

[1006]

[1007] 8-6. Chemical Formula-41c: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide (Compound 74)

[1008] Through the general procedure of Example 8-3, the compound of chemical formula 41c was obtained as a pale brown solid (8.3 mg, 2.1%).

[1009] 1 H NMR (400 MHz, DMSO-d6) δ11.98 (s, 1H), 7.93 (s, 1H), 7.91 (dd,J= 2.8, 1.4 Hz, 1H), 7.73 (s, 1H), 7.69 - 7.56 (m, 7H), 4.02 (s, 2H).

[1010]

[1011] 8-7. Chemical Formula-41d: N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)propanamide (Compound 75)

[1012] Through the general procedure of Example 8-3 above, a compound of chemical formula 41d was obtained as a white solid (6.8 mg, 2.7%).

[1013] 1 H NMR (400 MHz, DMSO-d6) δ11.71 (s, 1H), 7.91 (s, 1H), 7.91 - 7.88 (m, 1H), 7.67 - 7.52 (m, 8H), 3.02 (d,J= 7.1 Hz, 2H), 2.91 (s, 2H).

[1014]

[1015] 8-8. Chemical Formula-42: N-(5-Bromobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide (Compound 76)

[1016] Through the general procedure of Example 8-3 above, the compound of chemical formula 42 was obtained as a white solid (0.5 g, 55.5%).

[1017] 1 H NMR (400 MHz, DMSO-d6) δ12.62 (s, 1H), 8.36 (s, 1H), 8.31 (d,J= 7.8 Hz, 1H), 8.00 (d,J= 7.8 Hz, 1H), 7.78 (t,J= 7.9 Hz, 2H), 7.63 (d,J= 8.6 Hz, 1H), 7.46 (dd,J= 8.6, 1.9 Hz, 1H).

[1018]

[1019] 8-9. Chemical Formula-43: 1-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea (Compound 77)

[1020] To a solution of intermediate 40 (0.2 g, 0.924 mmol) and the appropriate isocyanate (0.259 g, 1.387 mmol) in THF was added Et3N (0.38 mL, 2.77 mmol), and the resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated under reduced pressure, and the crude product was purified with DCM containing MeOH to obtain the compound of formula 43 as a white solid (0.02 g, 5%).

[1021] 1 H NMR (400 MHz, DMSO-d6) δ11.69 - 11.52 (br S, 1H), 10.82 - 10.69 (br S, 1H), 8.25 - 8.03 (m, 2H), 7.78 (s, 1H), 7.70 - 7.28 (m, 7H).

[1022]

[1023] Example 9. Synthesis of different types of oxazole derivatives (Scheme 9)

[1024] [Reaction Formula 9]

[1025]

[1026] Reagents and conditions: (a) Et3N, DCM, room temperature, 3 h reaction; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 100 ℃, 2 h reaction; (c) KHMDS, THF, room temperature, 2 h reaction; (d) TFA, DCM, room temperature, 30 min reaction.

[1027]

[1028] 9-1. Intermediate-3b: 5-Bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine

[1029] To a stirred solution of 5-bromo-2-chlorobenzo[d]oxazole (2.00 g, 1.0 eq) and triethylamine (3.60 mL, 3.0 eq) in DCM (100 mL) was added 2,4-dimethoxybenzylamine (2.59 mL, 2.0 eq) at room temperature, and the solution was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (3 x 100 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 dried in air to give intermediate 3b as an off pale-yellow solid (2.89 g, 92.38%).

[1030] 1 H NMR (400 MHz, DMSO-d6) δ8.45 (t,J= 6.0 Hz, 1H), 7.40 (d,J= 2.0 Hz, 1H), 7.31 (d,J= 8.4 Hz, 1H), 7.19 (d,J= 8.3 Hz, 1H), 7.11 (dd,J= 8.4, 2.1 Hz, 1H), 6.57 (d,J= 2.4 Hz, 1H), 6.48 (dd,J= 8.4, 2.4 Hz, 1H), 4.40 (d,J= 4.8 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[1031]

[1032] 9-2. Intermediate-4b:N-(2,4-Dimethoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine

[1033] To a stirred solution of a 1,4-dioxane:H2O (9:1) mixture containing 5-bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine (8.00 g, 1.0 eq) and 3-thiopheneboronic acid (3.92 g, 1.2 eq) was added Cs2CO3 (8.25 g, 2.5 eq), and the resulting reaction mixture was purged with argon for 10 min, followed by Pd(dppf)Cl 2· DCM (2.09 g, 0.1 eq) was added to the reaction mixture. The resulting reaction mixture was then stirred 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 to give intermediate 4b as an off-brown solid (4.27 g, 84.65%).

[1034] 1 H NMR (400 MHz, DMSO-d6)δ8.26 (t,J= 6.0 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.60 (dd,J= 5.0, 2.9 Hz, 1H), 7.58 (s, 1H), 7.55 - 7.52 (m, 1H), 7.37 - 7.30 (m, 2H), 7.21 (d,J= 8.3 Hz, 1H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.4, 2.5 Hz, 1H), 4.41 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[1035]

[1036] 9-3. Intermediate-44:N-(2,4-Dimethoxybenzyl)-3-methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzenesulfonamide

[1037] To a stirred solution of THF (20 mL) containing intermediate 4b (0.50 g, 1.0 eq) of Example 9-2 was added KHMDS (6.82 mL, 3.0 eq) at room temperature. After 10 minutes, m-toluenesulfonyl chloride (1.31 mL, 3.0 eq) was added at room temperature, and the reaction mixture was stirred at ambient temperature for 2 hours. Then, 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 purified with EtOAc / hexane to give intermediate 44 as an orange solid (0.30 g, 42.23%).

[1038] 1 H NMR (400 MHz, Chloroform-d)δ7.78 (d,J= 1.6 Hz, 1H), 7.50 (s, 1H), 7.46 (dd,J= 8.4, 1.8 Hz, 1H), 7.42 (t,J= 1.4 Hz, 2H), 7.38 (ddd,J= 6.4, 4.9, 1.8 Hz, 4H), 7.34 - 7.31 (m, 2H), 7.24 (d,J= 8.4 Hz, 1H), 6.40 (dd,J= 8.4, 2.4 Hz, 1H), 6.23 (d,J= 2.4 Hz, 1H), 5.24 (s, 2H), 3.76 (s, 3H), 3.40 (s, 3H), 2.31 (s, 3H).

[1039]

[1040] 9-4. Chemical Formula-45: 3-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzenesulfonamide (Compound 78)

[1041] To a stirred solution of intermediate 44 (0.29 g, 1.0 eq) of Example 9-3 in DCM (20 mL) was added a diluted solution of trifluoroacetic acid (5 mL) in DCM (15 mL), and the reaction mixture was stirred at room temperature. The reaction mixture was then quenched with 5 mL of MeOH and evaporated under reduced pressure. The crude product was washed with ether and filtered to obtain the compound of chemical formula 45 as a yellow solid (0.15 g, 73.33%).

[1042] 1 H NMR (400 MHz, DMSO-d6) δ12.79 (s, 1H), 7.87 (d,J= 1.5 Hz, 1H), 7.76 (s, 1H), 7.74 (d,J= 6.4 Hz, 1H), 7.66 (dd,J= 4.8, 3.0 Hz, 1H), 7.56 (d,J= 3.9 Hz, 3H), 7.53 (d,J= 5.3 Hz, 1H), 7.46 (d,J= 6.9 Hz, 2H), 2.40 (s, 3H).

[1043]

[1044] Example 10. Synthesis of different types of oxazole derivatives (Scheme 10)

[1045] [Reaction Formula 10]

[1046]

[1047] Reagents and conditions: (a) Et3N, DCM, room temperature, 3 h reaction; (b) boronic acids, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:H2O(9:1), 100 ℃, 2 h reaction; (c) KHMDS, THF, room temperature, 2 h reaction; (d) TFA, DCM, room temperature, 30 min reaction.

[1048]

[1049] 10-1. Intermediate-46: 6-Bromo-N-(2,4-dimethoxybenzyl)benzo[d]oxazol-2-amine

[1050] To a stirred solution of 6-bromo-2-chlorobenzo[d]oxazole (2.00 g, 1.0 eq) and triethylamine (3.60 mL, 3.0 eq) in DCM (100 mL) was added 2,4-dimethoxybenzylamine (2.59 mL, 2.0 eq) at room temperature, and the solution was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (3 x 100 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 air dried to give intermediate 46 as an off pale-yellow solid (2.89 g, 92.38%).

[1051] 1 H NMR (400 MHz, DMSO-d6) δ8.38 (t,J= 5.9 Hz, 1H), 7.62 (d,J= 2.0 Hz, 1H), 7.26 (dd,J= 8.3, 1.9 Hz, 1H), 7.18 (t,J= 8.1 Hz, 2H), 6.57 (d,J= 2.3 Hz, 1H), 6.48 (dd,J= 8.4, 2.4 Hz, 1H), 4.39 (d,J= 5.8 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[1052]

[1053] 10-2. General procedure for intermediates 47a-47e

[1054] Cs2CO3 (2.5 eq) was added to a stirred solution of a 1,4-dioxane:H2O (9:1) mixture containing bromo compounds (1.0 eq) and boronic acids (1.2 eq), and the resulting reaction mixture was purged with argon for 10 minutes, followed by Pd(dppf)Cl 2·DCM (0.1 eq) was added to the reaction mixture. The resulting reaction mixture was then stirred 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.

[1055]

[1056] 10-3. Intermediate-47a:N-(2,4-Dimethoxybenzyl)-6-(furan-3-yl)benzo[d]oxazol-2-amine

[1057] Intermediate 47a was obtained as an off white solid (0.20 g, 69.1%) through the general procedure of Example 10-2 above.

[1058] 1 H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.37 (d,J= 8.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 2H), 6.95 (s, 1H), 6.57 (s, 1H), 6.49 (d,J= 8.6 Hz, 1H), 4.40 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[1059]

[1060] 10-4. Intermediate-47b:N-(2,4-Dimethoxybenzyl)-6-(2-methoxyphenyl)benzo[d]oxazol-2-amine

[1061] Intermediate 47b was obtained as an off white solid (0.17 g, 51.7%) through the general procedure of Example 10-2 above.

[1062] 1H NMR (400 MHz, DMSO-d6) δ8.21 (t,J= 5.8 Hz, 1H), 7.41 (s, 1H), 7.27 (d,J= 7.5 Hz, 2H), 7.21 - 7.16 (m, 3H), 7.07 (d,J= 8.1 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.55 (d,J= 2.3 Hz, 1H), 6.48 - 6.45 (m, 1H), 4.39 (d,J= 6.0 Hz, 2H), 3.79 (s, 3H), 3.73 (d,J= 7.4 Hz, 6H).

[1063]

[1064] 10-5. Intermediate-47c:N-(2,4-Dimethoxybenzyl)-6-(4-methoxyphenyl)benzo[d]oxazol-2-amine

[1065] Intermediate 47c was obtained as an off-white solid (0.20 g, 62.0%) through the general procedure of Example 10-2 above.

[1066] 1 H NMR (400 MHz, DMSO-d6)δ8.25 (t,J= 6.0 Hz, 1H), 7.61 - 7.56 (m, 3H), 7.38 - 7.34 (m, 1H), 7.22 (dd,J= 16.4, 8.2 Hz, 2H), 6.99 (d,J= 8.8 Hz, 2H), 6.58 (d,J= 2.3 Hz, 1H), 6.49 (dd,J= 8.5, 2.3 Hz, 1H), 4.41 (d,J= 5.9 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H).

[1067]

[1068] 10-6. Intermediate-47d: 5-(2-((2,4-Dimethoxybenzyl)amino)benzo[d]oxazol-6-yl)-2-fluorobenzonitrile

[1069] Intermediate 47d was obtained as an off-white solid (0.23 g, 69.0%) through the general procedure of Example 10-2 above.

[1070] 1 H NMR (400 MHz, DMSO-d6) δ8.39 (t,J= 6.0 Hz, 1H), 8.24 (dd,J= 6.2, 2.4 Hz, 1H), 8.10 - 8.06 (m, 1H), 7.77 (d,J= 1.4 Hz, 1H), 7.58 (t,J= 9.1 Hz, 1H), 7.49 (dd,J= 8.2, 1.7 Hz, 1H), 7.30 (d,J= 8.3 Hz, 1H), 7.21 (d,J= 8.3 Hz, 1H), 6.58 (d,J= 2.2 Hz, 1H), 6.49 (dd,J= 8.4, 2.3 Hz, 1H), 4.42 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[1071]

[1072] 10-7. Intermediate-47e:N-(2,4-Dimethoxybenzyl)-6-(thiophen-3-yl)benzo[d]oxazol-2-amine

[1073] Intermediate 47e was obtained as an off-white solid (0.20 g, 69.1%) through the general procedure of Example 10-2 above.

[1074] 1 H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.37 (d,J= 8.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 2H), 6.95 (s, 1H), 6.57 (s, 1H), 6.49 (d,J= 8.6 Hz, 1H), 4.40 (d,J= 5.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H).

[1075]

[1076] 10-8. General procedure for intermediates 48a-48e

[1077] To a stirred solution of intermediate 47a-e (1.0 eq) in THF (20 mL) was added KHMDS (3.0 eq) at room temperature. After 10 min, 3-methoxybenzoyl chloride (3.0 eq) was added at room temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then 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 purified with EtOAc / hexane.

[1078]

[1079] 10-9. Intermediate-48a:N-(2,4-Dimethoxybenzyl)-N-(6-(furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide

[1080] Intermediate 48a was obtained as an off white solid (0.18 g, 67.7%) through the general procedure of Example 10-8 above.

[1081] 1 H NMR (400 MHz, DMSO-d6) δ8.23 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.57 (s, 2H), 7.30 (d, J= 8.4 Hz, 1H), 7.25 (s, 1H), 7.02 (s, 3H), 6.98 (d,J= 7.4 Hz, 1H), 6.53 - 6.48 (m, 2H), 5.09 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H), 3.46 (s, 3H).

[1082]

[1083] 10-10. Intermediate-48b:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(4-methoxybenzo[d]oxazol-2-yl)benzamide

[1084] Intermediate 48b was obtained as a white solid (0.14 g, 65.13%) through the general procedure of Example 10-8 above.

[1085] 1 H NMR (400 MHz, DMSO-d6) δ7.61 (d,J= 1.4 Hz, 1H), 7.56 (d,J= 8.3 Hz, 1H), 7.41 - 7.38 (m, 1H), 7.34 - 7.28 (m, 3H), 7.26 (d,J= 7.8 Hz, 1H), 7.11 (d,J= 8.2 Hz, 1H), 7.05 (s, 2H), 7.01 (dd,J= 7.2, 5.6 Hz, 2H), 6.51 (d,J= 9.1 Hz, 2H), 5.11 (s, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 3.51 (s, 3H).

[1086]

[1087] 10-11. Intermediate-48c:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(6-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide

[1088] Intermediate 48c was obtained as an off-white solid (0.18 g, 68.9%) through the general procedure of Example 10-8 above.

[1089] 1 H NMR (400 MHz, DMSO-d6) δ7.80 - 7.77 (m, 1H), 7.65 - 7.62 (m, 2H), 7.58 (dd,J= 3.3, 1.2 Hz, 2H), 7.30 (d,J= 8.3 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.05 - 6.97 (m, 5H), 6.53 - 6.48 (m, 2H), 5.10 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H), 3.48 (s, 3H).

[1090]

[1091] 10-12. Intermediate-48d:N-(6-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-N-(2,4-dimethoxybenzyl)-3-methoxybenzamide

[1092] Intermediate 48d was obtained as an off-white solid (0.21 g, 69.2%) through the general procedure of Example 10-8 above.

[1093] 1 H NMR (400 MHz, DMSO-d6) δ8.30 (dd,J= 6.2, 2.5 Hz, 1H), 8.12 (ddd,J= 7.9, 5.1, 2.6 Hz, 1H), 7.96 (d,J= 1.6 Hz, 1H), 7.70 (dd,J= 8.3, 1.6 Hz, 1H), 7.66 (d,J= 8.4 Hz, 1H), 7.61 (t,J= 9.1 Hz, 1H), 7.30 (d,J= 8.2 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.06 - 6.98 (m, 3H), 6.53 - 6.48 (m, 2H), 5.12 (s, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.48 (s, 3H).

[1094]

[1095] 10-13. Intermediate-48e:N-(2,4-Dimethoxybenzyl)-3-methoxy-N-(6-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide

[1096] Intermediate 48e was obtained as an off white solid (0.22 g, 41.2%) through the general procedure of Example 10-8 above.

[1097] 1H NMR (400 MHz, DMSO-d6) δ8.23 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.57 (s, 2H), 7.30 (d, J= 8.4 Hz, 1H), 7.25 (s, 1H), 7.02 (s, 3H), 6.98 (d,J= 7.4 Hz, 1H), 6.53 - 6.48 (m, 2H), 5.09 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H), 3.46 (s, 3H).

[1098]

[1099] 10-14. General Procedure for Chemical Formulas 49a-49e

[1100] To a stirred solution of intermediate 48a-e (1.0 eq) in DCM (20 mL) was added a diluted solution of trifluoroacetic acid in DCM (5 mL of a 10x solution) at room temperature, and the reaction mixture was stirred at room temperature. The reaction mixture was then quenched with 5 mL of MeOH and evaporated under reduced pressure. The crude product was washed with ether and filtered to obtain the pure product.

[1101]

[1102] 10-15. Chemical Formula-49a: N-(6-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 79)

[1103] Through the general procedure of Examples 10-14 above, the compound of chemical formula 49a was obtained as a dark blue solid (13.7 mg, 11.7%).

[1104] 1 H NMR (400 MHz, DMSO-d6)δ12.04 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.60 (d,J=18.2 Hz, 3H), 7.48 (s, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 3.85 (s, 3H).

[1105]

[1106] 10-16. Chemical Formula-49b: 3-Methoxy-N-(6-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide (Compound 80)

[1107] Through the general procedure of Examples 10-14 above, the compound of chemical formula 49b was obtained as a white solid (78.5 mg, 46.2%).

[1108] 1 H NMR (400 MHz, DMSO-d6)δ12.05 (s, 1H), 7.75 (d,J= 6.8 Hz, 1H), 7.61 (s, 3H), 7.45 (d,J= 8.1 Hz, 2H), 7.37 (t,J= 7.1 Hz, 2H), 7.22 (s, 1H), 7.14 (d,J= 8.5 Hz, 1H), 7.06 (t,J= 7.4 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H).

[1109]

[1110] 10-17. Chemical Formula-49c: 3-Methoxy-N-(6-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide (Compound 81)

[1111] Through the general procedure of Examples 10-14 above, a compound of chemical formula 49c was obtained as a white solid (0.016 g, 13.2%).

[1112] 1 H NMR (400 MHz, DMSO-d6)δ12.05 (s, 1H), 7.91 (s, 1H), 7.68 (d,J= 8.3 Hz, 3H), 7.64 - 7.55 (m, 3H), 7.50 - 7.46 (m, 1H), 7.23 (d,J= 8.1 Hz, 1H), 7.07 - 7.02 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H).

[1113]

[1114] 10-18. Chemical Formula - 49d: N-(6-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide (Compound 82)

[1115] Through the general procedure of Examples 10-14 above, a compound of chemical formula 49d was obtained as a white solid (0.018 g, 12.5%).

[1116] 1 H NMR (400 MHz, DMSO-d6)δ12.14 (s, 1H), 8.35 (d,J= 4.0 Hz, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.73 (s, 2H), 7.65 (t,J= 9.1 Hz, 2H), 7.60 (s, 1H), 7.49 (d,J= 7.1 Hz, 1H), 7.23 (d,J= 8.4 Hz, 1H), 3.86 (s, 3H).

[1117]

[1118] 10-19. Chemical Formula-49e: 3-methoxy-N-(6-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide (Compound 83)

[1119] Through the general procedure of Examples 10-14 above, a compound of chemical formula 49e was obtained as a gray-white solid (0.15 g, 68.1%).

[1120] 1 H NMR (400 MHz, DMSO-d6) δ12.05 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 26.8 Hz, 5H), 7.48 (s, 1H), 7.23 (s, 1H), 3.86 (s, 3H).

[1121]

[1122] Example 11. Synthesis of different types of oxazole derivatives (Scheme 11)

[1123] [Reaction Formula 11]

[1124]

[1125] Reagents and conditions: (a) Et3N, DCM, room temperature, reaction time 3 h; (b) trans-N,N-dimethyl-1,2-cyclohexanediamine, copper (I) iodide, Cs2CO3, DMF, 100 ℃, reaction time 12 h; (c) Et3N, DMAP, DCM, room temperature, reaction time 12 h; (d) TFA, DCM, room temperature, reaction time 2 h.

[1126]

[1127] 11-1. General procedure for Ullmann coupling reaction

[1128] To a solution of bromo compound (1.0 eq) in DMF (20 mL) were added secondary amine (1.2 eq) and cesium carbonate (3.0 eq), and the resulting reaction mixture was purged with argon for 4 min, after which trans-N,N-dimethyl-1,2-cyclohexanediamine (0.3 eq) and Cu(I) iodide (0.3 eq) were added to the reaction mixture. The resulting reaction mixture was then stirred in a sealed tube at 100 °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.

[1129]

[1130] 11-2. Intermediate-50a: N-(4-Methoxybenzyl)-5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-amine (Compound 86)

[1131] Intermediate 50a was obtained as a pale-yellow solid (1.0 g, 57.47%) through the general procedure of Example 11-1 above.

[1132] 1H NMR (400 MHz, CDCl3)δ8.12 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.55 (d,J= 8.7 Hz, 2H), 7.44 (d,J= 8.3 Hz, 2H), 6.84 (d,J= 8.5 Hz, 2H), 5.30 (d,J= 5.6 Hz, 2H), 3.76 (s, 3H).

[1133]

[1134] 11-3. Intermediate-50b:N-(4-methoxybenzyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-amine

[1135] Intermediate 50b was obtained as a pale-yellow solid (1.0 g, 57.47%) through the general procedure of Example 11-1 above.

[1136] 1 H NMR (400 MHz, DMSO-d6) δ8.66 (t,J= 6.1 Hz, 1H), 8.37 (d,J= 3.4 Hz, 2H), 7.61 (d,J= 2.1 Hz, 1H), 7.50 (d,J= 8.5 Hz, 1H), 7.35 - 7.24 (m, 3H), 6.91 (d,J= 8.6 Hz, 2H), 4.47 (d,J= 6.0 Hz, 2H), 3.73 (s, 3H).

[1137]

[1138] 11-4. General procedure for acid-chloride coupling reactions (intermediates 52a-52e)

[1139] To a stirred solution of N-(4-methoxybenzyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-amine (1.0 eq), triethylamine (3.0 eq), and DMAP (0.5 eq) in DCM (20 mL) was added acyl chloride (5.0 eq) at room temperature, and the reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was then diluted with 50 mL of water and extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with EtOAc / hexane.

[1140]

[1141] 11-5. Intermediate-52a:N-(4-Methoxybenzyl)-3-(trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)benzamide (Compound 87)

[1142] Intermediate 52a was obtained as an off white solid (0.113 g, 15.63%) through the general procedure of Example 11-4 above.

[1143] 1 H NMR (400 MHz, DMSO-d6) δ11.98 - 11.88 (m, 1H), 9.16 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.88 (s, 1H), 7.82 (t,J= 6.6 Hz, 2H), 7.65 (d,J= 8.9 Hz, 2H), 7.39 (d,J= 8.5 Hz, 2H), 6.90 (d,J= 8.6 Hz, 2H), 5.26 (s, 2H), 3.71 (s, 3H).

[1144]

[1145] 11-6. Intermediate-52b:N-(4-Methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)nicotinamide

[1146] Intermediate 52b was obtained as an off white solid (0.01 g, 7.86%) through the general procedure of Example 11-4 above.

[1147] 1 H NMR (400 MHz, Chloroform-d)δ8.69 (s, 1H), 8.66 (d,J= 4.8 Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.85 (d,J= 7.9 Hz, 1H), 7.80 (s, 1H), 7.55 (d,J= 8.7 Hz, 1H), 7.44 (d,J= 8.3 Hz, 2H), 7.33 - 7.28 (m, 2H), 7.26 (s, 1H), 6.84 (d,J= 8.5 Hz, 2H), 5.30 (d,J= 5.6 Hz, 2H), 3.76 (s, 3H).

[1148]

[1149] 11-7. Intermediate-52c:N-(4-Methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)nicotinamide (Compound 88)

[1150] Intermediate 52c was obtained as an off white solid (0.01 g, 7.86%) through the general procedure of Example 11-4 above.

[1151] 1H NMR (400 MHz, Chloroform-d)δ8.69 (s, 1H), 8.66 (d,J= 4.8 Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.85 (d,J= 7.9 Hz, 1H), 7.80 (s, 1H), 7.55 (d,J= 8.7 Hz, 1H), 7.44 (d,J= 8.3 Hz, 2H), 7.33 - 7.28 (m, 2H), 7.26 (s, 1H), 6.84 (d,J= 8.5 Hz, 2H), 5.30 (d,J= 5.6 Hz, 2H), 3.76 (s, 3H).

[1152]

[1153] 11-8. Intermediate-52d:N-(4-Methoxybenzyl)-3-(trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide

[1154] Intermediate 52d was obtained as an off white solid (0.22 g, 39.2%) through the general procedure of Example 11-4 above.

[1155] 1 H NMR (400 MHz, Chloroform-d)δ7.82 (d,J= 9.5 Hz, 2H), 7.69 (dd,J= 17.2, 7.4 Hz, 2H), 7.62 (t,J= 7.0 Hz, 1H), 7.54 (dd,J= 12.7, 5.0 Hz, 2H), 7.48 - 7.40 (m, 3H), 7.32 (d,J= 8.6 Hz, 1H), 7.28 - 7.20 (m, 1H), 6.84 (d,J= 8.6 Hz, 2H), 5.32 (s, 2H), 3.76 (s, 3H).

[1156]

[1157] 11-9. Intermediate-52e: 3-Fluoro-N-(4-methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide

[1158] Intermediate 52e was obtained as an off white solid (0.21 g, 41.1%) through the general procedure of Example 11-4 above.

[1159] 1 H NMR (400 MHz, Chloroform-d)δ7.90 (d,J= 4.3 Hz, 2H), 7.78 (d,J= 9.2 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.48 - 7.40 (m, 3H), 7.32 - 7.23 (m, 5H), 6.84 (d,J= 8.6 Hz, 2H), 5.29 (s, 2H), 3.76 (s, 3H).

[1160]

[1161] 11-10. General procedure for chemical formulas 53a-53b

[1162] DCM (5 mL) containing TFA was added to a stirred solution of DCM (20 mL) containing the PMB-protected amine, and the reaction mixture was stirred at room temperature for 30 minutes. The RM was then diluted with 5 mL of methanol and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in 10 mL of ether, and the precipitated solid was filtered through a sintered funnel and washed again with 10 mL of ether. The obtained solid was then dried under suction vacuum to obtain the pure product.

[1163]

[1164] 11-11. Formula-53a: 3-(Trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide (Compound 84)

[1165] Through the general procedure of Example 11-10 above, a compound of chemical formula 53a was obtained as an off white solid (0.025 g, 16.00%).

[1166] 1 H NMR (400 MHz, DMSO-d6) δ12.62 - 12.46 (s, 1H), 8.36 (br s, 3H), 7.86 (br s, 2H), 7.72 (br s, 2H), 7.56 (br s, 3H).

[1167]

[1168] 11-12. Formula-53b: 3-Fluoro-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide (Compound 85)

[1169] Through the general procedure of Example 11-10 above, a compound of chemical formula 53b was obtained as an off white solid (0.025 g, 16.40%).

[1170] 1 H NMR (400 MHz, DMSO-d6) δ7.83 (d, J= 78.1 Hz, 9H), 7.53 (s, 2H), 7.36 (s, 3H).

[1171]

[1172] Example 12. Synthesis of different types of oxazole derivatives (Scheme 12)

[1173] [Reaction Formula 12]

[1174]

[1175] Reagents and conditions: (a) Corresponding acid chloride, pyridine, DCM, room temperature, reaction time 12 hours.

[1176]

[1177] 12-1. General procedure for coupling reactions of acid chlorides

[1178] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethylbenzoyl chloride (4.0 eq), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then 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, which was purified with EtOAc / hexane to obtain chemical formulas 54a-54d.

[1179]

[1180] 12-2. Chemical Formula-54a: N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-chlorobenzamide (Compound 89)

[1181] Through the general procedure of Example 12-1, the compound of chemical formula 54a was obtained as a pale brown solid (0.012 g, 1.4%).

[1182] 1 H NMR (400 MHz, DMSO-d6)δ12.50 (s, 1H), 8.09 (t,J= 1.9 Hz, 1H), 7.99 (d,J= 7.8 Hz, 1H), 7.86 (s, 1H), 7.76 - 7.72 (m, 1H), 7.69 (d,J= 1.7 Hz, 1H), 7.60 (t,J= 7.9 Hz, 1H).

[1183]

[1184] 12-3. Chemical Formula-54b: N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide (Compound 90)

[1185] Through the general procedure of Example 12-1 above, the compound of chemical formula 54b was obtained as a pale brown solid (0.112 g, 30.66%).

[1186] 1H NMR (400 MHz, DMSO-d6) 8.15 (br s, 2H), 7.97 (br s, 2H), 7.60 (d, J= 6.3 Hz, 4H).

[1187]

[1188] 12-4. Chemical Formula - 54c: N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-nitrobenzamide (Compound 91)

[1189] Through the general procedure of Example 12-1 above, a compound of chemical formula 54c was obtained as a pale brown solid (0.02 g, 2.5%).

[1190] 1 H NMR (400 MHz, DMSO-d6)δ12.83 (s, 1H), 8.88 (t,J= 2.1 Hz, 1H), 8.53 - 8.42 (m, 2H), 7.85 (dt,J= 19.2, 8.0 Hz, 2H), 7.71 (d,J= 1.7 Hz, 1H).

[1191]

[1192] 12-5. Chemical Formula - 54d: N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)thiophene-2-carboxamide (Compound 92)

[1193] Through the general procedure of Example 12-1, a compound of chemical formula 54d was obtained as a pink solid (0.034 g, 4.7%).

[1194] 1 H NMR (400 MHz, DMSO-d6) δ12.48 (s, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.27 (s, 1H).

[1195]

[1196] Example 13. Synthesis of different types of oxazole derivatives (Scheme 13)

[1197] [Reaction Formula 13]

[1198]

[1199] Reagents and conditions: (a) 3-trifluoromethylbenzoyl chloride, pyridine, room temperature, reaction time 2 hours; (b) 3-thiopheneboronic acid, PdCl2(dppf)·DCM, Et3N, EtOH, 80 ℃, reaction time 2 hours.

[1200]

[1201] 13-1. General procedure for chemical formulas 56a-56b

[1202] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethylbenzoyl chloride (4.0 eq), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then 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 with EtOAc / hexane to obtain chemical formula 56a-56b.

[1203]

[1204] 13-2. Chemical Formula-56a: N-(7-Bromonaphthalen-2-yl)-3-(trifluoromethyl)benzamide (Compound 93)

[1205] Through the general procedure of Example 13-1, a compound of chemical formula 56a was obtained as an off-white solid (0.12 g, 71.4%).

[1206] 1H NMR (400 MHz, Chloroform-d)δ8.24 (s, 1H), 8.17 (s, 1H), 8.11 (d,J= 8.4 Hz, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.84 (t,J= 7.2 Hz, 2H), 7.68 (d,J= 8.4 Hz, 2H), 7.63 (dd,J= 8.8, 2.0 Hz, 1H), 7.51 (dd, 1H); 13 C NMR (100 MHz, DMSO-d6) δ164.82, 137.92, 136.06, 135.04, 132.37, 130.24, 130.20, 129.83, 129.61, 129.51, 129.03, 128.87, 128.72, 128.34, 125.78, 124.74, 123.07, 121.95, 120.27, 116.44.

[1207]

[1208] 13-3. Chemical Formula-56b: N-(7-Bromoquinoxalin-2-yl)-3-(trifluoromethyl)benzamide (Compound 94)

[1209] Through the general procedure of Example 13-1, a compound of chemical formula 56b was obtained as an off white solid (0.18 g, 34.9%).

[1210] 1 H NMR (400 MHz, DMSO-d6) δ11.93 (s, 1H), 9.69 (s, 1H), 8.47 (s, 1H), 8.38 (d,J= 8.0 Hz, 1H), 8.13 (d,J= 2.1 Hz, 1H), 8.04 (dd,J= 8.3, 4.5 Hz, 2H), 7.91 (dd,J= 8.8, 2.2 Hz, 1H), 7.81 (t,J= 7.8 Hz, 1H).

[1211]

[1212] 13-4. Chemical Formula-57a: N-(7-(Thiophen-3-yl)naphthalen-2-yl)-3-(trifluoromethyl)benzamide (Compound 95)

[1213] Through the general procedure of Example 3-6 above, a compound of chemical formula 57a was obtained as an off-white solid (0.05 g, 70.1%).

[1214] 1 H NMR (400 MHz, DMSO-d6) δ10.69 (s, 1H), 8.51 (s, 1H), 8.39 - 8.29 (m, 2H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.87 - 7.81 (m, 2H), 7.80 - 7.74 (m, 2H), 7.70 (s, 1H); 13 C NMR (100 MHz, DMSO-d6) δ164.75, 141.77, 137.31, 136.27, 134.18, 133.49, 132.38, 130.24, 129.83, 129.70, 129.51, 128.56, 127.62, 126.86, 125.82, 124.74, 124.37, 123.10, 122.01, 121.25, 117.56.

[1215]

[1216] 13-5. Chemical Formula-57b: N-(7-(Thiophen-3-yl)quinoxalin-2-yl)-3-(trifluoromethyl)benzamide (Compound 96)

[1217] Through the general procedure of Example 3-6 above, a compound of chemical formula 57b was obtained as an off-white solid (0.03 g, 30.1%).

[1218] 1H NMR (400 MHz, DMSO-d6) δ11.83 (s, 1H), 9.61 (s, 1H), 8.48 (s, 1H), 8.39 (d,J= 7.8 Hz, 1H), 8.23 ​​(dd,J= 2.8, 1.3 Hz, 1H), 8.19 (dd,J= 4.6, 2.6 Hz, 2H), 8.12 (d,J= 9.2 Hz, 1H), 8.03 (d,J= 8.2 Hz, 1H), 7.83 (d,J= 7.9 Hz, 1H), 7.81 - 7.78 (m, 1H), 7.75 (dd,J= 5.0, 2.9 Hz, 1H).

[1219]

[1220] Example 14. Synthesis of different types of oxazole derivatives (Scheme 14)

[1221] [Reaction Formula 14]

[1222]

[1223] Reagents and conditions: (a) 3-trifluoromethylbenzoyl chloride, pyridine, room temperature, reaction time 2 hours; (b) 3-thiopheneboronic acid, Tetrakis, Cs2CO3, 1,4-dioxane:water, 100 ℃, reaction time 2 hours.

[1224]

[1225] 14-1. General procedure for coupling reactions of acid chlorides

[1226] To a stirred solution of pyridine containing amine (1.0 eq) was added 3-trifluoromethylbenzoyl chloride (4.0 eq), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then 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, which was purified with EtOAc / hexane to obtain intermediates 59, 62, and 65.

[1227]

[1228] 14-2. General procedure for Suzuki coupling reaction

[1229] To a stirred solution of dioxane and water (9:1) containing bromo compound (1.0 eq) and 3-thiopheneboronic acid (1.5 eq) was added Cs2CO3 (3.0 eq), and the resulting reaction mixture was purged with argon gas for 3 min, and then Tetrakis (0.05 eq) was added to the reaction mixture at room temperature. The reaction mixture was then stirred in a sealed tube at 100 °C for 2 h. The reaction mixture was 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 with EtOAc / hexane to obtain compounds 60, 63, and 66.

[1230]

[1231] 14-3. Intermediate-59:N-(6-Bromo-5-methoxypyridin-3-yl)-3-(trifluoromethyl)benzamide

[1232] Intermediate 59 was obtained as an off white solid (0.30 g, 32.6%) through the general procedure of Example 14-1 above.

[1233] 1 H NMR (400 MHz, DMSO-d6) δ10.78 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.35 - 8.25 (m, 2H), 8.04 - 7.95 (m, 2H), 7.83 (t, J = 7.9 Hz, 1H), 3.91 (s, 3H).

[1234]

[1235] 14-4. Intermediate-62:N-(6-Chloro-4-methoxypyridazin-3-yl)-3-(trifluoromethyl)benzamide

[1236] Intermediate 62 was obtained as an off white solid (0.30 g, 29.1%) through the general procedure of Example 14-1 above.

[1237] 1 H NMR (400 MHz, DMSO-d6) δ11.20 (s, 1H), 8.35 (s, 1H), 8.30 (d,J= 7.9 Hz, 1H), 8.03 (d,J= 7.8 Hz, 1H), 7.81 (t,J= 7.8 Hz, 1H), 7.68 (s, 1H), 3.95 (s, 3H).

[1238]

[1239] 14-5. Intermediate-65:N-(6-Chloro-4-methoxypyridin-3-yl)-3-(trifluoromethyl)benzamide

[1240] Intermediate 65 was obtained as a colorless liquid (0.66 g, 63.6%) through the general procedure of Example 14-1 above.

[1241] 1 H NMR (400 MHz, Chloroform-d)δ9.40 (s, 1H), 8.16 (d,J= 14.7 Hz, 2H), 8.06 (d,J= 7.6 Hz, 1H), 7.85 (d,J= 7.9 Hz, 1H), 7.67 (t,J= 7.8 Hz, 1H), 6.91 (s, 1H), 4.02 (s, 3H).

[1242]

[1243] 14-6. Formula-60:N-(5-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide (Compound 97)

[1244] Through the general procedure of Example 14-2, the compound of chemical formula 60 was obtained as an off white solid (0.04 g, 9.7%).

[1245] 1 H NMR (400 MHz, DMSO-d6)δ10.81 (s, 1H), 8.72 (d,J= 2.0 Hz, 1H), 8.34 - 8.29 (m, 2H), 8.24 (d,J= 11.4 Hz, 2H), 8.11 (d,J= 1.9 Hz, 1H), 8.00 (d,J= 8.4 Hz, 1H), 7.82 (t,J= 7.8 Hz, 1H), 7.72 (d,J= 7.9 Hz, 1H), 7.68 (d,J= 7.7 Hz, 1H), 3.90 (s, 3H).

[1246]

[1247] 14-7. Formula-63:N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)-3-(trifluoromethyl)benzamide (Compound 98)

[1248] Through the general procedure of Example 14-2, the compound of chemical formula 63 was obtained as an off white solid (0.04 g, 20.2%).

[1249] 1 H NMR (400 MHz, DMSO-d6)δ11.18 (s, 1H), 8.54 (d,J= 9.2 Hz, 2H), 8.38 (s, 1H), 8.34 (d,J= 7.9 Hz, 1H), 8.02 (d,J= 7.4 Hz, 1H), 7.99 (s, 1H), 7.92 (d,J= 7.5 Hz, 1H), 7.86 - 7.79 (m, 2H), 4.04 (s, 3H).

[1250]

[1251] 14-8. Formula-66:N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide (Compound 99)

[1252] Through the general procedure of Example 14-2, the compound of chemical formula 66 was obtained as an off white solid (0.16 g, 62.3%).

[1253] 1 H NMR (400 MHz, Chloroform-d)δ9.72 (s, 1H), 8.31 (s, 1H), 8.23 ​​(s, 1H), 8.19 (s, 2H), 8.10 (d,J= 8.3 Hz, 1H), 7.85 (d,J= 8.4 Hz, 1H), 7.67 (d,J= 5.0 Hz, 2H), 7.60 (d,J= 7.6 Hz, 1H), 7.32 (s, 1H), 4.12 (s, 3H).

[1254]

[1255] Example 15. Synthesis of different types of oxazole derivatives (Scheme 15)

[1256] [Reaction Formula 15]

[1257]

[1258] Reagents and conditions: (a) manganese (IV) oxide, MeOH, room temperature, reaction time 1 h; (b) 3-thiopheneboronic acid, Pd(dppf)Cl 2· DCM, Cs2CO3, 1,4-dioxane:water(9:1), 100 ℃, 2 h reaction; (c) zinc, EtOH:AcOH(7:3), 80 ℃, 2 h reaction; (d) 3-(trifluoromethyl)benzoic acid, HATU, DIPEA, DMF, room temperature, 2 h reaction.

[1259]

[1260] 15-1. Intermediate-69: 5-Bromo-2-(3-nitrophenyl)benzo[d]oxazole

[1261] To a stirred solution of 2-amino-4-bromophenol (3.00 g, 1.0 eq) and 3-nitrobenzaldehyde (2.41 g, 1.0 eq) in MeOH (200 mL) was added manganese(IV) oxide (6.00 g) at room temperature, and the solution was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (3 x 100 mL), and 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 69 as an off purple solid (0.32 g, 6.28%).

[1262] 1 H NMR (400 MHz, DMSO-d6) δ8.86 (s, 1H), 8.60 (d,J= 7.8 Hz, 1H), 8.49 (dd,J= 8.2, 1.4 Hz, 1H), 8.31 (s, 1H), 8.14 (d,J= 1.9 Hz, 1H), 8.00 (d,J= 7.9 Hz, 1H), 7.94 (t,J= 8.1 Hz, 1H).

[1263]

[1264] 15-2. Intermediate-70: 2-(3-Nitrophenyl)-5-(thiophen-3-yl)benzo[d]oxazole

[1265] To a stirred solution of 1,4-dioxane:H2O (9:1) mixture (30 mL) containing 5-bromo-2-(3-nitrophenyl)benzo[d]oxazole (0.30 g, 1.0 eq) and 3-thiopheneboronic acid (0.14 g, 1.2 eq) was added CS2CO3 (0.30 g, 2.5 eq), and the resulting reaction mixture was purged with argon for 10 min, followed by Pd(dppf)Cl 2·DCM (0.08 g, 0.1 eq) was added to the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 2 h, diluted with 100 mL of water, and extracted with EtOAc (3 x 100 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 70 as a brown solid (0.17 g, 56.10%).

[1266] 1 H NMR (400 MHz, DMSO-d6) δ8.89 (d,J= 1.7 Hz, 1H), 8.62 (d,J= 7.8 Hz, 1H), 8.50 - 8.47 (m, 1H), 8.23 ​​(s, 1H), 8.00 (t,J= 2.0 Hz, 2H), 7.93 - 7.89 (m, 2H), 7.69 (d,J= 2.1 Hz, 2H).

[1267]

[1268] 15-3. Intermediate-71: 3-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)aniline

[1269] To a stirred solution of a 7:3 mixture (100 mL) of EtOH:AcOH containing 2-(3-nitrophenyl)-5-(thiophen-3-yl)benzo[d]oxazole (0.15 g, 1.0 eq) was added zinc powder (0.30 g, 10.0 eq) at room temperature, and the solution was stirred at 80 °C for 2 h. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was washed with pentane to give intermediate 71 as a brown solid (0.035 g, 25.73%).

[1270] 1H NMR (400 MHz, DMSO-d6)δ8.13 (s, 1H), 7.95 (dd,J= 2.5, 1.5 Hz, 1H), 7.78 (s, 2H), 7.69 - 7.65 (m, 2H), 7.45 (s, 1H), 7.35 (d,J= 7.7 Hz, 1H), 7.24 (t,J= 7.8 Hz, 1H), 6.80 (dd,J= 7.9, 1.3 Hz, 1H), 5.50 (s, 2H).

[1271]

[1272] 15-4. Chemical Formula-72: N-(3-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 100)

[1273] A stirred solution of 3-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)aniline (0.030 g, 1.0 eq), HATU (0.078 g, 2.0 eq), and DIPEA (0.054 mL, 3.0 eq) in DMF (10 mL) was stirred at ambient temperature for 2 h, and the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 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 the compound of formula 72 as an off-yellow solid (0.015 g, 31.48%).

[1274] 1 H NMR (400 MHz, DMSO-d6) δ10.76 (s, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 8.33 (d,J= 8.0 Hz, 1H), 8.18 (s, 1H), 8.06 (d,J= 9.1 Hz, 1H), 8.03 - 7.97 (m, 3H), 7.84 (q,J= 8.5 Hz, 3H), 7.69 - 7.62 (m, 3H).

[1275]

[1276] [Experimental Example]

[1277] Experimental Example 1. Confirmation of MDH1 and MDH2 inhibitory effects of oxazole derivatives.

[1278] Inhibitory activity (IC) of MDH1 and MDH2 for the oxazole derivatives synthesized in Examples 1 to 15 above 50 ), inhibitory activity against cancer cells (GI 50 )(cell viability) was confirmed.

[1279] Specifically, lung cancer cells, A549 cells and H460 cells, were seeded at 3×10 in a 96-well plate. 3 After culturing for 24 hours by dispensing at a concentration of 20 μM, oxazole derivatives were 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 Table 1 below, it was confirmed that cell growth of lung cancer cell lines was inhibited, and the concentration that resulted in 50% inhibition was described.

[1280] Specifically, 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.

[1281] 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.

[1282] The results are shown in Tables 1 to 14 below.

[1283]

[1284]

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298] Based on the above results, major compounds were selected from among the synthesized compounds and further experiments were conducted.

[1299]

[1300] Experimental Example 2. Confirmation of the anticancer effects of major oxazole derivatives.

[1301] 2-1. Confirmation of MDH1 and MDH2 enzyme inhibitory activity and lung cancer cell proliferation inhibitory ability of compounds 49, 37, and 51.

[1302] MDH1 and MDH2 enzyme inhibitory activity (IC) of compounds 49, 37, 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 15 (compound 49), 16 (compound 37), and 17 (compound 51) below, it was found to have excellent MDH1 and MDH2 enzyme inhibitory activity and lung cancer cell proliferation inhibitory ability.

[1303]

[1304]

[1305]

[1306]

[1307] 2-2. Confirmation of ATP production by mitochondrial respiration and real-time ATP production by glycolysis

[1308] After treatment with compounds 49 and 37 in A549 cells with KRAS-LKB1 co-mutation (hereinafter, "A549-EV cells") and A549-EV cells expressing LKB1 and cells with normal LKB1 function (hereinafter, "A549-LKB1 cells"), 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. 1, it was confirmed that the total amount of ATP in the cell decreased, the production of glycol-ATP increased, and mito-ATP decreased after treatment with compounds 49 and 37.

[1309]

[1310] 2-3. Confirmation of the antitumor effects of compounds 49, 37, and 51.

[1311] To confirm the antitumor effect, the change in tumor size in mice following administration of compound 49, compound 37, and compound 51 was examined. Tumors were generated using A549 cells in BALB / c nude mice, and then compound 49 and compound 37 were orally administered at 60 mg / kg, and compound 51 was administered at 40 mg / kg once daily, and the change 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.

[1312] As a result, as shown in Fig. 2a, there was a slight decrease in body weight in the compound 49 administration group and the cisplatin administration group, and there were no specific findings in the compound 37 administration group. In addition, as shown in Fig. 2b, there was no change in body weight in the compound 51 administration group.

[1313] In addition, as shown in Fig. 3a, 25 days after administration of compound 49 and compound 37, the tumor weights of the compound 49 and compound 37 administration groups were confirmed to have decreased by 25.2% and 38.5%, respectively, compared to the negative control group, and the cisplatin administration group was confirmed to have decreased by 21.9%. As shown in Fig. 3b, the tumor weights of the compound 51 administration group were confirmed to have decreased by 39.7%.

[1314] As shown in Figures 4a and 4b, the tumor size increased in all groups, but the increase in tumor size was confirmed to be reduced in the groups administered compound 49, compound 37, and compound 51.

[1315]

[1316] 2-4. Confirmation of the efficacy of combination therapy with compound 51 and anti-PD-1 antibodies.

[1317] We examined whether a synergistic effect was observed when compound 51 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, a syngeneic mouse model experiment was conducted using a mouse colon cancer cell line CT26 with a KRAS mutation (KRAS mutation, LKB1 wt, hereinafter "CT26-sgNeg") and a mouse-derived colon cancer cell line CT26-sgLKB1 (KRAS mutation, LKB1 KO, hereinafter "CT26-sgLKB1") in which the LKB1 gene was deleted (knockout, KO).

[1318] The efficacy of combination of compound 51 and anti-PD-1 antibody was evaluated after tumor formation in CT26-sgNeg and CT26-sgLKB1 cell lines in BALB / c mice. Compound 51 was administered orally 5 times / week at a dose of 40 mg / kg, and anti-PD-1 antibody was administered 3 times / week at a dose of 5 mg / kg.

[1319] As a result, no specific symptoms were observed in all mice during general observation and long-term observation, and no abnormalities were found in major organs during autopsy on the final day. As shown in Figures 5a and 6a, no statistically significant weight loss was observed, and as shown in Figure 5b, in the CT26-sgNeg (KRAS mutation) cell line, the tumor weight was reduced by 30.1% when compound 51 was treated alone, by 24.7% when only anti-PD-1 antibody was treated, and by 52.5% when compound 51 was administered in combination with anti-PD-1 antibody.

[1320] In addition, as shown in Fig. 6b, in the CT26-sgLKB1 (KRAS-LKB1 KO) cell line, the tumor weight was reduced by 33.7% when treated with compound 51 alone, by 26.6% when treated with only anti-PD-1 antibody, and by 55.7% when administered in combination with compound 51 and anti-PD-1 antibody, compared to the control group.

[1321] In addition, as shown in FIGS. 5c and 6c, it was confirmed that when compound 51 and anti-PD-1 antibody were co-administered to CT26-sgNeg and CT26-sgLKB1 colon cancer cell lines, the increase in tumor size was reduced compared to the group administered compound 51 alone.

[1322] Therefore, it was found that there was a synergistic effect when compound 51 was co-administered with anti-PD-1 antibody in CT26-sgNeg and CT26-sgLKB1 colon cancer cell lines.

[1323]

[1324] 2-5. Confirmation of the efficacy of combination with compound 51 and gefitinib.

[1325] When gefitinib, a drug designed to block the growth of tumor cells by targeting EGFR, was combined with compound 51, we examined whether there was a synergistic effect in antitumor efficacy.

[1326] Specifically, a xenograft experiment was performed to confirm the efficacy of the combination of compound 51 and gefitinib (Korea Research Institute of Bioscience and Biotechnology, Laboratory Animal Support Center). A549 tumors were formed in Balb / c nude mice, and the tumor size was 100.8 mm. 3 At this time, drug administration was started. Compound 51 was administered orally at a dose of 60 mg / kg, and gefitinib was administered orally at a dose of 10 mg / kg, 5 times / week.

[1327] As a result, no specific symptoms were observed during general symptoms and long-term observation, and no abnormalities were found in major organs in the final autopsy. As shown in Fig. 7a, there was no statistically significant weight loss, and as shown in Fig. 7b, the tumor weight was reduced by 28.8% and 38.8%, respectively, when gefitinib and compound 51 were administered alone compared to the negative control group, and a 61.6% reduction was confirmed when gefitinib and compound 51 were administered together. In addition, as shown in Fig. 7c, it was confirmed that the increase in tumor size was reduced when compound 51 was administered together compared to the group administered compound 51 alone.

[1328] Therefore, it was found that compound 51 and gefitinib had a synergistic effect when administered together in lung cancer cell lines.

[1329]

[1330] 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.

[1331] The oxazole 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. Furthermore, it exhibits even more excellent anti-cancer effects when administered in combination with anti-PD-1 inhibitors or anti-cancer agents such as gefitinib. Therefore, the oxazole 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 oxazole derivative represented by the following chemical formula 1 or a salt thereof: [Chemical Formula 1] (In the above chemical formula 1, X1, X2, and X3 are each independently carbon (C) or nitrogen (N), Y1 is N=C-, CR6=N-, CH=C-, or NH-C=O-R8, Y2 is absent, hydrogen (H), oxygen (O), nitrogen (N), sulfur (S), CH=C-, N=C-, or NR7, R6 and R7 are each independently hydrogen (H) or a C1-C6 alkyl group, R8 is a substituted or unsubstituted aryl group, The above Cy is formed by Y1 and Y2 being fused and connected to each other, and forms a 5-membered or 6-membered unsaturated ring including one or more double bonds including Y1 and Y2, and the unsaturated ring contains at least one or more selected from the group consisting of C, N, O, and S, Z is absent, NH-C=O-, NH-SO2-, or NR 10 -and, R 10 is hydrogen (H), a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group, R1 is absent, a substituted or unsubstituted aryl group, a substituted or unsubstituted benzoyl group, or a heteroarylcarbonyl group, R2 is hydrogen (H), a halogen element, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polycyclic heteroaryl group, a C1-C6 alkoxy group, an amino group (NH2), a nitro group (NO2), or NH-R9, R9 is a heteroaryl group, a polycyclic heteroaryl group, a cycloalkyl group, a C1-C6 alkyl group, or a C1-C6 acyl group, R3 is hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, a halogen element, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, R4 is absent, hydrogen (H), a substituted or unsubstituted C1-C6 alkyl group, or a halogen element, R5 is absent, hydrogen (H), or a C1-C6 alkoxy 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 alkoxy groups, C1-C6 alkyl groups or C1-C6 alkoxy groups substituted with one or more halogen elements, cyano groups (C≡N), aryl groups, and nitro groups (NO2).

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, an ethyl group, an i-propyl group, an n-propyl group, an n-butyl group, or an i-butyl group, An oxazole derivative or a salt thereof, characterized in that the C1-C6 alkoxy group is a methoxy group.

3. In paragraph 1, An oxazole 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 oxazole 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) 3-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 1) (2)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-trifluoromethyl)benzamide; (Compound 2) (3) 3-chloro-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 3) (4)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 4) (5)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (Compound 5) (6) 3-Cyano-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 6) (7) 3-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 7) (8)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (Compound 8) (9) 4-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 9) (10) 4-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 10) (11)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-trifluoromethyl)benzamide; (화합물 11) (12)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-4-(trifluoromethoxy)benzamide; (화합물 12) (13) 2-N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)isonicotinamide; (Compound 13) (14) 2-Chloro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 14) (15) 2-Fluoro-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (Compound 15) (16) 2-Methoxy-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 16) (17)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(trifluoromethyl)benzamide; (화합물 17) (18)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (화합물 18) (19) 5-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)picolinamide; (Compound 19) (20)N-(4-Methoxybenzyl)-5-(thiophen-3-yl)benzo[d]oxazol-2-amine; (화합물 20) (21)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 21) (22) 3-Fluoro-N-(4-methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 22) (23)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 23) (24)N-(4-Methoxybenzyl)-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 24) (25)N-(5-Fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 25) (26)N-(5-Methoxybenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 26) (27)N-(5-Chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 27) (28) 5-(Thiophen-3-yl)benzo[d]thiazol-2-amine; (화합물 28) (29)N-(5-bromobenzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 29) (30)N-(5-Bromo-1-methyl-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 30) (31)N-(5-(Thiophen-3-yl)benzo[d]thiazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 31) (32)N-(5-(Thiophen-3-yl)benzo[d]isoxazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 32) (33)N-(1-Methyl-5-(thiophen-3-yl)-1H-indazol-3-yl)-3-(trifluoromethyl)benzamide; (화합물 33) (34) 3-Methoxy-N-(5-(thiophen-2-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 34) (35)N-(5-(4-Cyano-3-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 35) (36)N-(5-(4-Cyanophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 36) (37)N-(5-(Furan-2-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 37) (38) 3-Methoxy-N-(5-(3-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 38) (39) 3-Methoxy-N-(5-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 39) (40) 3-Methoxy-N-(5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 40) (41) 3-Methoxy-N-(5-phenylbenzo[d]oxazol-2-yl)benzamide; (화합물 41) (42) 3-Methoxy-N-(5-(5-methylthiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 42) (43)N-(5-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 43) (44) 3-Methoxy-N-(5-(2-methylfuran-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 44) (45)N-(5-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 45) (46)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 46) (47)N-(5-Bromo-7-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 47) (48)N-(5-Bromo-6-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 48) (49)N-(5-Bromo-6-fluorobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 49) (50)N-(5-Bromo-6-methylbenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 50) (51)N-(7-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 51) (52) 3-Methoxy-N-(7-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 52) (53)N-(6-Chloro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 53) (54)N-(6-Fluoro-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 54) (55) 3-Methoxy-N-(6-methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 55) (56)N-(5-(Thiophen-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 56) (57)N-(6-Methyl-5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 57) (58)N-(6-Bromooxazolo[5,4-b]pyridin-2-yl)-3-methoxybenzamide; (화합물 58) (59) 3-Methoxy-N-(6-(thiophen-3-yl)oxazolo[5,4-b]pyridin-2-yl)benzamide; (화합물 59) (60)N-(5-(Thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)-3-(trifluoromethyl)benzamide; (화합물 60) (61) 3-Methoxy-N-(5-(thiophen-3-yl)oxazolo[4,5-b]pyridin-2-yl)benzamide; (화합물 61) (62) 3-Methoxy-N-(5-((thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 62) (63)N-(5-((Furan-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 63) (64)N-(5-(Cyclohexylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 64) (65) 3-Methoxy-N-(5-((pyridin-3-ylmethyl)amino)benzo[d]oxazol-2-yl)benzamide; (화합물 65) (66)N-(5-((Benzo[b]thiophen-3-ylmethyl)amino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 66) (67)N-(5-(Isopropylamino)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 67) (68) 3-Methoxy-N-(5-(3-methylbutanamido)benzo[d]oxazol-2-yl)benzamide; (화합물 68) (69) 3-Methoxy-N-(5-propionamidobenzo[d]oxazol-2-yl)benzamide; (화합물 69) (70) 3-Methoxy-N-(5-nitrobenzo[d]oxazol-2-yl)benzamide; (화합물 70) (71)N-(5-Aminobenzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 71) (72) 2-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)acetamide; (화합물 72) (73) 3-Phenyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)propanamide; (화합물 73) (74)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide; (화합물 74) (75)N-(5-(Thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)propanamide; (화합물 75) (76)N-(5-Bromobenzo[d]oxazol-2-yl)-3-(trifluoromethyl)benzamide; (화합물 76) (77) 1-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea; (화합물 77) (78) 3-Methyl-N-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzenesulfonamide; (화합물 78) (79)N-(6-(Furan-3-yl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 79) (80) 3-Methoxy-N-(6-(2-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 80) (81) 3-Methoxy-N-(6-(4-methoxyphenyl)benzo[d]oxazol-2-yl)benzamide; (화합물 81) (82)N-(6-(3-Cyano-4-fluorophenyl)benzo[d]oxazol-2-yl)-3-methoxybenzamide; (화합물 82) (83) 3-methoxy-N-(6-(thiophen-3-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 83) (84) 3-(Trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 84) (85) 3-Fluoro-N-(5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-yl)benzamide; (화합물 85) (86)N-(4-Methoxybenzyl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]oxazol-2-amine; (화합물 86) (87)N-(4-Methoxybenzyl)-3-(trifluoromethyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)benzamide(화합물 87) (88)N-(4-Methoxybenzyl)-N-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzo[d]oxazol-2-yl)nicotinamide; (화합물 88) (89)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-chlorobenzamide; (화합물 89) (90)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-(trifluoromethoxy)benzamide; (화합물 90) (91)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)-3-nitrobenzamide; (화합물 91) (92)N-(5-Bromo-7-chlorobenzo[d]oxazol-2-yl)thiophene-2-carboxamide; (화합물 92) (93)N-(7-Bromonaphthalen-2-yl)-3-(trifluoromethyl)benzamide; (Compound 93) (94)N-(7-Bromoquinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (Compound 94) (95)N-(7-(Thiophen-3-yl)naphthalen-2-yl)-3-(trifluoromethyl)benzamide; (Compound 95) (96)N-(7-(Thiophen-3-yl)quinoxalin-2-yl)-3-(trifluoromethyl)benzamide; (Compound 96) (97)N-(5-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 97) (98)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 98) (99)N-(4-Methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide; (Compound 99) and (100)N-(3-(5-(thiophen-3-yl)benzo[d]oxazol-2-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 100).

5. In paragraph 1, The compound represented by the above chemical formula 1 is wherein X1, X2, and X3 are each independently carbon (C), Y1 is N=C-, Y2 is oxygen (O), Z is NH-C=O-, An oxazole derivative or a salt thereof, characterized in that R1 is a substituted or unsubstituted aryl group, R2 is a heteroaryl group or a halogen element, R3 and R4 are each independently hydrogen (H) or a halogen element, and R5 is hydrogen (H).

6. A pharmaceutical composition for preventing or treating cancer, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. In paragraph 6, 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).

8. In paragraph 6, 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.

9. In paragraph 6, A pharmaceutical composition for preventing or treating cancer, characterized in that the composition is administered in combination with an anticancer agent.

10. In paragraph 9, A pharmaceutical composition for preventing or treating cancer, characterized in that the anticancer agent is an immune checkpoint inhibitor or a chemotherapy agent.

11. In paragraph 10, 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.

12. In paragraph 10, 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.

13. A method for preventing or treating cancer, comprising administering a composition containing a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient in a pharmaceutically effective amount to a subject in need thereof.

14. Use of a composition comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

15. Use of a composition comprising a compound of any one of claims 1 to 5 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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