Benzoxazole derivatives as PCSK9 inhibitor

Abstract

The present invention relates to a benzoxazole derivative and a pharmaceutical composition for the prevention or treatment of diseases caused by PCSK9 overexpression. The benzoxazole derivative inhibits the overexpression of PCSK9 protein and suppresses the secretion of PCSK9 protein to the extracellular space, thereby being useful for the prevention, alleviation, or treatment of diseases associated with the protein interaction between PCSK9 and LDL-R.

Description

Benzoxazole derivatives as PCSK9 inhibitors

[0001] The present invention relates to a benzoxazole derivative as a PCSK9 inhibitor and a pharmaceutical composition containing the same as an active ingredient for preventing or treating hypercholesterolemia.

[0002]

[0003] Cholesterol, a steroid compound widely present in the cells of higher animals, is an essential nutrient for the human body. However, recent changes in Westernized eating habits and lifestyles have led to abnormally high blood cholesterol levels, leading to a rise in the incidence of cholesterol-related diseases such as dyslipidemia, heart disease, diabetes, and cardiovascular disease. Consequently, the development of drugs that lower blood cholesterol is actively underway.

[0004]

[0005] Hypercholesterolemia refers to a condition in which the cholesterol concentration in the serum (plasma) is 220-250 mg / L or higher. In this case, the cholesterol in low-density lipoprotein (LDL) is often 170 mg / dL or higher, and arteriosclerotic disease is likely to occur.

[0006]

[0007] Currently, there are two main methods for reducing blood cholesterol levels. The first is to directly reduce the amount of cholesterol produced in the liver. The second is to increase the amount of low-density lipoprotein receptors (LDL-R), which allows blood cholesterol to enter cells, where it is metabolized in the liver and excreted, ultimately reducing blood cholesterol levels.

[0008]

[0009] The most commonly used drugs that inhibit cholesterol production in the liver are statins. Statins inhibit the activity of hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), an enzyme involved in cholesterol synthesis, thereby reducing blood cholesterol levels. Secondarily, they increase the expression of low-density lipoprotein receptors on cell membranes. These effects make them effective treatments for dyslipidemias such as hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

[0010] Statin drugs include simvastatin, cilastatin, nystatin, lovastatin, somatostatin, mevastatin, pitavastatin, pravastatin, fluvastatin, atorvastatin, cervastatin, ulinastatin, and rosuvastatin.

[0011] However, these statin drugs are known to often cause side effects such as muscle pain due to muscle toxicity, diabetes due to increased blood sugar levels, and increased neurological abnormalities such as mental confusion and stupor. As the number of patients whose cholesterol levels are not controlled despite taking statins increases, there is a need to develop new drugs that can lower blood cholesterol levels.

[0012]

[0013] Meanwhile, it has been discovered that the proprotein convertase subtilisin / kexin type 9 (PCSK9) protein binds to the EGF-A domain of the low-density lipoprotein receptor present in the cell membrane in the liver, causing the low-density lipoprotein receptor to be degraded by lysosomes, thereby causing a quantitative decrease in the low-density lipoprotein receptor and increasing the blood cholesterol concentration. As a result, active attempts are being made to use PCSK9 inhibitors to lower blood cholesterol concentration.

[0014]

[0015] Proprotein convertase subtilisin kexin 9 (PCSK9) is a member of the subtilisin serine protease family. The other eight mammalian subtilisin proteases, PCSK1 to PCSK8 (also known as PC1 / 3, PC2, furin, PC4, PC5 / 6, PACE4, PC7, and S1P / SKI-1), are proprotein convertases that process various proteins in the secretory pathway and play roles in diverse biological processes. PCSK9 has been proposed to play a role in cholesterol metabolism. PCSK9 mRNA expression is downregulated by dietary cholesterol intake in mice, upregulated by statins in HepG2 cells, and upregulated in sterol regulatory element-binding protein (SREBP) transgenic mice, which are similar to cholesterol biosynthetic enzymes and the low-density lipoprotein receptor (LDLR). Furthermore, PCSK9 missense mutations have been found to be associated with a form of autosomal dominant hypercholesterolemia (Hchola3). PCSK9 may also play a role in determining LDL cholesterol levels in the general population, as single-nucleotide polymorphisms (SNPs) have been associated with cholesterol levels in a Japanese population. Autosomal dominant hypercholesterolemia (ADH) is a monogenic disease in which patients present with elevated total and LDL cholesterol levels, tendon xanthoma, and immature atherosclerosis. The pathogenesis of ADH and its recessive form, autosomal recessive hypercholesterolemia (ARH), is due to a defect in LDL uptake by the liver. ADH can be caused by mutations in the LDLR protein, which prevents LDL uptake, or by mutations in apolipoprotein B, a protein on LDL that binds to the LDLR. ARH is caused by mutations in the ARH protein, which is required for endocytosis of the LDLR-LDL complex through interaction with clathrin.Therefore, if PCSK9 mutations are causative in the Hchola3 family, PCSK9 appears to play a role in receptor-mediated LDL uptake. Overexpression studies point to a role for PCSK9 in the regulation of LDLR levels and, consequently, LDL uptake by the liver. Adenovirus-mediated overexpression of mouse or human PCSK9 in mice for 3 or 4 days results in elevated total and LDL cholesterol levels, an effect that is absent in LDLR knockout animals. Furthermore, PCSK9 overexpression leads to a significant decrease in hepatic LDLR protein without affecting LDLR mRNA levels, SREBP protein levels, or the nuclear-to-cytoplasmic ratio of SREBP protein. While hypercholesterolemia itself is asymptomatic, long-term elevations in serum cholesterol can lead to atherosclerosis. Over decades, chronically elevated serum cholesterol contributes to the formation of atheromatous plaques in arteries, which can lead to progressive narrowing or even complete occlusion of the affected artery. Smaller plaques can also rupture, forming clots that can block blood flow, potentially leading to, for example, myocardial infarction and / or stroke.

[0016]

[0017] However, since it is known that statin drugs increase the expression of PCSK9, the reason why the LDL-cholesterol lowering effect of statin drugs does not increase in proportion to the administered dose is explained by the simultaneous increase in the expression of PCSK9, which reduces the low-density lipoprotein receptor. This suggests that co-administration of PCSK9 inhibitors with statin drugs will increase the therapeutic effect, and thus the development of PCSK9 inhibitors is receiving more attention. However, in the case of drugs that directly inhibit the expression of PCSK9 in the liver, which are being developed most actively recently, there is an ongoing debate about the high risk of other side effects.

[0018]

[0019] The present inventors have previously proposed a PCSK9 inhibitor as Korean Patent Publication No. 2022-0047168, but have completed the present invention by discovering that a compound with a new structure containing a benzoxazole structure inhibits the expression of PCSK9 protein and inhibits secretion outside of cells.

[0020]

[0021] The purpose of the present invention is to provide a novel benzoxazole derivative compound that is effective in preventing, treating or improving hypercholesterolemia.

[0022]

[0023] To achieve the above purpose,

[0024] One aspect of the present invention provides a compound represented by the formula I described herein or a pharmaceutically acceptable salt thereof.

[0025] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] Another aspect of the present invention provides a health functional food composition for preventing or improving hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, containing the compound or a pharmaceutically acceptable salt thereof.

[0027] Another aspect of the present invention provides a method for treating hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, comprising administering the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0028] Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof for preparing a medicament for use in the prevention or treatment of hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia.

[0029]

[0030] In one aspect of the present invention, the compound or a pharmaceutically acceptable salt thereof not only inhibits the expression of PCSK9 protein, but also inhibits secretion outside of cells, thereby inhibiting protein interaction with LDL-R, and thus can be usefully used for the prevention, improvement, or treatment of hypercholesterolemia.

[0031]

[0032] Hereinafter, the present invention will be described in detail.

[0033]

[0034] Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, the embodiments of the present invention are provided to more fully explain the present invention to those with average knowledge in the relevant technical field.

[0035] Furthermore, reference to an element "including" throughout the specification does not exclude other elements, but rather includes other elements, unless specifically stated otherwise.

[0036] Defines terms used in this specification.

[0037] The term "alkylene" or "alkyl" includes straight or branched chain saturated hydrocarbon residues, unless otherwise specified. For example, "C1-C6 alkyl" means an alkyl having a skeleton of 1 to 6 carbons. Specifically, C1-C6 alkyl can include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, and the like.

[0038] "Alkenyl" includes some unsaturated hydrocarbon residues containing one or more, ranging from 1 to 5, carbon-to-carbon double bonds within the "alkyl" hydrocarbon chain.

[0039] The term "alkoxy" refers to a group in which an alkyl is substituted by being connected to the parent group through an oxygen atom.

[0040] The term "haloalkyl" or "haloalkoxy" means that carbon of an alkyl group or an alkoxy group is replaced by one or more halogen elements other than hydrogen, and for example, 1 to 6 halogen elements may be substituted, and the halogen elements are selected from F, Cl, Br or I, and when one or more halogens are substituted, the same halogen element or a different halogen element may be substituted, and examples of C1-C6 haloalkyl include CF3, CFH2, CF2H, CHFCF3, etc.

[0041] The term "cycloalkyl" includes a cyclized, fully saturated hydrocarbon residue, and "C3-C6 cycloalkyl" means a cycloalkyl having 3 to 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] The term “heterocycle” refers to a ring compound consisting of 1 to 3 rings containing at least one heteroatom, and when referring to a “5-membered heterocycle,” it means that there are 5 ring atoms, which are carbons and heteroatoms forming the ring.

[0043] The term “heterocycloalkyl” means a monovalent saturated moiety consisting of 1 to 3 rings containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S, unless otherwise specified. It may be bicyclic or tricyclic containing 2 or 3 rings, wherein these 2 or 3 rings may be bridged, fused or spiro-shaped heterocycloalkyl. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0044] The term “heteroaryl” means, unless otherwise specified, an aromatic radical having a single ring or two or three fused rings (the remaining ring atoms being C) containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S as ring atoms. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0045] When two or more substituents selected from the list are substituted in this specification, the substituents may be the same or different unless otherwise specified.

[0046] Unless otherwise indicated in this specification, “substituted” means unsubstituted.

[0047]

[0048] One aspect of the present invention relates to a compound represented by the following chemical formula I or a pharmaceutically acceptable salt thereof.

[0049]

[0050] In chemical formula I,

[0051] p is 2,

[0052] R 1 are each independently hydrogen, C1-C6 haloalkyl, nitro, halogen or C1-C6 haloalkoxy, R 1 At least one of them is not hydrogen,

[0053] R 2 is hydrogen, NH2, or substituted phenyl,

[0054] R 3 is hydrogen, C1-C6 haloalkyl, halogen, C1-C6 alkyl, 5-6 membered heteroaryl or nitro,

[0055] R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C1-C6 alkoxy, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, nitro, -NH-COR 6a or -SO2NH2, but at least one of these is not hydrogen,

[0056] R 6a is a 5-6 membered heterocycloalkyl or substituted C1-C6 alkyl, wherein the substituted C1-C6 alkyl is substituted with NH2 or one or more halogens,

[0057] The above substituted phenyl is R of 1 to 3 7 is replaced by,

[0058] R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -X-NR 7a R 7b , or -NH-YR 7c And,

[0059] X is SO2 or CO,

[0060] Y is SO2, CO or CO2

[0061] R 7a , and R 7b are each independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl,

[0062] R 7c is C1-C6 alkyl, or

[0063] or two R 7 The two adjacent carbon atoms of this phenyl can be substituted to form a 5-6 membered heteroaryl together with the two carbon atoms.

[0064]

[0065] In another specific embodiment, the compound of formula I is

[0066] R 1 is substituted at positions 5 and 6 of the benzoxazole ring,

[0067] R 1 One of them may be C1-C6 haloalkyl, nitro, halogen or C1-C6 haloalkoxy, and the other may be hydrogen or halogen. Meanwhile, the undefined part is as defined above, and the same applies to other specific examples of the compound of formula I presented below.

[0068]

[0069] In another specific embodiment, the compound of formula I is

[0070] R 4 is hydrogen, halogen, C1-C6 alkoxy, OH, NH2, C1-C6 alkyl or C1-C6 haloalkyl,

[0071] R 5 is hydrogen, NH2, halogen or -SO2NH2,

[0072] R 6 is hydrogen, NH2, halogen, C1-C6 alkyl, SO2NH2, nitro, -NH-COR 6a Or OH,

[0073] R 6a is a 5-6 membered heterocycloalkyl or substituted C1-C6 alkyl, wherein the substituted C1-C6 alkyl is substituted with NH2 or 1-3 halogen,

[0074] R 4 Inland R 6 At least one of them is not hydrogen.

[0075]

[0076] In another specific embodiment, the compound of formula I is

[0077] R 2 is hydrogen, NH2, or substituted phenyl,

[0078] The above substituted phenyl is R of 1 to 3 7 is replaced by,

[0079] R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -SO2NR 7a R 7b , -CONH2, -NHSO2R 7c , -NHCOR 7c , or -NHCO2R 7c And,

[0080] R 7a is hydrogen,

[0081] R 7b is hydrogen or C1-C6 alkyl,

[0082] R 7c are each independently C1-C6 alkyl, or

[0083] or two R 7 It can be substituted on the two adjacent carbon atoms of this phenyl to form a 5-6 membered heteroaryl together with the two carbon atoms.

[0084]

[0085] In another specific embodiment, the compound of formula I is

[0086] p is 2,

[0087] R1 is substituted at positions 5 and 6 of the benzoxazole ring,

[0088] R 1 One of which is C1-C3 haloalkyl, nitro, halogen or C1-C3 haloalkoxy, and the other is hydrogen or halogen,

[0089] R 2 is hydrogen, NH2, or substituted phenyl,

[0090] R 3 is hydrogen, C1-C3 haloalkyl, halogen, C1-C3 alkyl, 5-membered heteroaryl or nitro,

[0091] R 4 is hydrogen, halogen, C1-C3 alkoxy, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl,

[0092] R 5 is hydrogen, NH2, halogen or -SO2NH2,

[0093] R 6 is hydrogen, NH2, halogen, C1-C3 alkyl, SO2NH2, nitro, -NH-COR 6a Or OH,

[0094] R 6a is a 5-membered heterocycloalkyl or substituted C1-C3 alkyl, wherein the substituted C1-C3 alkyl is substituted with NH2 or three halogens,

[0095] R 4 Inland R 6 At least one of them is not hydrogen,

[0096] The above substituted phenyl is R of 1 to 3 7 is replaced by,

[0097] R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -SO2NR 7a R 7b , -CONH2, -NHSO2R 7c , -NHCOR 7c, or -NHCO2R 7c And,

[0098] R 7a is hydrogen,

[0099] R 7b is hydrogen, C1-C3 alkyl or C3 cycloalkyl,

[0100] R 7c are each independently C1-C3 alkyl, or

[0101] or two R 7 It can be substituted on the two adjacent carbon atoms of this phenyl to form a five-membered heteroaryl together with the two carbon atoms.

[0102]

[0103] In another specific embodiment, the compound of formula I is

[0104] p is 2,

[0105] R 1 is substituted at positions 5 and 6 of the benzoxazole ring,

[0106] R 1 One of them is CF3, nitro, F or OCF3, and the other is hydrogen or F,

[0107] R 2 is hydrogen, NH2, or substituted phenyl,

[0108] The above substituted phenyl is substituted with 1 to 3 identical or different substituents selected from Cl, F, methyl, methoxy, nitro, NH2, -SO2NH2, -SO2NHCH3, -SO2NH(cyclopropyl), -NHSO2CH3, -NHCOCH3, -NHCO2CH3, and -CONH2, or two adjacent carbon atoms of phenyl are substituted to form pyrazolyl together with the two carbon atoms,

[0109] R 3 is hydrogen, CF3, F, methyl, furanyl, triazolyl or nitro,

[0110] R 4is hydrogen, Cl, F, methoxy, OH, NH2, methyl or CF3,

[0111] R 5 is hydrogen, NH2, Cl or SO2NH2,

[0112] R 6 is hydrogen, NH2, F, Cl, methyl, SO2NH2, nitro, -NH-COR 6a Or OH,

[0113] R 6a is pyrrolidinyl or substituted C1-C3 alkyl, wherein the substituted C1-C3 alkyl is substituted with NH2 or three halogens,

[0114] R 4 Inland R 6 At least one of them may not be hydrogen.

[0115]

[0116] In another specific embodiment, the compound of formula I is

[0117] It may be a compound according to claim 1 selected from the following.

[0118] 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0119] 2-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0120] 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0121] 2,6'-Difluoro-4'-methoxy-3''-(5-nitrobenzo[d]oxazol-2-yl)-5''-(trifluoromethyl)-[1,1':3',1''-terphenyl]-4-amine;

[0122] 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0123] 3''-(5,6-Difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-N-methyl-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0124] N-(3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide;

[0125] N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide;

[0126] 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-sulfonamide;

[0127] N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide;

[0128] 6'-Fluoro-4'-methoxy-N-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0129] 3'',6'-Difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0130] 2,3'',6'-Trifluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0131] N-(3'',6'-difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide;

[0132] 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine;

[0133] 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3-amine;

[0134] 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine;

[0135] 2,6'-Difluoro-4'-methoxy-3''-methyl-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0136] 6'-Fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0137] N-(6'-fluoro-4'-methoxy-3''-(trifluoromethyl)-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide;

[0138] 6'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0139] N-(6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide;

[0140] 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine;

[0141] 2-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine;

[0142] Methyl (6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)carbamate;

[0143] N-Cyclopropyl-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0144] 2,3,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0145] 3-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0146] 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3,4-diamine;

[0147] 3''-(5,6-Difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3,4-diamine;

[0148] 2-Chloro-3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine;

[0149] 6'-Fluoro-4'-methoxy-2-nitro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0150] 2,6'-Difluoro-3,4'-dimethoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0151] 2,3-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0152] 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-2,4-diamine;

[0153] 3,5-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0154] 2,5,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0155] 2-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0156] 4'-Methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0157] 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-carboxamide;

[0158] 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,5,6'-trifluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine;

[0159] 2-Chloro-4'-methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0160] 4'-Methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0161] 6'-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide;

[0162] 4-Amino-2-chloro-6'-fluoro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4'-ol;

[0163] 2,6'-Dichloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0164] 2-Chloro-6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine;

[0165] 2-Chloro-3'-(5,6-difluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0166] 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-sulfonamide;

[0167] 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine;

[0168] 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-sulfonamide;

[0169] 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-2-amine;

[0170] 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine;

[0171] 6'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine;

[0172] 2-Chloro-3'-(5-fluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0173] 2-Chloro-3'-(5-(trifluoromethoxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0174] 2-Chloro-3'-nitro-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0175] 2-Chloro-3'-(trifluoromethyl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0176] 3-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0177] 2-(Trifluoromethyl)-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0178] 2-Methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0179] 6-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine;

[0180] 2-(2'-chloro-4'-nitro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole;

[0181] 2-(2'-chloro-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole;

[0182] 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-ol;

[0183] 2-Fluoro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0184] 2-Methyl-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0185] 2,3-dichloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; and

[0186] 2,4'-Dichloro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4,6'-diamine;

[0187] 2-(4'-Fluoro-5'-(1H-indazol-6-yl)-2'-methoxy-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole;

[0188] 2-Chloro-3'-(furan-3-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0189] 2-Chloro-3'-(2H-1,2,3-triazol-4-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine;

[0190] 2-Chloro-N-(2-chloro-3'-(5-trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)-2,2'-difluoroacetamide;

[0191] (S)-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-carboxamide;

[0192] 2-Amino-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)acetamide.

[0193]

[0194] In another specific example, the compound of formula I below may be a compound of formula Ia below.

[0195]

[0196] In the above chemical formula Ia, p. q, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is as defined for chemical formula I.

[0197]

[0198] The compound represented by the above chemical formula I of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0199] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula I in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0200] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Among the metal salts, sodium, potassium, or calcium salts are pharmaceutically suitable. Furthermore, the corresponding salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable anion salt (e.g., silver nitrate).

[0201] Furthermore, the present invention includes not only the compound represented by the above chemical formula I and its pharmaceutically acceptable salt, but also all solvates or hydrates that can be prepared therefrom.

[0202] The term "hydrate" refers to a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound represented by the above formula (I) of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent, preferably 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing a compound represented by the above formula (I) of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

[0203] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0204]

[0205] Another aspect of the present invention relates to the pharmaceutical use of a compound of formula I.

[0206] In relation to medicinal uses,

[0207] One specific example relates to a pharmaceutical composition for preventing, improving or treating a PCSK9-related disease, comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0208] Another specific example relates to a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the prevention, improvement or treatment of a PCSK9-related disease.

[0209] Another specific example relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for preventing, ameliorating or treating a PCSK9-related disease.

[0210] Another specific example relates to a method for preventing, improving or treating a PCSK9-related disease by administering a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof to a subject in need thereof.

[0211] Another specific example relates to a health functional food composition for preventing or improving a PCSK9-related disease, comprising a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as an active ingredient.

[0212] In terms of medical use, “PCSK9-related disease” is a disease caused by overexpression or oversecretion of PCSK9 outside of cells, and specifically includes hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, and obesity.

[0213] In a pharmaceutical application, the compound of the present invention or a pharmaceutically acceptable salt thereof can inhibit overexpression of PCSK9 protein and / or inhibit secretion outside of cells, resulting in inhibition of protein interaction between PCSK9 and LDL-R, and quantitative increase of low-density lipoprotein receptor, thereby lowering blood cholesterol concentration and preventing, improving or treating hypercholesterolemia.

[0214] The compound represented by the above chemical formula I or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing one or more compounds 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. 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, fragrances, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0215]

[0216] A pharmaceutical composition containing the compound represented by the above chemical formula I or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0217] At this time, in order to formulate a dosage form for parenteral administration, the compound represented by the above chemical formula I or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and / or contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control and / or buffers, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods.

[0218]

[0219] Oral dosage forms include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches, which contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and, if desired, disintegrating agents or effervescent mixtures such as starch, agar, alginic acid or its sodium salt, and / or absorbents, coloring agents, flavoring agents, and sweetening agents.

[0220]

[0221] The dosage of the pharmaceutical composition of the present invention varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity, and does not limit the scope of the present invention in any way. An individual dosage specifically includes the amount of effective drug administered at one time.

[0222] For example, it can be administered regularly or irregularly in a dose of 0.1 mg / kg to 1000 mg / kg.

[0223] The health functional beverage composition of the present invention has no particular limitations on other components other than containing the above-mentioned compound as an essential component in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional components like a conventional beverage. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, etc.; and polysaccharides such as dextrin, cyclodextrin, etc., and conventional sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc. As flavoring agents other than those described above, natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the above-mentioned natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the composition of the present invention.

[0224]

[0225] Furthermore, in addition to the above, the compound represented by the chemical formula I according to the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), 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 compound represented by the chemical formula I of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.

[0226]

[0227] Another aspect of the present invention relates to a method for preparing a compound of formula I.

[0228] One of the manufacturing methods relates to a method of manufacturing a compound of chemical formula I by cyclizing a compound of chemical formula C and a compound of chemical formula D as shown in the reaction scheme 1 below.

[0229] <Reaction Scheme 1>

[0230]

[0231] In the above reaction formula 11, p. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is defined as a compound of formula I.

[0232] Another manufacturing method relates to a method for manufacturing a compound of chemical formula Ia by coupling a compound of chemical formula G and a compound of chemical formula H as shown in the reaction scheme 2 below.

[0233] <Reaction Formula 2>

[0234]

[0235] In the above reaction formula 2, p. q, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 According to the definition of the compound of formula I, -OX is methanesulfonate or trifluoromethanesulfonate.

[0236] The following describes a general method for preparing the compound of chemical formula I.

[0237] 1. General manufacturing method 1

[0238] The compound of chemical formula I can be prepared as shown in the following reaction scheme 1.

[0239] <Reaction Scheme 1>

[0240]

[0241] The compound of chemical formula C in Scheme 1 can be formed through cyclization from the compound of chemical formula A, which is a phenol derivative, and is represented as in Scheme 1-1 below.

[0242] <Reaction Formula 1-1>

[0243]

[0244] In the above reaction formula 1 and reaction formula 1-1, p. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is defined as a compound of formula I.

[0245] In the above reaction scheme 1-1, step 1 is a step of obtaining a compound of chemical formula C by cyclizing a compound of chemical formula A and a compound of chemical formula B.

[0246] The reaction can be carried out using an aprotic solvent in a moisture-free environment. Examples of solvents that can be used include 1,4-dioxane, DMF, DMSO, toluene, and xylene. The reaction can be carried out at a temperature of 100°C or higher for 6 hours or longer.

[0247] Optionally, a compound of formula C is obtained through a conventional purification process and the next step is performed.

[0248] Step 2 is a step of obtaining a compound of formula I by coupling a compound of formula C and a compound of formula D in the presence of a palladium organometallic compound catalyst.

[0249] 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) can be used as a palladium catalyst. A base catalyst can be further added for the reaction, and the base can be an inorganic base such as an alkali or alkaline earth metal salt of carbonate, bicarbonate, or hydroxide, such as potassium carbonate, sodium carbonate, magnesium carbonate, or calcium carbonate. A mixture of an organic solvent and water can be used as a solvent for the reaction, and the organic solvent can be THF, chloroform, dichloromethane, or diethyl ether.

[0250] Optionally, the target compound of formula I is obtained through a conventional purification process.

[0251] In a specific embodiment of the present invention, R in chemical formula I 2 Compounds containing hydrogen or NH2 were prepared according to general manufacturing method 1.

[0252]

[0253] 2. General manufacturing method 2

[0254] As part of the compounds of formula I according to the present invention, R 2 A compound of formula I (represented by formula Ia in Scheme 2 below) which is a substituted phenyl can be prepared as in Scheme 2 below.

[0255] Terphenyl derivative compounds can be prepared by further coupling after preparing a biphenyl derivative compound. It is also apparent to those skilled in the art that terphenyl derivative compounds can be prepared by using an intermediate compound of chemical formula D and a biphenyl derivative, as in General Preparation Method 1.

[0256]

[0257] <Reaction Formula 2>

[0258]

[0259] The compound of chemical formula G in Scheme 2 can be prepared by the same method as Scheme 2-1 below.

[0260] <Reaction Formula 2-1>

[0261]

[0262] In the above reaction formula 2 and reaction formula 2-1, p. q, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 According to the definition of the compound of formula I, -OX is methanesulfonate or trifluoromethanesulfonate.

[0263] The compound of the above chemical formula E can be obtained according to Reaction Scheme 1. In Reaction Scheme 1, R 2 The reaction is carried out according to Scheme 1-1 and Scheme 1, except that a compound of formula D' substituted with OAc (acetyloxy) is used.

[0264] In general manufacturing method 2,

[0265] Steps 1' and 2' are performed in the same manner as steps 1 and 2 of general manufacturing method 2.

[0266] Step 3' is a step of removing acetyl as a protecting group, and is a step of obtaining a compound of chemical formula F by removing acetyl. An inorganic base such as a carbonate, hydroxide, or bicarbonate of an alkali metal or alkaline earth metal can be used as a base, and for example, sodium carbonate or potassium carbonate can be used. The solvent for the reaction is an organic solvent with some water and / or alcohol added to dissolve the inorganic base, and methanol or ethanol can be used as the alcohol.

[0267] After the reaction, a normal purification process can be performed.

[0268] Step 4' is a step in which the alcohol group (OH) from which the acetyl protecting group is removed becomes a leaving group in the next reaction. -X can be methanesulfonyl or trifluoromethanesulfonyl so that OX can become a leaving group. To introduce X, an anhydride in the form of XOX, for example, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or a sulfonyl halide in the form of X-halogen is used. For example, an organic solvent such as THF, dichloromethane, chloroform, or diethyl ether is used, and the reaction is performed by adding an amine, preferably a tertiary amine such as pyridine or triethylamine.

[0269] After the reaction, a normal purification process can be performed.

[0270] Step 5' can be performed in the same manner as Step 2 of General Manufacturing Method 1.

[0271]

[0272] Hereinafter, specific examples of the compound of the chemical formula I of the present invention are presented together with manufacturing examples.

[0273]

[0274] <Example 1>

[0275] As a specific example manufactured according to Reaction Scheme 1, a specific manufacturing example of the following compound I-1 is presented.

[0276]

[0277] Step 1:

[0278]

[0279] To synthesize 2-(3-bromophenyl)-5-(trifluoromethyl)benzo[d]oxazole of compound (C-1), 3-bromobenzoyl chloride (B-1, 929 mg, 4.23 mmol) was slowly added to a solution of compound A (500 mg, 2.82 mmol) in 1,4-dioxane (10 ml) in a sealed tube, and the mixture was stirred at 150 ℃ for 17 hours. After cooling to room temperature, the reaction was quenched with 1 N NaOH aqueous solution, and extracted with dichloromethane (DCM) (30 ml) and water (20 ml). The organic layer was dried over Na2SO4 and filtered under reduced pressure, and the dried mixture was purified by MPLC under hexane:ethyl acetate conditions to obtain compound C-1 (740 mg, 77%) as a white solid.

[0280] Step 2:

[0281]

[0282] In order to synthesize the target compound of Example 1, the compound of formula I-1 (2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.81 mg, 5.85 umol) was added to a solution of the compound of formula C-1 (20 mg, 0.058 mmol), the compound of formula D-1 (3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (16.30 mg, 0.064 mmol), potassium carbonate (16.16 mg, 0.117 mmol), THF (1 ml), and water (0.3 ml). The mixed solution was stirred at 70 °C for 2 h after N2 substitution. The mixture was stirred at ℃ for 18 hours, and after completion of the reaction, it was filtered under reduced pressure using Celite. The residue was extracted with EA (20 ml) and water (10 ml), and the organic layer was dried over Na2SO4 and filtered under reduced pressure. The dried mixture was purified by MPLC under hexane:ethyl acetate conditions to obtain the target compound of chemical formula I-1 (12 mg, 53%) as a yellow solid.

[0283]

[0284] <Example 2>

[0285] As a specific example of the general manufacturing method according to Reaction Scheme 2, a specific manufacturing example of the following compound I-2 is presented.

[0286]

[0287] Step 1:

[0288] It was performed as in step 1 of Example 1.

[0289] Step 2:

[0290]

[0291] To a solution of the compound of formula C-1 (500 mg, 1.46 mmol), the compound of formula D-2 (2-fluoro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl acetate (635 mg, 2.05 mmol), potassium carbonate (606 mg, 4.38 mmol), THF (6 ml), and water (1.5 ml) was added 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (191 mg, 0.29 mmol). The mixed solution was stirred at 65 ℃ for 18 hours after N2 purging, and after completion of the reaction, filtered under reduced pressure using Celite. The residue was extracted with dichloromethane (30 ml) and water (20 ml), and the organic layer was dried over Na2SO4 and filtered under reduced pressure. The dried mixture was purified by MPLC under hexane:ethyl acetate conditions to obtain the target compound 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl acetate (420 mg, 65%) of chemical formula E-2 as a white solid.

[0292]

[0293] Step 3:

[0294]

[0295] To synthesize 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-ol, a solution of 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl acetate (600 mg, 1.35 mmol), THF (4 ml), MeOH (2 ml), and water (1 ml) of the formula E-2 was added potassium carbonate (930 mg, 6.74 mmol), and the mixture was stirred at room temperature for 4 hours. At the end of the reaction, a 1N HCl aqueous solution was added, the resulting solid was filtered, and washed with water and EtOH solvent to obtain 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-ol (510 mg, 94%) of chemical formula F-2 as a white solid.

[0296]

[0297] Step 4:

[0298]

[0299] To synthesize the compound 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl trifluorometalsulfonate of G-2, 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-ol (430 mg, 1.06 mmol) of the chemical formula F-2 was slowly added pyridine (84 mg, 1.06 mmol) and trifluoromethanesulfonic anhydride (301 mg, 1.06 mmol) to a solution in dichloromethane (2.5 ml), and the mixed solution was stirred at room temperature for 1 hour after N2 replacement. The mixture was extracted with dichloromethane (30 ml) and 1 N HCl aqueous solution (10 ml), and the organic layer was extracted once more with saturated NaHCO3 aqueous solution, dried over Na2SO4, and filtered under reduced pressure. The dried mixture was purified by MPLC under hexane:ethyl acetate conditions to obtain 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl trifluoromethanesulphonate (530 mg, 93%) of the formula G-2 as a white solid.

[0300] Step 5:

[0301]

[0302] To synthesize 2-c-chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine of formula I-2, 4-fluoro-6-methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl trifluoromethanesulfonate (20 mg, 0.037 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (19 mg, 0.075 mmol), potassium carbonate (16 mg, 0.12 mmol), THF (1.5 ml), water (0.3 ml) solution was added. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (7.3 mg, 0.01 mmol) was added. The mixed solution was stirred at 65°C for 2 h after N2 replacement. o The mixture was stirred at C for 18 hours, and after completion of the reaction, the mixture was filtered under reduced pressure using Celite. The residue was extracted with dichloromethane (10 ml) and water (3 ml), and the organic layer was dried over Na2SO4 and filtered under reduced pressure. The dried mixture was purified by MPLC under hexane:ethyl acetate conditions to obtain 2-chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine (15 mg, 78%) of the formula 5 as an ivory solid.

[0303]

[0304] <Example 3-75>

[0305] The biphenyl derivative compound was prepared as in Example 1 according to the general manufacturing method of Scheme 1. The terphenyl derivative compound was prepared as in Example 2 according to the general manufacturing method of Scheme 2.

[0306]

[0307] The chemical structures of the manufactured example compounds are presented in Table 1 below.

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314] The names and analysis results of the manufactured example compounds are presented in Table 2 below.

[0315] Example name 1 H NMRLCMS12-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.28 - 8.23 ​​(m, 1H), 8.08 (s, 1H), 7.74 - 7.57 (m, 4H), 7.23 (d,J= 8.3 Hz, 1H), 6.86 (d,J= 2.3 Hz, 1H), 6.69 (dd,J= 8.2, 2.3 Hz, 1H), 3.86 (brs, 2H).389 [M+H] + 22-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.27 (s, 1H), 8.20 (d,J= 7.9 Hz, 1H), 8.05 (d,J= 8.6 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.70 (t,J= 7.8 Hz, 1H), 7.28 (d,J= 8.7 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.73 (d,J= 2.2 Hz, 1H), 6.59 (dd,J= 8.3, 2.2 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 3H).513 (M+H) +32,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.21 (d,J= 6.5 Hz, 1H), 8.05 (s, 1H), 7.75 (d,J= 6.5 Hz, 1H), 7.70 - 7.56 (m, 3H), 7.38 (d,J= 8.5 Hz, 1H), 7.19 (t,J= 8.2 Hz, 1H), 6.83 (d,J= 11.8 Hz, 1H), 6.54 - 6.47 (m, 2H), 3.87 (s, 3H), 3.85 (s, 2H)497 (M+H) + 42,6'-Difluoro-4'-methoxy-3''-(5-nitrobenzo[d]oxazol-2-yl)-5''-(trifluoromethyl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d,J= 2.3 Hz, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 8.40 (dd,J= 2.3, 9.0 Hz, 1H), 8.18 (s, 1H), 8.11 (d,J= 9.0 Hz, 1H), 7.46 (d,J= 8.6 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.49 - 6.40 (m, 2H), 5.58 (s, 2H), 3.87 (s, 3H)583 (M+ACN) + 53''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide 1H NMR (400 MHz, Acetone-d6) δ 8.41 (s, 1H), 8.22 (d,J= 7.9 Hz, 1H), 7.99 (d,J= 8.2 Hz,2H), 7.88 - 7.82 (m, 4H), 7.77 (dd,J= 10.1, 7.5Hz, 1H), 7.72 - 7.65 (m, 2H), 7.16 (d,J= 12.9 Hz, 1H), 6.66 (d,J= 5.0 Hz, 2H), 3.98 (s, 3H).552 (M+ACN) + 63''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-N-methyl-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, CDCl3)δ8.33 (s, 1H), 8.19 (d,J= 7.9 Hz, 1H), 7.93 (d,J= 8.51 Hz, 2H),7.72 (m, 3H), 7.59 (t,J= 7.9 Hz, 1H), 7.55 (dd,J= 9.6 Hz, 7.3 Hz, 1H), 7.47 (d,J= 8.8 Hz, 1H),7.44 (dd,J= 9.0, 6.6 Hz, 1H), 6.87 (d,J= 12.5 Hz, 1H), 4.37 (q,J= 5.4 Hz, 1H), 3.90 (s, 3H),2.72 (d,J= 5.4 Hz, 3H).566 (M+ACN) + 7N-(3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide 1H NMR (400 MHz, Acetone-d6) δ 8.40 (s, 1H), 8.20 (d,J= 7.8 Hz, 1H), 7.84 (dd,J= 9.5, 7.0Hz, 2H), 7.77 (dd,J= 10.1, 7.5 Hz, 1H), 7.69 (d,J= 7.8 Hz, 1H), 7.64 (d,J= 7.6 Hz, 2H), 7.58(d,J= 9.1 Hz, 1H), 7.44 (d,J= 8.6 Hz, 2H), 7.11 (d,J= 12.9 Hz, 1H), 3.95 (s, 3H), 3.04 (s, 3H).566 (M+ACN) + 8N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.24 (d,J= 7.8 Hz, 1H), 8.06 (s, 1H), 7.75 (d,J= 7.8 Hz, 1H), 7.73 - 7.49 (m, 7H), 7.46 (d,J= 8.9 Hz, 1H), 7.22 (s, 1H), 6.84 (d,J= 12.4 Hz, 1H), 3.88 (s, 3H), 2.21 (s, 3H).562 [M+ACN] + 96'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.40 (t,J= 1.5 Hz, 1H), 8.28 - 8.23 ​​(m, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.94 - 7.89 (m, 1H), 7.82 (dd,J= 7.8, 1.1 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.70 (d,J= 8.5 Hz, 1H), 7.66 - 7.55 (m, 3H), 7.48 (d,J= 8.9 Hz, 1H), 6.88 (d,J= 12.5 Hz, 1H), 4.88 (s, 2H), 3.91 (s, 3H).543 [M+H] + 10N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.40 (t,J= 1.6 Hz, 1H), 8.27 - 8.22 (m, 1H), 8.05 (s, 1H), 7.79 - 7.74 (m, 1H), 7.71 - 7.55 (m, 4H), 7.45 (d,J= 8.9 Hz, 1H), 7.33 - 7.28 (m, 2H), 6.86 (d,J= 12.5 Hz, 1H), 6.38 (s, 1H), 3.89 (s, 3H), 3.07 (s, 3H).598 [M+ACN] + 116'-Fluoro-4'-methoxy-N-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.40 (t,J= 1.5 Hz, 1H), 8.29 - 8.24 (m, 1H), 8.06 (s, 1H), 7.93 (d,J= 8.5 Hz, 2H), 7.80 - 7.59 (m, 6H), 7.52 - 7.47 (m, 1H), 6.88 (d,J= 12.5 Hz, 1H), 3.91 (s, 3H), 2.73 (d,J= 5.4 Hz, 3H).598 [M+ACN] +123'',6'-Difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.25 (s, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.99 - 7.77 (m, 7H), 7.70 (d,J= 9.0 Hz, 1H), 7.43 (s, 2H), 7.30 (d,J= 13.1 Hz, 1H), 3.91 (s, 3H)602 (M+ACN)+132,3'',6'-trifluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.19 (s, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.96 (dt,J= 8.6, 2.0 Hz, 1H), 7.84 (dd,J= 8.7, 1.8 Hz, 1H), 7.73 (dt,J= 10.0, 2.0 Hz, 1H), 7.40 (d,J= 8.6 Hz, 1H), 7.22 - 7.10 (m, 2H), 6.51 - 6.37 (m, 2H), 5.59 (s, 2H), 3.88 (s, 3H)515 (M+H)+14N-(3'',6'-difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.22 (s, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.85 (dd,J= 8.7, 1.8 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.59 - 7.56 (m, 3H), 7.27 - 7.21 (m, 3H), 3.90 (s, 3H), 2.99 (s, 3H)616 (M+ACN)+153''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.33 (t,J= 1.8 Hz, 1H), 8.16 (dt,J= 7.8, 1.4 Hz, 1H), 7.72 (dt,J= 7.8, 1.4 Hz, 1H), 7.57 (d,J= 7.1 Hz, 1H), 7.55 (dd,J= 7.1, 2.4 Hz, 1H), 7.43 (dd,J= 9.0, 6.6 Hz, 1H), 7.37 (d,J= 8.3 Hz, 1H), 7.18 (d,J= 8.3 Hz, 1H), 6.83 (d,J= 11.8 Hz, 1H), 6.54 - 6.47 (m, 2H), 3.87 (s, 3H), 3.85 (s, 2H).465(M+1) + 506(M+ACN) + 163''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3-amine 1H NMR (400 MHz, CDCl3) δ 8.34 (t,J= 1.8 Hz, 1H), 8.17 (dt,J= 7.8, 1.4 Hz, 1H), 7.73 (dt,J=7.8, 1.4 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.46 (d,J= 8.8 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.23 (t,J=7.8 Hz, 1H), 6.97 (dd,J= 7.8, 1.4 Hz, 1H), 6.90 (q,J= 1.8 Hz, 1H), 6.82 (d,J= 12.4 Hz, 1H),6.69 (dd,J= 8.0, 3.4 Hz, 1H), 3.87 (s, 3H), 3.74 (s, 2H).447(M+1) + 488(M+ACN) + 176'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine 1 H NMR (400 MHz, CDCl3) δ 8.41 (t,J= 1.8 Hz, 1H), 8.24 (d,J= 7.9 Hz, 1H), 8.05 (s,1H), 7.76 (d,J= 7.9 Hz, 1H), 7.69 (d,J= 8.5 Hz, 1H), 7.64 (dd,J= 8.5, 1.8 Hz, 1H), 7.60 (t,J=7.9 Hz, 1H), 7.47 (d,J= 8.9 Hz, 1H), 7.24 (t,J= 7.8 Hz, 1H), 6.97 (d,J= 7.9 Hz, 1H), 6.91 (q,J= 1.8 Hz, 1H), 6.83 (d,J= 12.4 Hz, 1H), 6.70 (dd,J= 7.9, 1.8 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 2H).480(M+1) + 521(M+ACN) + 182,6'-Difluoro-4'-methoxy-3''-methyl-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.14 (s, 1H), 8.05 - 8.03 (m, 2H), 7.81 (dd,J= 8.6, 1.8 Hz, 1H), 7.62 (s, 1H), 7.32 (d,J= 8.7 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.48 - 6.39 (m, 2H), 5.58 (s, 2H), 3.85 (s, 3H), 2.48 (s, 3H)552 (M+ACN)+196'-Fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.38 - 8.35 (m, 1H), 8.25 - 8.20 (m, 1H), 8.04 - 7.96 (m, 3H), 7.78 - 7.70 (m, 3H), 7.62 (t,J= 7.8 Hz, 1H), 7.48 (d,J= 4.6 Hz, 1H), 7.46 (d,J= 5.0 Hz, 1H), 6.88 (d,J= 12.5 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 3H).602 [M+ACN] + 20N-(6'-fluoro-4'-methoxy-3''-(trifluoromethyl)-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.73 (d,J=8.6 Hz, 1H), 7.69 (td,J=8.6, 1.5 Hz, 1H), 7.58 (dd,J= 8.6, 1.5 Hz, 2H), 7.45 (d,J= 8.7 Hz,1H), 7.31 (d,J= 8.6 Hz, 2H), 6.88 (d,J= 12.3 Hz, 1H), 3.91 (s, 3H), 3.07 (s, 3H).666 (M+ACN) +216'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.24 (d,J= 7.8 Hz, 1H), 8.05 (s, 1H), 7.87 (s, 1H),7.81 (dd,J= 8.0, 1.7 Hz, 1H), 7.75 (d,J= 7.8 Hz, 1H), 7.69 (d,J= 8.4 Hz, 1H), 7.64 (dd,J=8.7, 1.3 Hz, 1H), 7.60 (t,J= 7.8 Hz, 1H), 7.43 (d,J= 8.0 Hz, 1H), 7.26 (d,J= 8.4 Hz, 1H), 6.86(d,J= 11.6 Hz, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 2.35 (s, 3H).598 (M+ACN) + 22N-(6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.20 (d,J= 7.8 Hz, 1H), 8.01 (d,J= 6.3 Hz, 1H), 7.75 (d,J= 7.8 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.49 - 7.40 (m, 2H), 7.31 (d,J= 8.6 Hz, 2H), 6.85 (d,J= 12.4 Hz, 1H), 6.76 (s, 1H), 3.89 (s, 3H), 3.07 (s, 3H).616 [M+ACN] + 232,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.26 (s, 1H), 8.21 (td,J= 7.8, 1.4 Hz, 1H), 8.05 (d,J= 8.6 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.71 (t,J= 7.8 Hz, 1H), 7.41 (d,J= 8.5 Hz, 1H), 7.22 (d,J= 12.2 Hz, 1H), 6.95 (t,J= 7.8 Hz, 1H), 6.83 - 6.79 (m, 1H), 6.63 - 6.59 (m, 1H), 5.23 (s, 2H), 3.89 (s, 3H)497 (M+H)+242-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (t,J= 1.8 Hz, 1H), 8.27 (s, 1H), 8.21 (td,J= 7.8, 1.4 Hz, 1H), 8.06 (d,J= 8.5 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.70 (t,J= 7.8 Hz, 1H), 7.32 (d,J= 8.5 Hz, 1H), 7.20 (d,J= 12.0 Hz, 1H), 7.10 (t,J= 7.8 Hz, 1H), 6.85 (dd,J= 8.2, 1.6 Hz, 1H), 6.62 (dd,J= 7.4, 1.6 Hz, 1H), 5.47 (s, 2H), 3.89 (s, 3H) 513 (M+H) + 25 Methyl (6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)carbamate 1H NMR (400 MHz, CDCl3) δ 8.40 (t,J= 1.5 Hz, 1H), 8.24 (d,J= 7.9 Hz, 1H), 8.05 (s, 1H), 7.77 - 7.72 (m, 1H), 7.69 (d,J= 8.5 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.56 - 7.51 (m, 2H), 7.50 - 7.42 (m, 3H), 6.84 (d,J= 12.4 Hz, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.80 (s, 3H).578 [M+ACN] + 26N-Cyclopropyl-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.26 (d,J= 7.8 Hz, 1H), 8.05 (s, 1H), 7.98 (d,J= 8.5 Hz, 2H), 7.79 - 7.72 (m, 3H), 7.72 - 7.58 (m, 3H), 7.50 (d,J= 8.8 Hz, 1H), 6.88 (d,J= 12.5 Hz, 1H), 4.92 (s, 1H), 3.91 (s, 3H), 2.35 - 2.27 (m, 1H), 0.73 - 0.58 (m, 4H).624 [M+ACN] + 272,3,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, DMSO-d6) δ 8.34 (t,J= 1.8 Hz, 1H), 8.26 (s, 1H), 8.21 (dt,J= 7.9, 1.4 Hz, 1H), 8.04 (d,J= 8.5 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.69 (t,J= 7.8 Hz, 1H), 7.39 (d,J= 8.6 Hz, 1H), 7.20 (d,J= 12.2 Hz, 1H), 7.00 (t,J= 7.9 Hz, 1H), 6.67 - 6.63 (m, 1H), 5.65 (s, 2H), 3.87 (s, 3H)515 (M+H)+283-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (t,J= 1.7 Hz, 1H), 8.26 (d,J= 1.7 Hz, 1H), 8.21 (dt,J= 7.8, 1.4 Hz, 1H), 8.05 (d,J= 8.6 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.71 (t,J= 7.8 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.30 (dt,J= 8.4, 1.8 Hz, 1H), 7.17 (d,J= 13.1 Hz, 1H), 6.88 (d,J= 8.4 Hz, 1H), 5.52 (s, 2H), 3.86 (s, 3H)513 (M+H)+292,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3,4-diamine 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.23 ​​(d,J= 7.9 Hz, 1H), 8.05 (s, 1H), 7.75 (d,J= 7.9 Hz, 1H), 7.68 (d,J= 8.4 Hz, 1H), 7.63 (dd,J= 8.4, 1.3 Hz, 1H), 7.58 (t,J= 7.8 Hz, 1H),7.39 (d,J= 8.4 Hz, 1H), 6.84 (d,J= 11.7 Hz, 1H), 6.74 (t,J= 7.9 Hz, 1H), 6.58 (dd,J=8.1, 1.3Hz, 1H), 3.88 (s, 3H), 3.60 (s, 2H), 3.42 (s, 2H).512(M+1) + 552(M+ACN) + 303''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3,4-diamine 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.16 (d,J= 7.8 Hz, 1H), 7.73 (d,J= 7.8 Hz,1H), 7.57 (d,J= 7.5 Hz, 1H), 7.54 (dd,J= 8.4, 1.8 Hz, 1H), 7.43 (dd,J= 9.0, 6.6 Hz, 1H), 7.38(d,J= 8.4 Hz, 1H), 6.83 (d,J= 11.7 Hz, 1H), 6.73 (t,J= 8.0 Hz, 1H), 6.57 (d,J= 8.2 Hz, 1H),3.87 (s, 3H), 3.59 (s, 2H), 3.42 (s, 2H).480(M+1) + 312-Chloro-3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.15 (d,J= 7.8 Hz, 1H), 7.74 (dt,J= 8.0, 1.3 Hz,1H), 7.57 (d,J= 7.7 Hz, 1H), 7.55 (d,J= 7.3 Hz, 1H), 7.43 (dd,J= 9.1, 6.6 Hz, 1H), 7.32 (d,J=8.5 Hz, 1H), 7.14 (d,J= 8.2 Hz, 1H), 6.83 (d,J= 1.3 Hz, 1H), 6.81 (d,J= 7.7 Hz, 1H), 6.63 (dd,J= 8.3, 2.4 Hz, 1H), 3.88 (s, 3H), 3.80 (bs, 2H).481(M+1) + 522(M+ACN) + 326'-Fluoro-4'-methoxy-2-nitro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (t,J= 1.8 Hz, 1H), 8.27 (s, 1H), 8.22 (dt,J= 7.9, 1.4 Hz, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.71 (t,J= 7.8 Hz, 1H), 7.41 (d,J= 8.9 Hz, 1H), 7.30 (d,J= 8.4 Hz, 1H), 7.20 (d,J= 2.4 Hz, 1H), 7.13 (d,J= 12.5 Hz, 1H), 6.93 (dd,J=8.4, 2.4 Hz, 1H), 5.94 (s, 2H), 3.87 (s, 3H) 524 (M+H) + 332,6'-Difluoro-3,4'-dimethoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, CDCl3) δ 8.40 (t,J= 1.6 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.05 (s, 1H), 7.78 - 7.73 (m, 1H), 7.69 (d,J= 8.5 Hz, 1H), 7.63 (dd,J= 8.5, 1.4 Hz, 1H), 7.59 (t,J= 7.8 Hz, 1H), 7.38 (d,J= 8.6 Hz, 1H), 6.92 (t,J= 7.7 Hz, 1H), 6.84 (d,J= 11.7 Hz, 1H), 6.57 (dd,J=8.3, 1.4 Hz, 1H), 4.00 (brs, 2H), 3.96 (d,J= 1.1 Hz, 3H), 3.88 (s, 3H).568 [M+ACN] + 342,3-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (t,J= 1.8 Hz, 1H), 8.27 (s, 1H), 8.21 (dt,J= 7.9, 1.4 Hz, 1H), 8.06 (d,J= 8.5 Hz, 1H), 7.84 - 7.81 (m, 2H), 7.69 (t,J= 7.8 Hz, 1H), 7.32 (d,J= 8.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.84 (d,J= 8.4 Hz, 1H), 5.85 (s, 2H), 3.88 (s, 3H)547 (M+H)+356'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-2,4-diamine 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.22 (d,J= 7.8 Hz, 1H), 8.05 (s, 1H), 7.75 (d,J= 7.8 Hz, 1H), 7.68 (d,J= 8.5 Hz, 1H), 7.63 (dd,J= 8.7, 1.2 Hz, 1H), 7.58 (t,J= 7.8 Hz, 1H), 7.39 (d,J= 8.6 Hz, 1H), 6.96 (d,J= 8.1 Hz, 1H), 6.84 (d,J= 11.5 Hz, 1H), 6.22 (dd,J=8.1, 2.1 Hz, 1H), 6.16 (d,J= 1.7 Hz, 1H), 3.88 (s, 3H).494 [M+H] + 363,5-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (t,J= 1.8 Hz, 1H), 8.27 (s, 1H), 8.22 (dt,J= 7.9, 1.4 Hz, 1H), 8.06 (d,J= 8.5 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.71 (t,J= 7.8 Hz, 1H), 7.56 - 7.53 (m, 3H), 7.19 (d,J= 13.2 Hz, 1H), 5.71 (s, 2H), 3.87 (s, 3H)547 (M+H)+372,5,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 ​​(d,J= 7.8 Hz, 1H), 8.07 (s, 1H), 7.74 (d,J= 7.8 Hz, 1H), 7.69 (d,J= 8.4 Hz, 1H), 7.64 (dd,J= 8.4 Hz, 1.3 Hz, 1H), 7.59 (t,J= 7.8 Hz,1H), 7.37 (d,J= 8.3 Hz, 1H), 7.07 (dd,J= 11.1, 6.5 Hz, 1H), 6.84 (d,J= 11.8 Hz, 1H), 6.64 (dd,J= 10.6, 7.5 Hz, 1H), 3.88 (s, 3H), 3.88 (bs, 2H).515 (M+1) + 556 (M+ACN) + 382-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (t,J= 1.8 Hz, 1H), 8.30 - 8.25 (m, 1H), 8.21 (dt,J= 8.0, 1.3 Hz, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.83 (ddd,J= 10.8, 7.6, 1.6 Hz, 2H), 7.71 (t,J= 7.8 Hz, 1H), 7.41 (dd,J= 8.5, 2.4 Hz, 1H), 7.37 (d,J= 2.4 Hz, 1H), 7.22 (d,J= 8.6 Hz, 1H), 7.14 (d,J= 8.3 Hz, 1H), 6.72 (d,J= 2.2 Hz, 1H), 6.60 (dd,J= 8.3, 2.3 Hz, 1H), 5.48 (s, 2H), 3.85 (s, 3H) 494 (M+H)+394'-Methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1H NMR (400 MHz, DMSO-d6) δ 8.41 (t,J= 1.8 Hz, 1H), 8.28 (s, 1H), 8.24 (dt,J= 7.8, 1.4 Hz, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.95 - 7.86 (m, 5H), 7.83 (dd,J= 8.6, 2.3 Hz, 2H), 7.78 (d,J= 2.4 Hz, 1H), 7.74 (t,J= 7.8 Hz, 1H), 7.40 (s, 2H), 7.33 (d,J= 8.7 Hz, 1H), 3.88 (s, 3H)524 (M+H)+406'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-carboxamide 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (t,J= 1.8 Hz, 1H), 8.26 (s, 1H), 8.23 ​​(dt,J= 7.8, 1.4 Hz, 1H), 8.06 - 8.04 (m, 2H), 7.96 (d,J= 8.3 Hz, 2H), 7.87 (dt,J= 7.8, 1.4 Hz, 1H), 7.82 (dd,J= 8.7, 1.8 Hz, 1H), 7.73 - 7.70 (m, 3H), 7.61 (d,J= 9.0 Hz, 1H), 7.43 (s, 1H), 7.26 (d,J=13.0 Hz, 1H), 3.89 (s, 3H)507 (M+H)+413''-(5,6-Difluorobenzo[d]oxazol-2-yl)-2,5,6'-trifluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, CDCl3) δ 8.32 (t,J= 1.6 Hz, 1H), 8.16 (dt,J= 7.7, 1.3 Hz, 1H), 7.71(dt,J= 7.7, 1.3 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.44 (dd, J = 9.0, 6.5 Hz, 1H), 7.36 (d,J= 8.5 Hz,1H), 7.05 (dd,J= 11.2, 6.5 Hz, 1H), 6.83 (d,J= 11.8 Hz, 1H), 6.59 (dd,J= 10.7, 7.5 Hz, 1H),3.87 (s, 3H).483 (M+1) + 524 (M+ACN) + 422-Chloro-4'-methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.22 (d,J= 7.8 Hz, 1H), 8.07 (s, 1H), 7.82 (d,J= 7.9 Hz, 1H), 7.74 - 7.53 (m, 4H), 7.27 - 7.23 (m, 1H), 7.20 (s, 1H), 7.12 - 7.04 (m, 1H), 6.96 - 6.92 (m, 1H), 3.92 (d,J= 2.0 Hz, 3H), 2.23 (s, 3H).509 [M+H] + 434'-Methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.44 (t,J= 1.5 Hz, 1H), 8.27 - 8.22 (m, 1H), 8.07 (s, 1H), 8.04 - 7.99 (m, 2H), 7.83 - 7.78 (m, 1H), 7.71 (d,J= 8.5 Hz, 1H), 7.66 (dd,J= 8.6, 1.3 Hz, 1H), 7.61 (t,J= 7.8 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.29 (s, 1H), 6.97 (s, 1H), 4.83 (s, 2H), 3.93 (s, 3H), 2.39 (s, 3H).539 [M+H] + 446'-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.26 (s, 1H), 8.23 ​​(d,J= 7.7 Hz, 1H), 8.05 (d,J=8.5 Hz, 1H), 7.91 (d,J= 8.3 Hz, 2H), 7.87 (d,J= 7.7 Hz, 1H), 7.82 (d,J= 8.5 Hz, 1H), 7.72 (m,3H), 7.50 (s, 1H), 7.44 (s, 2H), 7.43 (s, 1H), 3.92 (s, 3H).559 (M+1) + 600 (M+ACN) + 454-Amino-2-chloro-6'-fluoro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4'-ol 1H NMR (400 MHz, DMSO-d6) δ 8.44 (t,J= 1.8 Hz, 1H), 8.26 (d,J= 1.7 Hz, 1H), 8.18 (dt,J= 7.9, 1.4 Hz, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.88 (dt,J= 7.8, 1.5 Hz, 1H), 7.82 (dd,J= 8.8, 1.8 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 7.25 (d,J= 8.8 Hz, 1H), 7.08 (d,J= 8.3 Hz, 1H), 6.84 (d,J=11.4 Hz, 1H), 6.73 (d,J= 2.3 Hz, 1H), 6.58 (dd,J= 8.3, 2.3 Hz, 1H), 5.50 (s, 2H) 499 (M+H) + 46 2,6'-Dichloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (t,J= 1.8 Hz, 1H), 8.26 (d,J= 1.8 Hz, 1H), 8.21 (dt,J=7.8, 1.4 Hz, 1H), 8.06 (d,J= 8.4 Hz, 1H), 7.84 - 7.80 (m, 2H), 7.70 (t,J= 7.8 Hz, 1H), 7.34 (s,1H), 7.29 (s, 1H), 7.05 (d,J= 8.4 Hz, 1H), 6.76 (d,J= 2.2 Hz, 1H), 6.62 (dd,J= 8.4, 2.2 Hz,1H), 3.90 (s, 3H).530(M+1) + 472-Chloro-6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine 1H NMR (400 MHz, MeOD) δ 8.38 (t,J= 1.6 Hz, 1H), 8.22 - 8.17 (m, 1H), 8.08 (d,J= 6.4 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.63 (t,J= 7.8 Hz, 1H), 7.27 (d,J= 8.5 Hz, 1H), 7.10 (d,J= 8.3 Hz, 1H), 6.99 (d,J= 11.7 Hz, 1H), 6.85 (d,J= 2.3 Hz, 1H), 6.70 (dd,J= 8.3, 2.3 Hz, 1H), 3.91 (s, 3H).531 [M+H] + 482-Chloro-3'-(5,6-difluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.16 - 8.09 (m, 3H), 8.02 (dd,J= 10.3, 7.6 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.17 (d,J= 8.3 Hz, 1H), 6.76 (d,J= 2.2 Hz, 1H), 6.64 (dd,J= 8.3, 2.2 Hz, 1H),5.62 (s, 2H).398(M+ACN) + 493'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-sulfonamide 1 H NMR (400 MHz, DMSO) δ 8.54 (t,J= 1.6 Hz, 1H), 8.34 - 8.28 (m, 2H), 8.12 - 8.06 (m, 2H), 8.06 - 7.94 (m, 4H), 7.85 (dd,J= 8.8, 1.6 Hz, 1H), 7.81 (t,J= 7.8 Hz, 1H), 7.48 (s, 2H).419 [M+H] + 502-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine 1H NMR (400 MHz, MeOD) δ 8.30 (s, 1H), 8.28 (d,J= 6.3 Hz, 1H), 8.07 (s, 1H), 7.88 (d,J= 8.6 Hz, 1H), 7.75 (d,J= 8.5 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.16 (t,J= 7.8 Hz, 1H), 6.92 (d,J= 8.1 Hz, 1H), 6.72 (d,J= 7.4 Hz, 1H).389 [M+H] + 513'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-sulfonamide 1 H NMR (400 MHz, MeOD) δ 8.61 (t,J= 1.6 Hz, 1H), 8.39 - 8.32 (m, 1H), 8.30 (t,J= 1.7 Hz, 1H), 8.12 (s, 1H), 8.04 - 7.97 (m, 3H), 7.93 (d,J= 8.6 Hz, 1H), 7.82 - 7.68 (m, 3H)460 [M+ACN] + 523'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-2-amine 1 H NMR (400 MHz, DMSO) δ 8.28 (dd,J= 6.9, 1.0 Hz, 2H), 8.24 - 8.18 (m, 1H), 8.06 (d,J= 8.6 Hz, 1H), 7.83 (dd,J= 8.6, 1.3 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.15 - 7.06 (m, 2H), 6.82 (dd,J= 8.0, 0.7 Hz, 1H), 6.69 (td,J= 7.5, 1.1 Hz, 1H), 4.96 (s, 2H).355 [M+H] + 533'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine 1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.21 (d,J= 7.8 Hz, 1H), 8.06 (s, 1H), 7.87 (t,J= 9.4 Hz, 2H), 7.75 (dd,J= 8.6, 1.0 Hz, 1H), 7.65 (t,J= 7.8 Hz, 1H), 7.29 (t,J= 7.8 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.11 (d,J= 7.7 Hz, 1H), 6.86 (dd,J= 7.9, 1.6 Hz, 1H).396 [M+ACN] + 546'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (t,J= 1.6 Hz, 1H), 8.26 (s, 1H), 8.20 (dt,J= 7.8, 1.2 Hz,1H), 8.05 (d,J= 8.6 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.70 (t,J= 7.8 Hz, 1H), 7.26 (d,J= 8.6 Hz,1H), 7.17 (d,J= 12.0 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.76 - 6.69 (m, 2H), 3.88 (s, 3H), 2.13 (s,3H)493 (M+1) + 552-Chloro-3'-(5-fluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.16 - 8.12 (m, 1H), 7.85 (dd,J= 8.6, 4.3 Hz, 1H), 7.71 (dd,J =8.6, 2.5 Hz, 1H), 7.65 (d,J =4.9 Hz, 2H), 7.31 (td,J =9.3, 2.5 Hz, 1H), 7.18 (d,J= 8.2 Hz, 1H), 6.77 (d,J= 2.0 Hz, 1H), 6.65 (dd,J= 8.2, 2.0 Hz, 1H), 5.61 (s, 2H).370 (M+ACN) + 562-Chloro-3'-(5-(trifluoromethoxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.16 - 8.12 (m, 1H), 7.93 (d,J= 8.9 Hz, 1H), 7.91(s, 1H), 7.66 (d,J= 5.1 Hz, 2H), 7.45 (d,J= 8.9, 1.5 Hz, 1H), 7.17 (d,J= 8.3 Hz, 1H), 6.75 (d,J= 2.2 Hz, 1H), 6.64 (dd,J= 8.3, 2.2 Hz, 1H), 5.60 (s, 2H).446 (M+ACN) + 572-Chloro-3'-nitro-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd,J= z2.2, 1.5 Hz, 1H), 8.59 (t,J= 1.6 Hz, 1H), 8.44 (t,J= 1.9 Hz, 1H), 8.35 (s, 1H), 8.13 (d,J= 8.6 Hz, 1H), 7.87 (dd,J= 8.8, 1.8 Hz, 1H), 7.32 (d,J= 8.4 Hz, 1H), 6.80 (d,J= 2.3 Hz, 1H), 6.68 (dd,J= 8.4, 2.3 Hz, 1H), 5.80 (s, 2H)434 (M+H)+582-Chloro-3'-(trifluoromethyl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.09 (d,J= 8.6 Hz, 1H), 8.00 (s, 1H), 7.86 (dd,J= 8.7, 1.8 Hz, 1H), 7.28 (d,J= 8.3 Hz, 1H), 6.79 (d,J= 2.2 Hz, 1H), 6.68 (dd,J= 8.3, 2.2 Hz, 1H), 5.75 (s, 2H)498 (M+ACN)+593-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.44 (t,J= 1.6 Hz, 1H), 8.20 (d,J= 7.8 Hz, 1H), 8.09 (s, 1H), 7.77 - 7.70 (m, 2H), 7.67 (dd,J= 8.6, 1.3 Hz, 1H), 7.64 (d,J= 2.1 Hz, 1H), 7.60 (t,J= 7.8 Hz, 1H), 7.45 (dd,J= 8.3, 2.1 Hz, 1H), 6.90 (d,J= 8.3 Hz, 1H).389 [M+H] + 602-(Trifluoromethyl)-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1H NMR (400 MHz, CDCl3) δ 8.18 (d,J= 7.2 Hz, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.65 - 7.53 (m, 2H), 7.52 - 7.41 (m, 2H), 7.19 (s, 2H), 7.09 (d,J= 8.2 Hz, 1H), 6.99 (d,J= 1.6 Hz, 1H), 6.80 (d,J= 8.0 Hz, 1H).464 [M+ACN] + 612-Methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.15 (d,J= 7.8 Hz, 1H), 8.05 (s, 1H), 7.73 (d,J= 7.7 Hz, 1H), 7.68 (d,J= 8.5 Hz, 1H), 7.62 (d,J= 8.5 Hz, 1H), 7.54 (t,J= 7.8 Hz, 1H), 7.21 (d,J= 8.0 Hz, 1H), 6.46 - 6.31 (m, 2H), 3.81 (s, 3H).426 [M+ACN] + 626-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine 1 H NMR (400 MHz, MeOD) δ 8.35 - 8.32 (m, 1H), 8.32 - 8.27 (m, 1H), 8.09 (s, 1H), 7.91 (d,J= 8.6 Hz, 1H), 7.77 (dd,J= 8.5, 1.3 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.24 (d,J= 8.6 Hz, 1H), 6.80 (d,J= 2.7 Hz, 1H), 6.75 (dd,J= 8.5, 2.8 Hz, 1H).389 [M+H] + 632-(2'-chloro-4'-nitro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d,J= 2.3 Hz, 1H), 8.37 - 8.27 (m, 3H), 8.27 (s, 1H), 8.06 (d,J= 8.5 Hz, 1H), 7.87 - 7.83 (m, 4H)460 (M+ACN)+642-(2'-Chloro-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (m, 3H), 8.05 (d,J= 8.6 Hz, 1H), 7.84 - 7.74 (m, 3H), 7.63 (m, 2H), 7.39 (td,J= 8.5, 2.7 Hz, 1H) 392 (M+H) + 652-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-ol 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.24 - 8.21 (m, 2H), 8.05 (d,J= 8.5 Hz, 1H), 7.82 (dd,J= 8.6, 1.4 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.34 (d,J= 8.4 Hz, 1H), 6.98 (d,J= 2.4 Hz, 1H), 6.87 (dd,J= 8.4, 2.4 Hz, 1H) 390 (M+H) + 662-Fluoro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, MeOD) δ 8.40 (d,J= 1.4 Hz, 1H), 8.20 (d,J= 7.8 Hz, 1H), 8.09 (s, 1H), 7.91 (d,J= 8.6 Hz, 1H), 7.78 (d,J= 1.1 Hz, 1H), 7.76 (s, 1H), 7.64 (t,J= 7.8 Hz, 1H), 7.32 (t,J= 8.7 Hz, 1H), 6.63 (dd,J= 8.3, 2.2 Hz, 1H), 6.55 (dd,J= 13.4, 2.2 Hz, 1H).414 [M+ACN] +672-Methyl-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, MeOD) δ 8.23 ​​- 8.17 (m, 2H), 8.07 (s, 1H), 7.89 (d,J= 8.6 Hz, 1H), 7.75 (dd,J= 8.5, 1.1 Hz, 1H), 7.63 (t,J= 7.7 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.05 (d,J= 8.1 Hz, 1H), 6.72 (d,J= 2.0 Hz, 1H), 6.68 (dd,J= 8.1, 2.2 Hz, 1H), 2.25 (s, 3H).410 [M+ACN] + 682,3-Dichloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 8.30 - 8.25 (m, 1H), 8.10 (s, 1H), 7.92 (d,J= 8.5 Hz, 1H), 7.77 (dd,J= 8.6, 1.2 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.16 (d,J= 8.4 Hz, 1H), 6.91 (d,J= 8.4 Hz, 1H).423 [M+H] + 692,4'-Dichloro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4,6'-diamine 1 H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 8.25 (d,J= 7.8 Hz, 1H), 8.09 (s, 1H), 7.91 (d,J= 8.5 Hz, 1H), 7.76 (d,J= 8.7 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.65 (t,J= 7.7 Hz, 1H), 7.09 (d,J= 8.2 Hz, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.88 (d,J= 2.2 Hz, 1H), 6.73 (dd,J= 8.2, 2.3 Hz, 1H).555 [M+ACN]+ 702-(4'-Fluoro-5'-(1H-indazol-6-yl)-2'-methoxy-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.66 - 7.58 (m, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 12.4 Hz, 1H), 3.91 (s, 3H).504 [M+H]+712-Chloro-3'-(furan-3-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.28 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H) 1.6 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.66 (dd, J = 8.3, 2.2 Hz, 1H), 5.63 (s, 2H).496 [M+H+ACN]+722-Chloro-3'-(2H-1,2,3-triazol-4-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.32 (t, J = 1.6 Hz, 1H), 8.15 - 8.03 (m, 3H), 7.76 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 1.3 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.73 (dd, J = 8.2, 2.3 Hz, 1H).456 [M+H]+732-Chloro-N-(2-chloro-3'-(5-trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)-2,2'-difluoroacetamide 1 H NMR (400 MHz, CDCl3) δ 8.36 (m, 1H), 8.32 (dt, J = 7.2, 1.7 Hz, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.73 - 7.64 (m, 4H), 7.61 (dd, J = 8.4, 2.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H).501 [M+H]+74(S)-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-carboxamide 1H NMR (400 MHz, CD3OD) δ 8.35 (m, 1H), 8.31 (dt, J = 7.1, 1.8 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 8.4, 1.1 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.63 (dd, J = 8.4, 2.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 3.85 (dd, J = 8.6, 5.8 Hz, 1H), 3.12 (dt, J = 10.5, 6.4 Hz, 1H), 3.02 (dt, J = 10.5, 6.4 Hz, 1H), 2.30 - 2.25 (m, 1H), 1.97 - 1.91 (m, 1H), 1.89 - 1.82 (m, 2H).486 [M+H]+752-Amino-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)acetamide 1 H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.31 (s, 1H), 8.23 ​​(d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.65 - 7.57 (m, 5H), 7.36 (d, J = 8.1 Hz, 1H), 3.58 (s, 2H).487 [M+H+ACN]+

[0316]

[0317] <Experimental Method>

[0318] 1. Real-time PCR

[0319] HepG2 cells are seeded into a 12-well plate at a concentration of 2x105 cells / well.

[0320] Culture conditions: DMEM with 10% FBS, 1% Penicillin / Streptomycin

[0321] One day later, the cells were treated with the compound and incubated at 37°C. The final DMSO concentration was 0.1%.

[0322] After 24 hours, RNA was extracted using Hybrid-R (Geneall #305-101). cDNA was synthesized using the High Capacity cDNA Reverse Transciption Kit (Thermo Fisher Scientific #4368814).

[0323] Real-time PCR was performed using the StepOnePlus system using Power SYBR Green PCR Mater Mix (Thermo Fisher Scientific #4367659). The expression levels of target genes were normalized to GAPDH values ​​and 2 -△△Ct It is expressed as a value.

[0324] As a result of quantifying PCSK9 mRNA, it was confirmed that there was no significant difference between the treatment groups treated with the example compounds (Example 1, Example 2, Example 3) compared to the control group not treated with the example compounds. Through this, it was confirmed that the example compounds of the present invention do not affect the PCSK9 transcription process.

[0325]

[0326] 2. Analysis of intracellular PCSK9 and LDLR expression

[0327] To analyze the expression of PCSK9 and LDLR in cells, 200,000 HepG2 cells were seeded in a 12-well plate and cultured in assay media (10% Lipoprotein-depleted FBS in DMEM) for 24 hours. The cells were washed once with DMEM medium and 1 mL of assay media was added to prepare a compound concentration of 10 uM (0.1% DMSO). After 24 hours of culture, the cells were washed twice with PBS and lysed by adding Ripa buffer. The protein concentration was measured using a BCA protein assay kit (Thermo, 2322S), and 4X Laemmli sample buffer (Bio-Rad, 1610747) was added and reacted at 95°C for 5 minutes. Perform SDS-PAGE on Mini-Protein TGX gels (Bio-Rad, #4561096) using Tris-Glycine-SDS buffer (iNtRON, IBS-BT014-1), then transfer to PVDF membranes (Millipore, IPVH00010). The membranes are stirred for 1 hour with 5% skim milk, and the primary antibodies (PCSK9_AF3888, LDLR_AF2148, GAPDH_SC-47724) are added and reacted at 4°C for 18 hours. The membranes are washed three times for 10 minutes with T-BST, and the secondary antibodies are added in 5% skim milk, stirred for 1 hour at room temperature, and then washed three more times for 10 minutes. SuperSignal West PicoPlus Chemiluminescent substrate (Thermo, 34580) is reacted with the membrane and protein expression is analyzed using LuminoGraphⅢLite (ATTO).

[0328] The results are presented in Table 3.

[0329]

[0330] 3. Measurement of PCSK9 secretion levels

[0331] To determine whether the compound inhibits PCSK9 secretion outside the cell, 200,000 HepG2 cells were seeded in a 12-well plate and cultured in assay medium (10% Lipoprotein-depleted FBS in DMEM) for 24 hours. The cells were washed once with DMEM medium, and 1 mL of the compound was added to 1 mL of assay medium at a concentration of 10 μM (0.1% DMSO). After 24 hours of culture, the medium was collected and centrifuged using a QIA shredder (QLAGEN) to completely remove debris.

[0332] To measure secreted human PCSK9, a PCSK9 immunoassay (R&D system, DPC900) was performed. To establish a standard curve, 0.625 ng / mL to 20 ng / mL recombinant human PCSK9 was prepared in immunoassay buffer according to the procedure, and 50 uL each of the collected medium and assay media was added to the immunoassay plate and incubated at room temperature for 2 hours. 400 uL of wash buffer was added to each well and washed four times. 200 uL of human PCSK9 conjugate was added and incubated at room temperature for 2 hours, followed by four washes using the same method. 200 uL of substrate solution was added and incubated in a dark room for 30 minutes, and 50 uL of stop solution was added. The absorbance value was measured at 450 nm using a microplate reader (BioTek, Synergy neo), and the final absorbance value was derived by excluding the absorbance value measured at 570 nm for correction.

[0333] After calculating the secreted PCSK9 concentration of the control group and the experimental group treated with the example compound through the standard curve value, the PCSK9 secretion inhibition rate was derived through the calculation formula [(1-(test well value-average of background value) / (vehicle well value-average of background value))*100]. If the PCSK9 secretion inhibition rate compared to the control group was less than 30%, it was given grade A, if it was 30% or more but less than 50%, it was given grade B, if it was 50% or more but less than 80%, it was given grade C, and if it was more than 80%, it was given grade D.

[0334] The results are presented in Table 3.

[0335]

[0336] 4. Cytotoxicity analysis

[0337] To confirm cell viability, 10,000 HepG2 cells were seeded in a 96-well plate and cultured for 24 hours in assay media (10% Lipoprotein depleted FBS in DMEM). 0.1 mL of the compound concentration was adjusted to 10 μM (0.1% DMSO) and exchanged. After 24 hours of culture, 10 μL of CCK-8 reagent (DOJINDO, CK04) was added and incubated in a cell incubator for 2 hours and 30 minutes. The absorbance value was measured at 450 nm using a microplate reader (BioTek, Synergy neo). The changed cell viability value was derived as a percentage through the calculation formula [(1-(test well value-average of background value) / (vehicle well value-average of background value))*100].

[0338] The results are presented in Table 3.

[0339]

[0340] Example Survival rate, 10uM, 24hr (% of DMSO) PCSK9 secretion rate, 10uM, 24hr (% of DMSO) Protein expression rate, HepG2, 10uM, 24hr (% of DMSO) CCK-8 ELISA Pro PCSK9 Mature PCSK9 LDLR 198.8 ± 4.3 B~037119291.3 ± 3.8 B~045546384.5 A3.015.2210.3488.5 B594.4 A691.8 A799.5 A897.3 A998 A1095.7 A1191.9 A1273.9 A1385.4 B1488.8 B1575.3 A1684.4 B1780.4 B1883 B1980. 5A20101.9C2180.4A2287.7A2388.1B2488.5B2594.1B26100.8C2786.5C2895. 4C2977.7B3078.4B3171.1B3276B3377.3B34101.4C3579.2B36100D3786.1C38 98C3978.8B4083B4185.2B42100B4387.3B4495.9A4594.3C4696.8C4789.1B48 94.6C4996.8B50100.8B5191.5C5294.9C5389.9B5493.3D55102.2C56100.1B5 793.5C58102.3D5994.9B6082.7C61100.8C6295C6396.3B6497.8D65103B6610 0B6797.2B6897.7B6989.9B7070.9B7193.2B7291.7A7394.9C7499.3B7590.4D

[0341] As shown in the results in the table above, it was confirmed that the compound of formula I of the present invention does not exhibit cytotoxicity and inhibits the secretion of PCSK9 protein outside of cells. Furthermore, it is effective in inhibiting the expression of PCSK9 protein, and thus, the compounds of the present invention are expected to be useful for treating PCSK9-related diseases.

Claims

1. A compound represented by the following chemical formula I or a pharmaceutically acceptable salt thereof: In chemical formula I, p is 2, R 1 are each independently hydrogen, C1-C6 haloalkyl, nitro, halogen or C1-C6 haloalkoxy, R 1 At least one of them is not hydrogen, R 2 is hydrogen, NH2, or substituted phenyl, R 3 is hydrogen, C1-C6 haloalkyl, halogen, C1-C6 alkyl, 5-6 membered heteroaryl or nitro, R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C1-C6 alkoxy, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, nitro, -NH-COR 6a or -SO2NH2, but at least one of these is not hydrogen, R 6a is a 5-6 membered heterocycloalkyl or substituted C1-C6 alkyl, wherein the substituted C1-C6 alkyl is substituted with NH2 or one or more halogens, The above substituted phenyl is R of 1 to 3 7 is replaced by, R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -X-NR 7a R 7b , or -NH-YR 7c And, X is SO2 or CO, Y is SO2, CO or CO2 R 7a , and R 7b are each independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, R 7c is C1-C6 alkyl, or or two R 7 The two adjacent carbon atoms of this phenyl can be substituted to form a 5-6 membered heteroaryl together with the two carbon atoms.

2. Compound according to paragraph 1 or pharmaceutically acceptable salt thereof: R 1 is substituted at positions 5 and 6 of the benzoxazole ring, R 1 One of them is C1-C6 haloalkyl, nitro, halogen or C1-C6 haloalkoxy, and the other is hydrogen or halogen.

3. Compound according to paragraph 1 or pharmaceutically acceptable salt thereof: R 4 is hydrogen, halogen, C1-C6 alkoxy, OH, NH2, C1-C6 alkyl or C1-C6 haloalkyl, R 5 is hydrogen, NH2, halogen or -SO2NH2, R 6 is hydrogen, NH2, halogen, C1-C6 alkyl, SO2NH2, nitro, -NH-COR 6a Or OH, R 6a is a 5-6 membered heterocycloalkyl or substituted C1-C6 alkyl, wherein the substituted C1-C6 alkyl is substituted with NH2 or 1-3 halogen, R 4 Inland R 6 At least one of them is not hydrogen.

4. Compound according to paragraph 1 or pharmaceutically acceptable salt thereof: R 2 is hydrogen, NH2, or substituted phenyl, The above substituted phenyl is R of 1 to 3 7 is replaced by, R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -SO2NR 7a R 7b , -CONH2, -NHSO2R 7c , -NHCOR 7c , or -NHCO2R 7c And, R 7a is hydrogen, R 7b is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, R 7c are each independently C1-C6 alkyl, or or two R 7 The two adjacent carbon atoms of this phenyl can be substituted to form a 5-6 membered heteroaryl together with the two carbon atoms.

5. Compound according to paragraph 1 or a pharmaceutically acceptable salt thereof: p is 2, R 1 is substituted at positions 5 and 6 of the benzoxazole ring, R 1 One of which is C1-C3 haloalkyl, nitro, halogen or C1-C3 haloalkoxy, and the other is hydrogen or halogen, R 2 is hydrogen, NH2, or substituted phenyl, R 3 is hydrogen, C1-C3 haloalkyl, halogen, C1-C3 alkyl, 5-membered heteroaryl or nitro, R 4 is hydrogen, halogen, C1-C3 alkoxy, OH, NH2, C1-C3 alkyl or C1-C3 haloalkyl, R 5 is hydrogen, NH2, halogen or -SO2NH2, R 6 is hydrogen, NH2, halogen, C1-C3 alkyl, SO2NH2, nitro, -NH-COR 6a Or OH, R 6a is a 5-membered heterocycloalkyl or substituted C1-C3 alkyl, wherein the substituted C1-C3 alkyl is substituted with NH2 or three halogens, R 4 Inland R 6 At least one of them is not hydrogen, The above substituted phenyl is R of 1 to 3 7 is replaced by, R 7 are each independently halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, NH2, -SO2NR 7a R 7b , -CONH2, -NHSO2R 7c , -NHCOR 7c , or -NHCO2R 7c And, R 7a is hydrogen, R 7b is hydrogen, C1-C3 alkyl or C3 cycloalkyl, R 7c are each independently C1-C3 alkyl, or or two R 7 It can be substituted on the two adjacent carbon atoms of this phenyl to form a five-membered heteroaryl together with the two carbon atoms.

6. Compound according to paragraph 1 or pharmaceutically acceptable salt thereof: p is 2, R 1 is substituted at positions 5 and 6 of the benzoxazole ring, R 1 One of them is CF3, nitro, F or OCF3, and the other is hydrogen or F, R 2 is hydrogen, NH2, or substituted phenyl, The above substituted phenyl is substituted with 1 to 3 identical or different substituents selected from Cl, F, methyl, methoxy, nitro, NH2, -SO2NH2, -SO2NHCH3, -SO2NH(cyclopropyl), -NHSO2CH3, -NHCOCH3, -NHCO2CH3, and -CONH2, or two adjacent carbon atoms of phenyl are substituted to form pyrazolyl together with the two carbon atoms, R 3 is hydrogen, CF3, F, methyl, furanyl, triazolyl or nitro, R 4 is hydrogen, Cl, F, methoxy, OH, NH2, methyl or CF3, R 5 is hydrogen, NH2, Cl or SO2NH2, R 6 is hydrogen, NH2, F, Cl, methyl, SO2NH2, nitro, -NH-COR 6a Or OH, R 6a is pyrrolidinyl or substituted C1-C3 alkyl, wherein the substituted C1-C3 alkyl is substituted with NH2 or three halogens, and R 4 Inland R 6 At least one of them is not hydrogen.

7. Compound according to paragraph 1 or pharmaceutically acceptable salt thereof: The compound of the above chemical formula I is a compound of the following chemical formula Ia, In the above chemical formula Ia, p. q, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is as defined for chemical formula I.

8. A compound according to paragraph 1 selected from the following or a pharmaceutically acceptable salt thereof: 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,6'-Difluoro-4'-methoxy-3''-(5-nitrobenzo[d]oxazol-2-yl)-5''-(trifluoromethyl)-[1,1':3',1''-terphenyl]-4-amine; 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide; 3''-(5,6-Difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-N-methyl-[1,1':3',1''-terphenyl]-4-sulfonamide; N-(3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide; N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)acetamide; 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-sulfonamide; N-(6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide; 6'-Fluoro-4'-methoxy-N-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 3'',6'-Difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 2,3'',6'-Trifluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; N-(3'',6'-difluoro-4'-methoxy-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide; 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine; 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3-amine; 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine; 2,6'-Difluoro-4'-methoxy-3''-methyl-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 6'-Fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-sulfonamide; N-(6'-fluoro-4'-methoxy-3''-(trifluoromethyl)-5''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide; 6'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; N-(6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-yl)methanesulfonamide; 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine; 2-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3-amine; Methyl (6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-yl)carbamate; N-Cyclopropyl-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 2,3,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 3-Chloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,6'-Difluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-3,4-diamine; 3''-(5,6-Difluorobenzo[d]oxazol-2-yl)-2,6'-difluoro-4'-methoxy-[1,1':3',1''-terphenyl]-3,4-diamine; 2-Chloro-3''-(5,6-difluorobenzo[d]oxazol-2-yl)-6'-fluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine; 6'-Fluoro-4'-methoxy-2-nitro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,6'-Difluoro-3,4'-dimethoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,3-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-2,4-diamine; 3,5-Dichloro-6'-fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2,5,6'-Trifluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 4'-Methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 6'-Fluoro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-carboxamide; 3''-(5,6-difluorobenzo[d]oxazol-2-yl)-2,5,6'-trifluoro-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine; 2-Chloro-4'-methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 4'-Methoxy-6'-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 6'-Chloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-sulfonamide; 4-Amino-2-chloro-6'-fluoro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4'-ol; 2,6'-Dichloro-4'-methoxy-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2-Chloro-6'-fluoro-3''-(6-fluoro-5-(trifluoromethyl)benzo[d]oxazol-2-yl)-4'-methoxy-[1,1':3',1''-terphenyl]-4-amine; 2-Chloro-3'-(5,6-difluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-sulfonamide; 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine; 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-sulfonamide; 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-2-amine; 3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine; 6'-Fluoro-4'-methoxy-2-methyl-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4-amine; 2-Chloro-3'-(5-fluorobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-3'-(5-(trifluoromethoxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-3'-nitro-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-3'-(trifluoromethyl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 3-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-(Trifluoromethyl)-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Methoxy-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 6-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-amine; 2-(2'-chloro-4'-nitro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole; 2-(2'-chloro-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole; 2-Chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-ol; 2-Fluoro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Methyl-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2,3-dichloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; and 2,4'-Dichloro-3''-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1':3',1''-terphenyl]-4,6'-diamine; 2-(4'-Fluoro-5'-(1H-indazol-6-yl)-2'-methoxy-[1,1'-biphenyl]-3-yl)-5-(trifluoromethyl)benzo[d]oxazole; 2-Chloro-3'-(furan-3-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-3'-(2H-1,2,3-triazol-4-yl)-5'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-amine; 2-Chloro-N-(2-chloro-3'-(5-trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)-2,2'-difluoroacetamide; (S)-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-2-carboxamide; 2-Amino-N-(2-chloro-3'-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-4-yl)acetamide.

9. A method for producing a compound of chemical formula I by cyclizing a compound of chemical formula C and a compound of chemical formula D as shown in the following reaction scheme 1: <Reaction Scheme 1> In the above reaction formula 11, p. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is as described in Article 1.

10. A method for preparing a compound of chemical formula Ia by coupling a compound of chemical formula G and a compound of chemical formula H as shown in the following reaction scheme 2: <Reaction Formula 2> In the above reaction formula 2, p. q, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 is as described in paragraph 1, and -OX is methanesulfonate or trifluoromethanesulfonate.

11. A pharmaceutical composition for the prevention or treatment of hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, containing a compound represented by the chemical formula I of paragraph 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. In paragraph 11, A pharmaceutical composition characterized in that the compound inhibits the expression of PCSK9 protein.

13. In paragraph 11, A pharmaceutical composition characterized in that the compound inhibits secretion of PCSK9 protein outside of cells.

14. A health functional food composition for preventing or improving hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, containing a compound represented by the chemical formula I of Article 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

15. A pharmaceutical composition for preventing or treating a disease related to PCSK9 protein, containing a compound represented by the chemical formula I of paragraph 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

16. A pharmaceutical composition for preventing or treating a disease caused by overexpression of PCSK9 protein, containing a compound represented by the chemical formula I of Article 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

17. A method for treating hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia, comprising a step of administering a compound represented by the chemical formula I of paragraph 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

18. Use of a compound represented by the chemical formula I of claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for use in the prevention or treatment of hyperlipidemia, hypertriglyceridemia, fatty liver disease, atherosclerosis, obesity, or hypercholesterolemia.

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