Stilbene derivatives and methods for their preparation

Abstract

The present invention relates to stilbene derivatives and a method for preparing the same. More particularly, the present invention relates to novel stilbene derivatives which inhibit the function of cyclophilins and are effective in preventing cyclophilin-related diseases or treating symptoms thereof, and a method for preparing the same.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel stilbene derivatives having improved pharmaceutical profiles for inhibiting the function of cyclophilins and methods of preparing the same. BACKGROUND

[0002] Cyclophilins are known as effective drug targets for many diseases, including viral infectious diseases such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza virus, and the like; diseases caused by inflammatory responses such as cardiovascular diseases; rheumatoid arthritis; sepsis; asthma; periodontitis; aging; alopecia; neurodegenerative diseases caused by mitochondrial dysfunction; cancer, and the like (Nigro P et al., Cell Death Dis 2013, 4, e888).

[0003] Cyclophilins (CyPs) belong to the family of immunophilins, which are proteins found in all cells of all organisms (both prokaryotes and eukaryotes) and have been well conserved structurally through evolution. Humans contain a total of 16 endogenous proteins present in humans, including seven major CyPs, CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, and CyP NK.

[0004] Cyclophilins are found in most cells in the human body, and CyP A and CyP 40 in mammals have cytoplasmic message sequences, while CyP B and CyP C have N-terminal message sequences targeting the endoplasmic reticulum. CyP D has a message sequence directed to mitochondria, CyP E has an amino-terminal RNA-binding domain and is located in the nucleus, and CyP 40 has TPR and is located in the cytoplasm. Human CyP NK is the largest CyP, which has a large hydrophilic and positively charged carboxyl terminal, and is located in the cytoplasm.

[0005] Cyclophilins are multifunctional proteins involved in cellular processes and are responsible for essential functions in cells. Cyclophilins have been shown to have enzymatic properties that catalyze the cis-trans isomerization of peptide acyl-prolyl bonds. Thus, cyclophilins are referred to as peptide acyl-prolyl cis-trans isomerases (PPIases) that can act as accelerators in the proper folding of newly synthesized proteins. PPIases are also involved in the repair of damaged proteins due to environmental stresses including heat stress, ultraviolet radiation, changes in cellular environmental pH, and treatment with oxidizing agents. This function is referred to as chaperone activity. PPIase activity of cyclophilins has also been shown to be involved in intracellular protein trafficking, mitochondrial function, and precursor signaling RNA processing.

[0006] Cyclosporin is one of the cyclophilin inhibitors that binds in the hydrophobic pocket of CyPA to thereby inhibit PPIase activity. CyPA is the prototype of the cyclophilin family and shows very high sequence homology with CyPB, CyPC, and CyPD in humans. The binding pocket of all cyclophilins is formed by approximately 109 amino acids corresponding to a highly conserved region, and the sequence homology between CyPA and CyPD is 100%. Thus, CyPA binding affinity is the best predictor of CyPD binding affinity and vice versa.

[0007] This sequence homology between cyclophilins implies that not only CyPD but all cyclophilins are potential targets for functional inhibitors with binding affinity to CyPA, which indicates that functional inhibitors of CyPA can be useful in treating many diseases caused by numerous intracellular processes associated with cyclophilins. SUMMARY

[0008] Accordingly, the present invention intends to provide a compound for inhibiting the function of cyclophilins with an improved pharmaceutical profile so as to prevent diseases or treat symptoms of such diseases, including viral infectious diseases such as HBV, HCV, HIV, influenza, and the like; cardiovascular diseases; rheumatoid arthritis; sepsis; asthma; periodontitis; aging; alopecia; neurodegenerative diseases; cancer, and the like.

[0009] Accordingly, the present invention provides a compound capable of inhibiting the function of cyclophilins. The present invention provides a stilbene derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt, a hydrate, a hydrated salt, a polymorphic crystal structure, a racemate, a diastereomer, or an enantiomer thereof. It is for preventing cyclophilin-related diseases or for treating symptoms of such diseases.

[0010] [Chemical Formula 1]

[0011]

[0012] In Chemical Formula 1,

[0013] A is CRaor N,

[0014] B is CRbor N,

[0015] G is CReor N,

[0016] J is CRfor N,

[0017] M is CRgor N,

[0018] D, E, and L are CRhor N,

[0019] Rx is H, CH3, CN, NH2, F, Cl, Br, or I,

[0020] wherein when Rx is H, CH3, NH2, F, Cl, Br, or I,

[0021] Ra is hydrogen, NO2, CN, OH, C1-C5 alkyl, C2-C10 alkenyl, C1-C2 alkoxy, -COOR1 (R1 is hydrogen or C1-C5 alkyl), or -OCOR2 (R2 is C1-C5 alkyl),

[0022] Rb is hydrogen, C1-C20 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, -COOR1 (R1 is hydrogen or C1-C5 alkyl), or -OCOR2 (R2 is C1-C5 alkyl),

[0023] Rc is OH, NO2, C1-C20 alkyl, C3-C10 cycloalkyl, C2-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl, or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl, or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl, or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl, or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl),

[0024] Rd is halogen, NO2, COOH, CN, C2-C20alkyl, C3-C10cycloalkyl, C1-C10alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NR3R4(R3is hydrogen, C1-C20alkyl or C6-C12aryl, R4is hydrogen, C1-C20alkyl or C6-C12aryl, and R3and R4may be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5(R5is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -OCOR6(R6is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -NR7CYR8(Y is O or S, R7is hydrogen or C1-C5alkyl, and R8is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), -NHS(O)2R9(R9is C6-C12aryl or C5-C12heterocyclyl), or COR10(R10is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl),

[0025] Re is hydrogen, NH2, OH, CN, C1-C20alkyl, C2-C10alkenyl, C1-C10alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NR7CYR8(Y is O or S, R7is hydrogen or C1-C5alkyl, and R8is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), or -NHS(O)2R9(R9is C6-C12aryl or C5-C12heterocyclyl),

[0026] Rf is hydrogen, NH2, OH, NO2, C1-C4alkyl, C2-C10alkenyl, C1-C4alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NHR11(R11is C1-C2alkyl), -COOR12(R12is C1-C2alkyl), -OCOR13(R13is C1-C2alkyl), or -COR14(R14is C1-C2alkyl),

[0027] Rgis hydrogen, NH2, OH, halogen, NO2, COOH, CN, C1-C20alkyl, C2-C10alkenyl, C3-C10cycloalkyl, C1-C10alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NR3R4(R3is hydrogen, C1-C20alkyl or C6-C12aryl, R4is hydrogen, C1-C20alkyl or C6-C12aryl, and R3and R4may be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5(R5is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -OCOR6(R6is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -NR7CYR8(Y is O or S, R7is hydrogen or C1-C5alkyl, and R8is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), -NHS(O)2R9(R9is C6-C12aryl or C5-C12heterocyclyl), or -COR10(R10is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), and

[0028] Rh is hydrogen, NH2, OH, C1-C5alkyl or C2-C10alkenyl,

[0029] when Rx is CN,

[0030] Ra is hydrogen,

[0031] Rb is hydrogen, C1-C20alkyl, C2-C10alkenyl, C1-C10alkoxy, -COOR1(R1is hydrogen or C1-C5alkyl) or -OCOR2(R2is C1-C5alkyl),

[0032] Rc is OH, NO2, C1-C20 alkyl, C3-C10 cycloalkyl, C2-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl),

[0033] Rd is hydrogen, halogen, NO2, COOH, CN, C2-C20 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl),

[0034] Re is hydrogen, CN, C2-C20 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), or -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl),

[0035] Rfand Rgare each hydrogen, and

[0036] Rh is hydrogen, C1-C5 alkyl or C2-C10 alkenyl,

[0037] The heteroatom of the heterocyclyl group can be at least one selected from the group consisting of nitrogen, oxygen and sulfur,

[0038] The alkyl group can be substituted with at least one substituent selected from the group consisting of OH, amine, C6-C12 aryl, C5-C10 heterocyclyl and C3-C10 cycloalkyl,

[0039] The alkoxy group can be substituted with at least one substituent selected from the group consisting of halogen, C6-C12 aryl, C3-C10 cycloalkyl, amine and aminocarbonyl,

[0040] The heterocyclyl group can be substituted with at least one substituent selected from the group consisting of alkyl, alkyl substituted with amine, amine, amido and carboxyl,

[0041] The aryl group can be substituted with at least one substituent selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, carboxyl, ester, nitro and amido,

[0042] A, B, D, E, G, J, L and M can be linked with adjacent groups to form a fused ring, and

[0043] When Rb is CH3, Rd cannot be NO2.

[0044] According to the present invention, stilbene derivatives are effective in inhibiting the function of cyclophilins, and thus are useful for preventing cyclophilin-related diseases, or for treating symptoms of such diseases, including viral infectious diseases such as hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), avian influenza (AI) virus and the like; cardiovascular diseases; rheumatoid arthritis; sepsis; asthma; periodontitis; aging; alopecia; neurodegenerative diseases; cancer and the like. In addition, the stilbene derivatives of the present invention can be used in combination with existing therapeutic agents to thereby increase the therapeutic effect. DETAILED DESCRIPTION

[0045] Hereinafter, a detailed description of the present invention will be given.

[0046] The present invention is directed to stilbene derivatives represented by the following Chemical Formula 1. The stilbene derivatives of the present invention have a structure suitable for binding to the active pocket maintained in any protein having the function of cyclophilin and thus are suitable for use as cyclophilin inhibitors.

[0047] [Chemical Formula 1]

[0048]

[0049] in Chemical Formula 1,

[0050] A is CRaor N,

[0051] B is CRbor N,

[0052] G is CReor N,

[0053] J is CRfor N,

[0054] M is CRgor N,

[0055] D, E, and L are CRhor N,

[0056] Rx is H, CH3, CN, NH2, F, Cl, Br, or I,

[0057] wherein when Rx is H, CH3, NH2, F, Cl, Br, or I,

[0058] Ra is hydrogen, NO2, CN, OH, C1-C5 alkyl, C2-C10 alkenyl, C1-C2 alkoxy, -COOR1 (R1 is hydrogen or C1-C5 alkyl), or -OCOR2 (R2 is C1-C5 alkyl),

[0059] Rb is hydrogen, C1-C20 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, -COOR1 (R1 is hydrogen or C1-C5 alkyl), or -OCOR2 (R2 is C1-C5 alkyl),

[0060] Rc is OH, NO2, C1-C20 alkyl, C3-C10 cycloalkyl, C2-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl, or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl, or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl, or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl, or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl),

[0061] Rdis halogen, NO2, COOH, CN, C2-C20alkyl, C3-C10cycloalkyl, C1-C10alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NR3R4(R3is hydrogen, C1-C20alkyl or C6-C12aryl, R4is hydrogen, C1-C20alkyl or C6-C12aryl, and R3and R4may be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5(R5is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -OCOR6(R6is C1-C20alkyl, C6-C12aryl or C3-C10cycloalkyl), -NR7CYR8(Y is O or S, R7is hydrogen or C1-C5alkyl, and R8is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), -NHS(O)2R9(R9is C6-C12aryl or C5-C12heterocyclyl), or COR10(R10is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl),

[0062] Reis hydrogen, NH2, OH, CN, C1-C20alkyl, C2-C10alkenyl, C1-C10alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NR7CYR8(Y is O or S, R7is hydrogen or C1-C5alkyl, and R8is C1-C20alkyl, C6-C12aryl, C3-C10cycloalkyl or C5-C12heterocyclyl), or -NHS(O)2R9(R9is C6-C12aryl or C5-C12heterocyclyl),

[0063] Rfis hydrogen, NH2, OH, NO2, C1-C4alkyl, C2-C10alkenyl, C1-C4alkoxy, C6-C12aryl, C5-C12heterocyclyl, -NHR11(R11is C1-C2alkyl), -COOR12(R12is C1-C2alkyl), -OCOR13(R13is C1-C2alkyl), or -COR14(R14is C1-C2alkyl),

[0064] Rg is hydrogen, NH2, OH, halogen, NO2, COOH, CN, C1-C20 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), and

[0065] Rh is hydrogen, NH2, OH, C1-C5 alkyl or C2-C10 alkenyl,

[0066] when Rx is CN,

[0067] Ra is hydrogen,

[0068] Rb is hydrogen, C1-C20 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, -COOR1 (R1 is hydrogen or C1-C5 alkyl) or -OCOR2 (R2 is C1-C5 alkyl),

[0069] Rc is OH, NO2, C1-C20 alkyl, C3-C10 cycloalkyl, C2-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl, or C5-C12 heterocyclyl),

[0070] Rd is hydrogen, halogen, NO2, COOH, CN, C2-C20 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR3R4 (R3 is hydrogen, C1-C20 alkyl or C6-C12 aryl, R4 is hydrogen, C1-C20 alkyl or C6-C12 aryl, and R3 and R4 can be linked to form a heterocyclic ring, further containing at least one heteroatom), -COOR5 (R5 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -OCOR6 (R6 is C1-C20 alkyl, C6-C12 aryl or C3-C10 cycloalkyl), -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl), or -COR10 (R10 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl),

[0071] Re is hydrogen, CN, C2-C20 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C6-C12 aryl, C5-C12 heterocyclyl, -NR7CYR8 (Y is O or S, R7 is hydrogen or C1-C5 alkyl, and R8 is C1-C20 alkyl, C6-C12 aryl, C3-C10 cycloalkyl or C5-C12 heterocyclyl), or -NHS(O)2R9 (R9 is C6-C12 aryl or C5-C12 heterocyclyl),

[0072] Rf and Rg are each hydrogen, and

[0073] Rh is hydrogen, C1-C5 alkyl, or C2-C10 alkenyl,

[0074] The heteroatom of the heterocyclyl group can be at least one selected from the group consisting of nitrogen, oxygen, and sulfur,

[0075] The alkyl group can be substituted with at least one substituent selected from the group consisting of OH, amine, C6-C12 aryl, C5-C10 heterocyclyl, and C3-C10 cycloalkyl,

[0076] The alkoxy group can be substituted with at least one substituent selected from the group consisting of halogen, C6-C12 aryl, C3-C10 cycloalkyl, amine, and aminocarbonyl,

[0077] The heterocyclyl group can be substituted with at least one substituent selected from the group consisting of alkyl, alkyl substituted with amine, amine, amido, and carboxyl,

[0078] The aryl group can be substituted with at least one substituent selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, carboxyl, ester, nitro, and amido,

[0079] A, B, D, E, G, J, L, and M can be linked with adjacent groups to form a fused ring, and

[0080] When Rb is CH3, Rd cannot be NO2.

[0081] The compounds of the present application can be synthesized via various methods, and typically the synthesis process of the case where Rx of Chemical Formula 1 is CN can be different from those of other cases.

[0082] When Rx is CN, the stilbene derivative represented by Chemical Formula 1 can be prepared by reacting a phenylacetonitrile derivative represented by Chemical Formula 2 with a benzaldehyde derivative represented by Chemical Formula 3.

[0083] The phenylacetonitrile derivative represented by Chemical Formula 2 and the benzaldehyde derivative represented by Chemical Formula 3 can be commercially available products, or can be used after being prepared via methods known in the art.

[0084] The above reaction can be performed in the presence of an organic solvent or without any solvent. In this case, when using a microwave, the reaction time can be reduced and the yield can be increased.

[0085] The organic solvent is not limited, but preferably includes an alcohol, and more preferably is butanol, methanol, ethanol, or propanol. A catalyst such as triphenylphosphine, piperidine, or the like can be added to facilitate the reaction.

[0086] [Chemical Formula 1]

[0087]

[0088] Rx = CN

[0089] [Chemical Formula 2]

[0090]

[0091] [Chemical Formula 3]

[0092]

[0093] In Chemical Formula 2 and Chemical Formula 3,

[0094] A, B, D, E, G, J, L, M, Rcand Rdare as defined in A, B, D, E, G, J, L, M, Rcand Rdof Chemical Formula 1.

[0095] When Rxis H, CH3, NH2, F, Cl, Br, or I, the stilbene derivative represented by Chemical Formula 1 can be prepared by reacting an olefin derivative represented by Chemical Formula 4 with an organic halide derivative represented by Chemical Formula 5.

[0096] The olefin derivative represented by Chemical Formula 4 and the organic halide derivative represented by Chemical Formula 5 can be commercially available products, or can be used after being prepared via a process known in the art.

[0097] The above reaction is preferably performed using triethanolamine organic solvent in the presence of a palladium (II) acetate catalyst.

[0098] [Chemical Formula 1]

[0099]

[0100] Rx = H, CH3, NH2, F, Cl, Br, I

[0101] [Chemical Formula 4]

[0102]

[0103] [Chemical Formula 5]

[0104]

[0105] In Chemical Formula 4 and Chemical Formula 5,

[0106] Rx is hydrogen, CH3, NH2, F, Cl, Br, or I,

[0107] X is F, Cl, Br, or I, and

[0108] A, B, D, E, G, J, L, M, Rcand Rdare as defined in A, B, D, E, G, J, L, M, Rcand Rdof Chemical Formula 1.

[0109] The stilbene derivative represented by Chemical Formula 1 according to the present application can be used as a prophylactic or therapeutic agent for a cyclophilin-related disease, together with a pharmaceutically acceptable carrier.

[0110] Further, the stilbene derivative represented by Chemical Formula 1 according to the present application can be used as a comparative reference material for the efficacy of a therapeutic agent for a cyclophilin-related disease.

[0111] In the present application, the alkyl group or the alkenyl group can be linear or branched.

[0112] As used herein, the term "halogen atom" can refer to fluorine, chlorine, bromine, or iodine.

[0113] In the present application, when A, B, D, E, G, J, L, and M are connected with adjacent groups to form a fused ring, the fused ring is preferably a six-membered ring or a five-membered ring. Further, the fused ring can contain at least one heteroatom such as N, O, and S. The fused ring can be furan or thiophene.

[0114] In an embodiment of the present application, A is preferably CRaor N, B is preferably CRb, G is preferably CRe, J is preferably CRf, M is preferably CRgor N, and D, E, and L are preferably CH, but the present application is not limited thereto.

[0115] In another embodiment of the present application, Rbis preferably hydrogen or C1-C8alkyl, but the present application is not limited thereto.

[0116] In still another embodiment of the present application, Rcis preferably C1-C20alkyl, C2-C10alkoxy, phenylalkyl, nitro, C3-C10cycloalkyl, C5-C12heterocyclyl, or C1-C10alkyl ketone, but the present application is not limited thereto.

[0117] In another embodiment of the present application, Rd is preferably C2-C20alkyl; C3-C10ester; C3-C10cycloalkyl; methoxy substituted with cycloalkyl; ethoxy substituted with amine; carboxyl; C2-C20alkyl substituted with phenyl, which is unsubstituted or substituted with C1-C5alkyl, C1-C5alkoxy, carboxyl, or amine; amine; N-methylpiperazine; piperidine; morpholine; or -COOR5(R5is C1-C20alkyl, C6-C12aryl, or C3-C10cycloalkyl), but the present application is not limited thereto.

[0118] In still another embodiment of the present application, Reis preferably hydrogen, OH, C1-C20alkyl, or C1-C10alkoxy, but the present application is not limited thereto.

[0119] In another embodiment of the present application, Rgis preferably hydrogen, OH, C1-C20alkyl; C3-C10ester; C3-C10cycloalkyl; methoxy substituted with cycloalkyl; ethoxy substituted with amine; C2-C20alkyl substituted with phenyl, which is unsubstituted or substituted with C1-C5alkyl, C1-C5alkoxy, carboxyl, or amine; amine; N-methylpiperazine; piperidine; morpholine; or carboxyl, but the present application is not limited thereto.

[0120] In another embodiment of the present application, Rhis preferably hydrogen, but the present application is not limited thereto.

[0121] In the present application, alkyl can be substituted or unsubstituted alkyl such as -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH2)2CH3, -CH2(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(CH3)2, -C(CH3)3, -CH2C(CH3)3, -CH2CH(CH3)2, -CH(CH3)CH(CH3)2, -CH(CH3)C(CH3)3, -C(CH3)2CH2CH3, -C(CH3)2CH(CH3)2, -C(CH3)2C(CH3)3, -CH2CH2C(CH3)3, -CH2CH(CH3)CH(CH3)2, -CH2CH2C(CH3)2CH2CH3, -CH2CH2CH(CH3)CH2C(CH3)3, -CH2Ph, CH2CH2Ph, , , , , , , , , , , , , , , , , , , , or but the present application is not limited thereto.

[0122] In the present application, the alkyl group can be a substituted or unsubstituted alkyl group such as -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CONH2, -CH2CH2N(CH3)2, , , , , , or , but the present application is not limited thereto.

[0123] In the present application, the heterocyclic group can be , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , but the present application is not limited thereto.

[0124] In the present application, -NR3R4may be -NH2, -NHCH3, -N(CH3)2, , , , , , , or , but the present application is not limited thereto.

[0125] In the present application, -COOR5may be COOCH3, -COOCH2CH3, COO(CH2)2CH3, -COO(CH2)3CH3, COO(CH2)4CH3, COOCH(CH3)2, , , or but the present application is not limited thereto.

[0126] In the present application, -OCOR6may be , , , , or but the present application is not limited thereto.

[0127] In the present application, -NR7CYR8group can be , , , , , , or but the present application is not limited thereto.

[0128] In the present application, -NHS(O)2R9group can be , , , or but the present application is not limited thereto.

[0129] In the present application, COR10may be COC(CH3)3, but the present application is not limited thereto.

[0130] As used herein, the term "pharmaceutically acceptable carrier" can be defined as a carrier or diluent that does not abrogate the biological activity or properties of the composition.

[0131] The pharmaceutically acceptable carrier or additive can include at least one of the diluents or excipients typically used, such as stabilizers, fillers, extenders, wetting agents, disintegrants, lubricants, binders, surfactants, and the like.

[0132] The disintegrants can include agar, starch, alginic acid or its sodium salt, anhydrous dibasic calcium phosphate, and the like. The lubricants can include silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, magnesium aluminum silicate, and the like. The binders can include magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, lower substituted hydroxypropylcellulose, and the like.

[0133] In addition thereto, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycine can be used as the diluent. In some cases, the boiling salt, absorbent, colorant, flavoring agent, sweetener, and the like, which are generally known, can be used therewith.

[0134] Further, the stabilizer can include a sodium (Na)-free stabilizer, examples of which include magnesium aluminum metasilicate, magnesium aluminum silicate, magnesium aluminate, anhydrous aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, L-arginine, potassium phosphate, dipotassium hydrogen phosphate, monopotassium phosphate, ammonium chloride, aluminum chloride, and the like, which can be used alone or in combination of two or more thereof.

[0135] The pharmaceutical composition containing the stilbene derivative of Chemical Formula 1 of the present application can be administered in various ways to facilitate administration of the compound into an organism. The pharmaceutical composition containing the compound of the present application can be administered via oral administration, intrarectal administration, intravaginal administration, intranasal administration, intraocular administration, intraoral administration, sublingual administration, subcutaneous administration, intramuscular administration, intravenous administration, intrathecal administration, intradermal administration, epidural administration, and the like.

[0136] The pharmaceutical composition containing the compound of the present application can be provided in the dosage form of a tablet, a capsule, a powder, a dripping pill, a powder, a bolus, a tincture, or a cataplasm. Preferably, the tablet can be a typical tablet, a coated tablet, a dispersible tablet, a foaming tablet, or the like, or can be a multiple compressed tablet such as a double tablet, a tablet-in-tablet, a multi-layer tablet, or the like.

[0137] The preferred administration amount of the stilbene derivative or a pharmaceutically acceptable salt thereof included in the pharmaceutical composition containing the compound of the present application varies depending on the state and weight of the patient, the severity of the disease, the type of the drug, the administration route, and the duration, but can be appropriately selected by one skilled in the art.

[0138] A better understanding of the present application can be obtained through the following non-limiting examples, which are set forth to illustrate, but are not intended to limit the scope of the present application. The following examples can be suitably modified and altered within the scope of the present application.

[0139] Example 1. Preparation of a stilbene derivative in which Rx is CN

[0140] 1) Use of a solvent

[0141] One equivalent of the phenylacetonitrile derivative of Chemical Formula 2 and 1.3 equivalents of the benzaldehyde derivative of Chemical Formula 3 are refluxed with 0.2 equivalents of triphenylphosphine in a butanol solvent, followed by a Knoevenagel condensation reaction, thus producing the compound of Chemical Formula 1.

[0142] 2) Use of a microwave

[0143] One equivalent of the phenylacetonitrile derivative of Chemical Formula 2, 1.3 equivalents of the benzaldehyde derivative of Chemical Formula 3, and 0.2 equivalents of triphenylphosphine are treated using a microwave, thus producing the compound of Chemical Formula 1. When a microwave is used, the reaction time can be shortened and the yield can be increased.

[0144] [Scheme 1]

[0145]

[0146] Rx= CN

[0147] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 1]

[0148] Example 2. Preparation of derivatives in which Rx is hydrogen, CH3, NH2, F, Cl, Br, I

[0149] One equivalent of the olefin derivative of Chemical Formula 4 and 1 equivalent of the organic halide derivative of Chemical Formula 5 are refluxed with 0.01 equivalent of palladium (II) acetate in a triethanolamine solvent, followed by a Heck olefination reaction, thus producing the compound of Chemical Formula 1.

[0150] [Scheme 2]

[0151]

[0152] X = F, Cl, Br, I Rx = H, CH3, NH2, F, Cl, Br, I

[0153] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 1]

[0154] Test Example 1. Evaluation of the cis-trans isomerase inhibitory activity of stilbene derivatives

[0155] Chymotrypsin cleaves a trans-proline peptide bond. When Suc-AAPF-pNA (a peptide substrate) and chymotrypsin are mixed, the trans peptide substrate is cleaved and the cis peptide substrate remains. The remaining cis peptide substrate is converted to trans by a cis-trans isomerase, and then is cleaved again by chymotrypsin. When a cis-trans isomerase is present, chymotrypsin is able to cleave a larger amount of the trans peptide substrate within a predetermined period of time, and thus the activity of the cis-trans isomerase can be determined. The amount of the cleaved trans peptide substrate is measured using absorbance at 390 nm.

[0156] Cyclophilin has cis-trans isomerase activity and facilitates the cleavage of a trans peptide substrate by chymotrypsin. When the stilbene derivative of the present application is treated together with cyclophilin, no acceleration of the cleavage of the peptide substrate by chymotrypsin is observed. Thus, it can be concluded that the stilbene derivative of the present application inhibits the activity of cyclophilin.

[0157] The compounds 1 to 155 (Tables 1 to 10) can be grouped as follows based on cis-trans isomerase inhibitory activity (IC 50 ) values:

[0158] Group A (G A ): IC 50 ,

[0159] Group B (G B ): IC 50 , and

[0160] Group C (G C ): IC 50 .

[0161] [Table 1]

[0162]

[0163] [Table 2]

[0164]

[0165] [Table 3]

[0166]

[0167] [Table 4]

[0168]

[0169] [Table 5]

[0170]

[0171] [Table 6]

[0172]

[0173] [Table 7]

[0174]

[0175] [Table 8]

[0176]

[0177] [Table 9]

[0178]

[0179] [Table 10]

[0180]

[0181] Test Example 2. Evaluation of the cytotoxicity of stilbene derivatives

[0182] The cytotoxicity of the stilbene derivative was measured. Replicant cells stably replicating the hepatitis C virus genome were plated into 96-well plates and cultured in a CO2 incubator at 37°C for 24 hours. After one day of culture, the replicant cells were washed with phosphate-buffered saline (PBS), treated with the compound of the present invention, and then cultured for 72 hours. Subsequently, the C6C of the compound of the present invention was measured by the MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. 50 The CC50 value of the compound of this invention is 200. M or larger. For example, compound 64 has 320. M's CC 50 Compound 65 has 284 M's CC 50 Compound 66 has 245 M's CC 50 Therefore, the compounds of Formula 1 of the present invention do not exhibit cytotoxicity.

[0183] Test Example 3. Evaluation of the antiviral activity of stilbene derivatives

[0184] The antiviral activity of stilbene derivatives against hepatitis C virus was measured. Replicant cells stably replicating the hepatitis C virus genome were plated and cultured in a CO2 incubator at 37°C for 24 hours. Replicant cells cultured for one day were washed with PBS, treated with the compound of the present invention, and then cultured for 72 hours. Replicant cells treated with the stilbene derivative were washed with cold PBS and supplemented with 20... Prepare a cell lysis solution (L) and allow cells to dissolve in ice for 20 minutes. Add 100 L of the solution. The Renilla luciferase substrate of L was used, and its luminescence was then measured to estimate the amount of hepatitis C virus genome. The amount of hepatitis C virus genome in replicon cells treated with the stilbene derivative according to the invention is shown relative to the amount of hepatitis C virus genome in replicon cells treated with dimethyl sulfoxide (DMSO).

[0185] Compounds 1 to 155 in Tables 1 to 10 can be identified as follows based on their antiviral activity (EC). 50 Value grouping:

[0186] Group D (G D ): 50 M or more but less than 5 M of EC 50 ,

[0187] Group E (G E ): 5 M or more but less than 0.5 M of EC 50 , and

[0188] Group F (G F ): 0.5 M or less of EC 50 .

[0189] Accordingly, the compound of Chemical Formula 1 of the present application exhibits an antiviral effect.

[0190] Test Example 4. Inhibition activity test on mitochondria swelling

[0191] Cyclophilin is a key protein for forming a permeability transition pore (PTP) in mitochondria. When the permeability transition pore is formed, mitochondria swell, the outer membrane thereof is thereby ruptured, and thus cell death progresses. Such a mitochondria dysfunction causes many diseases including neurodegenerative diseases, cancer, and the like. Cyclosporin is a known cyclophilin inhibitor, which can prevent the formation of the permeability transition pore to thereby inhibit mitochondria swelling.

[0192] Mitochondria swelling test was performed as follows. In particular, liver cells were disrupted using a Dounce tissue grinder. The disrupted cells were centrifuged at 700 x g for 10 min and the supernatant was transferred to a new tube. The supernatant was centrifuged at 12,000 x g for 15 min, thereby obtaining mitochondria.

[0193] When the extracted mitochondria are added with calcium, they swell, which can be observed by measuring the absorbance at 520 nm. The stilbene derivatives are effective in inhibiting mitochondria swelling due to calcium.

[0194] The activity of Compounds 1 to 155 of Tables 1 to 10 on inhibiting mitochondria swelling can be determined based on IC 50 values, and can be grouped as follows:

[0195] Group G (G G ): 500 M or more but less than 50 M of IC 50 ,

[0196] Group H (G H): 50 M or less but more than 5 IC of M 50 , and

[0197] Group I (G I ): 5 IC of M or less 50 .

[0198] The results of NMR (nuclear magnetic resonance) analysis and LCMS (liquid chromatography mass spectrometry) analysis of compounds 1 to 155 corresponding to the stilbene derivatives prepared in Example 1 and Example 2 are as follows.

[0199] Compound 1:

[0200] NMR (400MHz, CDCl3): 8.03 (d, 1H), 7.84 (s, 1H), 7.63 (d, 2H), 7.37 (m, 1H) 7.27 (m, 2H), 7.10 (m, 2H), 2.78 (s, 6H), 2.42 ppm (s, 3H)

[0201] LCMS: MH + = 263.1

[0202] Compound 2:

[0203] NMR (400MHz, DMSO-D6): 8.41 (s, 1H), 8.05 (d, 1H), 7.78 (m, 2H), 7.62 (m, 3H) 7.36 (d, 2H), 2.65 (m, 2H), 1.20 ppm (m, 3H)

[0204] LCMS: MH + = 260.1

[0205] Compound 3:

[0206] NMR (400MHz, CDCl3): 8.03 (d, 1H), 7.85 (s, 1H), 7.66 (d, 2H), 7.38 (m, 1H) 7.28 (m, 2H), 7.12 (m, 2H), 2.78 (s, 6H), 2.70 (m, 2H), 1.28 ppm (m, 3H)

[0207] LCMS: MNa + = 300.1

[0208] Compound 4:

[0209] NMR (400MHz, CDCl3): 8.11 (m, 1H), 7.87 (s, 1H), 7.65 (d, 2H), 7.47(d, 1H) 7.39 (m, 2H), 7.27 (s, 2H), 2.98 (m, 1H), 1.29 ppm (d, 6H)

[0210] LCMS: MH + = 282.0

[0211] Compound 5:

[0212] NMR (400MHz, CDCl3): 8.33 (s, 1H), 8.24 (m, 1H), 7.91 (d, 1H), 7.72(m, 1H) 7.67 (d, 2H), 7.56 (m, 1H), 7.33 (d, 2H), 2.98 (m, 1H), 1.29 ppm (d,6H)

[0213] LCMS: MNa + = 314.1

[0214] Compound 6:

[0215] NMR (400MHz, CDCl3): 8.13 (d, 1H), 7.93 (s, 1H), 7.63 (m, 2H), 7.41(m, 1H) 7.31 (m, 2H), 7.27 (m, 1H), 6.94 (d, 1H), 3.89 (s, 3H), 2.97 (m, 1H),1.28 ppm (d, 6H)

[0216] LCMS: MH + = 278.1

[0217] Compound 7:

[0218] NMR (400MHz, CDCl3): 8.31 (m, 2H), 8.10 (m, 2H), 7.91 (d, 2H), 7.44(m, 1H) 7.14 (m, 2H), 2.80 ppm (s, 6H)

[0219] LCMS: MH+ = 294.1

[0220] Compound 8:

[0221] NMR (400MHz, DMSO-D6): 8.41 (s, 1H), 8.04 (m, 1H), 7.76 (m, 2H), 7.62 (m, 3H) 7.35 (d, 2H), 2.63 (m, 2H), 1.58 (m, 2H), 1.32 (m, 2H), 0.92 ppm (m, 3H)

[0222] LCMS: MH + = 304.1

[0223] Compound 9:

[0224] NMR (400MHz, CDCl3): 8.33 (s, 1H), 8.23 (d, 1H), 7.92 (d, 1H), 7.73 (m, 1H) 7.67 (d, 2H), 7.56 (m, 1H), 7.28 (m, 2H), 2.67 (m, 1H), 1.66 (m, 2H), 1.28 (d, 3H), 0.860 ppm (m, 3H)

[0225] LCMS: MNa + = 288.1

[0226] Compound 10:

[0227] NMR (400MHz, CDCl3): 8.34 (s, 1H), 8.23 (m, 1H), 7.92 (d, 1H), 7.73 (d, 1H) 7.68 (d, 2H), 7.49 (m, 1H), 7.27 (s, 2H), 1.37 ppm (s, 9H)

[0228] LCMS: MNa + = 328.3

[0229] Compound 11:

[0230] NMR (400MHz, CDCl3): 8.15 (d, 1H), 7.95 (s, 1H), 7.64 (d, 2H), 7.46 (d, 2H) 7.27 (s, 1H), 7.07 (m, 1H), 6.94 (d, 1H), 3.89 (s, 3H), 1.36 ppm (s, 9H)

[0231] LCMS: MH + = 292.2

[0232] Compound 12:

[0233] NMR (300MHz, CDCl3): 7.83 (d, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 7.31 (d, 1H) 7.16 (m, 2H), 7.08 (d, 2H), 3.70 (s, 3H), 2.30 ppm (d, 6H)

[0234] LCMS: MH + = 264.1

[0235] Compound 13:

[0236] NMR (300MHz, CDCl3): 7.85 (d, 1H), 7.49 (m, 1H), 7.37 (m, 1H), 7.28 (d, 1H) 7.15 (m, 2H), 7.02 (d, 2H), 2.28 ppm (d, 6H)

[0237] LCMS: MNa + = 299.1

[0238] Compound 14:

[0239] NMR (300MHz, CDCl3): 7.58 (d, 2H), 7.55 (d, 1H), 7.36 (m, 1H), 7.32 (d, 1H) 7.01 (m, 2H), 6.91 (d, 2H), 3.89 (s, 3H), 1.38 ppm (s, 9H)

[0240] LCMS: MH + = 320.2

[0241] Compound 15:

[0242] NMR (300 MHz, CDC13): 7.75 (d, IH), 7.72 (m, 2H), 7.65 (d, 2H), 7.61 (d, IH) 7.43 (d, 2H), 7.39 (s, IH), 1.37 ppm (s, 9H)

[0243] LCMS: MNa + = 355.1

[0244] Compound 16:

[0245] NMR (300 MHz, CDC13): 7.83 (d, IH), 7.80 (s, IH), 7.75 (d, 2H), 7.60 (m, IH) 7.25 (d, IH), 7.19 (m, IH), 7.08 (d, 2H), 4.12 (m, 2H), 3.89 (s, 3H), 1.42 ppm (m, 3H)

[0246] LCMS: MH + = 280.1

[0247] Compound 17:

[0248] NMR (300 MHz, CDC13): 7.94 (d, IH), 7.90 (s, IH), 7.83 (d, 2H), 7.65 (m, IH) 7.30 (d, IH), 7.22 (m, IH), 7.14 (d, 2H) 4.17 (m, 2H), 1.43 ppm (m, 3H)

[0249] LCMS: MNa + = 315.1

[0250] Compound 18:

[0251] NMR (300 MHz, CDC13): 7.82 (d, IH), 7.67 (s, IH), 7.55 (m, IH), 7.50 (d, 2H) 7.17 (m, 2H), 6.97 (m, 2H), 3.92 (m, 2H), 3.63 (s, 3H), 1.77 (m, 2H), 1.50 (m, 2H), 0.99 ppm (m, 3H)

[0252] LCMS: MH + = 308.2

[0253] Compound 19:

[0254] NMR (300MHz, CDCl3): 7.90 (d, 1H), 7.79 (s, 1H), 7.60 (m, 1H), 7.53 (d, 2H) 7.24 (m, 2H), 7.04 (m, 2H), 4.02 (m, 2H), 1.83 (m, 2H0, 1.57 (m, 2H), 1.01 ppm (m, 3H)

[0255] LCMS: MNa + = 343.1

[0256] Compound 20:

[0257] NMR (300MHz, CDCl3): 7.84 (d, 1H), 7.81 (s, 1H), 7.75 (m, 3H), 7.59 (m, 1H) 7.26 (m, 3H), 7.20 (m, 4H), 7.09 (m, 1H), 4.04 (s, 2H), 3.89 ppm (s, 3H)

[0258] LCMS: MH + = 326.2

[0259] Compound 21:

[0260] NMR (300MHz, CDCl3): 7.86 (d, 1H), 7.82 (s, 1H), 7.78 (m, 3H), 7.59 (m, 1H) 7.28 (m, 3H), 7.23 (m, 4H), 7.11 (m, 1H), 4.09 ppm (s, 2H)

[0261] LCMS: MNa + = 361.1

[0262] Compound 22:

[0263] NMR (300MHz, CDCl3): 8.23 (d, 2H), 8.15 (s, 1H), 7.83 (d, 2H), 7.67 (m, 1H) 7.53 (m, 2H), 7.38 (m, 1H), 2.76 (m, 2H), 1.23 ppm (m, 3H)

[0264] LCMS: MH += 279.1

[0265] Compound 23:

[0266] NMR (300MHz, CDCl3): 8.22 (d, 2H), 8.16 (s, 1H), 7.84 (d, 2H), 7.66 (m, 1H) 7.53 (m, 2H), 7.37 (m, 1H), 2.96 (m, 1H), 1.24 ppm (d, 6H)

[0267] LCMS: MH + = 293.1

[0268] Compound 24:

[0269] NMR (300MHz, CDCl3): 8.30 (d, 1H), 7.57 (d, 1H), 7.50 (s, 1H), 7.35 (m, 2H) 6.78 (m, 2H), 6.69 (m, 2H), 6.15 ppm (s, 2H)

[0270] LCMS: MH + = 266.1

[0271] Compound 25:

[0272] NMR (300MHz, CDCl3): 8.36 (d, 2H), 8.16 (d, 1H), 8.13 (s, 1H), 7.91 (d, 2H) 7.52 (m, 1H), 7.25 (d, 1H), 7.19 (d, 1H), 3.07 (m, 4H), 2.62 (broads, 4H), 2.41 ppm (s, 3H)

[0273] LCMS: MH + = 349.2

[0274] Compound 26:

[0275] NMR (300MHz, CDCl3): 8.29 (d, 2H), 8.23 (m, 2H), 7.84 (d, 2H), 7.48 (m, 1H) 7.07 (m, 1H), 7.00 (m, 1H), 4.50 (m, 1H), 1.86 (m, 2H), 1.39 (d, 3H), 1.07 ppm (m, 3H)

[0276] LCMS: MH + = 323.1

[0277] Compound 27:

[0278] NMR (300MHz, CDCl3): 8.38 (d, 2H), 8.28 (m, 1H), 8.24 (s, 1H), 7.88 (d, 2H) 7.64 (m, 1H), 6.84 (m, 1H), 6.69 (d, 1H), 3.93 (d, 2H), 0.92 (m, 1H), 0.72 (m, 2H), 0.42 ppm (m, 2H)

[0279] LCMS: MH + = 339.1

[0280] Compound 28:

[0281] NMR (300MHz, CDCl3): 8.34 (d, 2H), 8.26 (d, 1H), 8.20 (s, 1H), 7.88 (d, 2H) 7.50 (m, 1H), 7.13 (m, 1H), 7.03 (d, 1H), 4.15 (m, 2H), 2.53 (m, 2H), 2.31 ppm (s, 6H)

[0282] LCMS: MH + = 338.1

[0283] Compound 29:

[0284] NMR (300MHz, CDCl3): 8.35 (d, 2H), 8.17 (d, 1H), 8.14 (s, 1H), 7.92 (d, 2H) 7.48 (m, 1H), 7.18 (m, 2H), 2.98 (m, 4H), 1.74 ppm (m, 6H)

[0285] LCMS: MH + = 334.2

[0286] Compound 30:

[0287] NMR (300 MHz, CDCl3): 8.36 (d, 2H), 8.18 (d, 1H), 8.15 (s, 1H), 7.91 (d, 2H) 7.55 (m, 1H), 7.26 (m, 1H), 7.19 (d, 1H), 3.89 (m, 4H), 3.03 ppm (m, 4H)

[0288] LCMS: MH + = 336.1

[0289] Compound 31:

[0290] NMR (300 MHz, CDCl3): 8.35 (d, 2H), 8.10 (s, 1H), 7.89 (m, 3H), 7.46 (m, 3H) 2.72 (m, 1H), 1.87 (m, 4H), 1.60 ppm (m, 6H)

[0291] LCMS: MH + = 333.2

[0292] Compound 32:

[0293] NMR (300 MHz, CDCl3): 8.34 (d, 2H), 7.88 (d, 2H), 7.68 (s, 1H), 7.56 (s, 1H) 7.46 (m, 2H), 7.08 (d, 1H), 4.10 (m, 2H), 1.92 (m, 1H), 1.88 (m, 2H), 1.02 ppm (d, 6H)

[0294] LCMS: MH + = 337.2

[0295] Compound 33:

[0296] NMR (300 MHz, CDCl3): 8.27 (d, 2H), 7.82 (d, 2H), 7.64 (s, 1H), 7.52 (s, 1H) 7.41 (m, 3H), 4.07 (m, 2H), 2.48 (m, 2H), 2.28 (d, 6H), 2.03 ppm (m, 2H)

[0297] LCMS: MH + = 352.2

[0298] Compound 34:

[0299] NMR (300MHz, CDCl3): 8.34 (d, 2H), 8.02 (d, 2H), 7.88 (d, 2H), 7.46(m, 2H) 7.36 (m, 1H), 2.65 (d, 2H), 1.86 (m, 1H), 0.96 ppm (d, 6H)

[0300] LCMS: MH + = 307.1

[0301] Compound 35:

[0302] NMR (400MHz, CDCl3): 8.36 (m, 3H), 8.05 (d, 1H), 7.94 (d, 1H), 7.87(d, 2H) 7.75 (d, 1H), 7.45 (m, 2H), 2.68 (s, 2H), 0.94 ppm (s, 9H)

[0303] LCMS: MH + = 321.2

[0304] Compound 36:

[0305] NMR (300MHz, CDCl3): 8.35 (d, 2H), 8.02 (d, 2H), 7.90 (d, 2H), 7.39(m, 3H) 2.76 (m, 2H), 1.67 (m, 1H), 1.52 (m, 2H), 0.98 ppm (d, 6H)

[0306] LCMS: MH + = 321.2

[0307] Compound 37:

[0308] NMR (400MHz, CDCl3): 8.30 (m, 3H), 7.87 (s, 1H), 7.75 (d, 2H), 7.63(m, 2H) 7.53 (m, 2H), 7.08 (d, 2H), 3.98 ppm (s, 2H)

[0309] LCMS: MH + = 409.0

[0310] Compound 38:

[0311] NMR (400MHz, CDCl3): 8.29 (m, 3H), 7.88 (s, 1H), 7.75 (d, 2H), 7.63 (m, 2H) 7.54 (m, 2H), 7.24 (m, 2H), 7.06 (d, 2H), 3.07 (m, 2H), 2.96 ppm (m, 2H)

[0312] LCMS: MH + = 355.1

[0313] Compound 39:

[0314] NMR (300MHz, CDCl3): 8.34 (d, 2H), 8.27 (d, 1H), 8.02 (d, 2H), 7.88 (d, 2H) 7.46 (m, 1H), 7.35 (m, 1H), 2.77 (m, 2H), 1.83 (m, 5H), 1.55 (m, 2H), 1.34 (m, 4H), 1.02 ppm (m, 2H)

[0315] LCMS: MH + = 361.2

[0316] Compound 40:

[0317] NMR (300MHz, CDCl3): 8.38 (d, 2H), 8.26 (d, 1H), 8.02 (d, 2H), 7.88 (d, 2H), 7.43 (m, 1H), 7.36 (m, 1H), 2.73 (m, 2H), 1.67 (m, 8H), 1.27 (m, 3H), 1.16 (m, 2H), 1.04 ppm (m, 2H)

[0318] LCMS: MH + = 375.2

[0319] Compound 41:

[0320] NMR (300MHz, CDCl3): 8.36 (d, 2H), 8.03 (d, 2H), 7.87 (d, 2H), 7.42 (m, 3H), 2.65 (d, 2H), 1.89 (m, 1H), 1.72 ppm (m, 10H)

[0321] LCMS: MH += 347.2

[0322] Compound 42:

[0323] NMR (300MHz, CDCl3): 8.33 (d, 2H), 8.02 (d, 1H), 7.79 (s, 1H), 7.70 (d, 2H) 7.47 (m, 1H), 7.40 (d, 2H), 7.30 (m, 5H), 2.7 (m, 4H), 1.99 ppm (m, 2H)

[0324] LCMS: MH + = 369.2

[0325] Compound 43:

[0326] NMR (300MHz, CDCl3): 8.37 (d, 2H), 8.03 (d, 2H), 7.88 (d, 2H), 7.46 (m, 1H) 7.35 (m, 2H), 2.72 (m, 2H), 1.49 (m, 2H), 1.00 ppm (s, 9H)

[0327] LCMS: MH + = 335.2

[0328] Compound 44: LCMS: MH + = 385.2

[0329] Compound 45: LCMS: MH + = 411.2

[0330] Compound 46: LCMS: MH + = 389.1

[0331] Compound 47: LCMS: MH + = 389.1

[0332] Compound 48: LCMS: MH + = 389.1

[0333] Compound 49: LCMS: MH + = 385.2

[0334] Compound 50: LCMS: MH + = 385.2

[0335] Compound 51: LCMS: MNa + = 420.1

[0336] Compound 52: LCMS: MH + = 369.2

[0337] Compound 53: LCMS: MH + = 370.2

[0338] Compound 54:

[0339] NMR (300MHz, CDCl3): 7.99 (d, 1H), 7.82 (s, 1H), 7.61 (d, 2H), 7.32 (m, 1H) 7.25 (m, 2H), 7.12 (m, 2H), 2.21 (s, 2H), 0.97 ppm (s, 9H)

[0340] LCMS: MH + = 320.1

[0341] Compound 55:

[0342] NMR (300MHz, CDCl3): 8.23 (d, 2H), 7.81 (d, 2H), 7.61 (s, 1H), 7.50 (s, 1H) 7.39 (m, 3H), 2.77 (m, 1H), 2.08 (m, 1H), 1.22 (s, 3H), 0.76 ppm (m, 6H)

[0343] LCMS: MH + = 320.1

[0344] Compound 56:

[0345] NMR (300MHz, CDCl3): 8.19 (d, 1H), 7.83 (s, 1H), 7.63 (d, 2H), 7.54 (m, 1H) 7.45 (m, 2H), 7.37 (m, 2H), 2.99 (m, 1H), 1.32 (m, 3H), 1.03 ppm (s, 9H)

[0346] LCMS: MH + = 334.1

[0347] Compound 57:

[0348] NMR (300 MHz, CDCl3): 8.31 (s, 1H), 8.23 (m, 1H), 7.94 (d, 1H), 7.71 (m, 1H) 7.68 (d, 2H), 7.53 (m, 1H), 7.34 (d, 2H), 2.88 (m, 2H), 1.69 (m, 2H), 0.98 ppm (s, 9H)

[0349] LCMS: MH + = 334.1

[0350] Compound 58:

[0351] NMR (300 MHz, CDCl3): 8.26 (d, 2H), 7.87 (d, 2H), 7.61 (s, 1H), 7.55 (s, 1H) 7.40 (m, 3H), 2.67 (m, 2H), 2.08 (m, 1H), 1.88 (m, 1H), 0.96 ppm (m, 9H)

[0352] LCMS: MH + = 334.1

[0353] Compound 59:

[0354] NMR (300 MHz, CDCl3): 8.35 (s, 1H), 8.24 (m, 1H), 7.91 (d, 1H), 7.73 (m, 1H) 7.66 (d, 2H), 7.57 (m, 1H), 7.38 (d, 2H), 2.65 (d, 2H), 1.77 (m, 1H), 1.71 ppm (m, 10H)

[0355] LCMS: MH + = 346.1

[0356] Compound 60:

[0357] NMR (300 MHz, CDCl3): 8.33 (s, 1H), 8.22 (m, 1H), 7.92 (d, 1H), 7.74 (m, 1H) 7.67 (d, 2H), 7.56 (m, 1H), 7.36 (d, 2H), 2.71 (s, 2H), 1.67 (m, 8H), 1.29 (m, 3H), 1.17 (m, 2H), 1.06 ppm (m, 2H)

[0358] LCMS: MH + = 360.1

[0359] Compound 61:

[0360] NMR (300MHz, CDCl3): 8.32 (s, 1H), 8.20 (m, 1H), 7.92 (d, 1H), 7.74 (m, 1H) 7.64 (d, 2H), 7.53 (m, 1H), 7.34 (d, 2H), 2.62 (s, 2H), 1.66 (m, 1H), 0.43 (m, 2H), 0.20 ppm (m, 2H)

[0361] LCMS: MH + = 304.1

[0362] Compound 62:

[0363] NMR (300MHz, CDCl3): 8.34 (s, 1H), 8.21 (m, 1H), 7.94 (d, 1H), 7.74 (m, 1H) 7.65 (d, 2H), 7.53 (m, 1H), 7.35 (d, 2H), 2.67 (s, 2H), 1.69 (m, 2H), 0.40 (m, 3H), 0.15 ppm (m, 2H)

[0364] LCMS: MH + = 318.1

[0365] Compound 63:

[0366] NMR (300MHz, CDCl3): 8.36 (s, 1H), 8.23 (m, 1H), 7.96 (d, 1H), 7.76 (m, 1H) 7.64 (d, 2H), 7.56 (m, 1H), 7.34 (d, 2H), 2.68 (s, 2H), 1.22 (d, 2H), 1.02 (s, 6H), 0.40 (m, 3H), 0.15 ppm (m, 2H)

[0367] LCMS: MH + = 360.1

[0368] Compound 64:

[0369] NMR (400MHz, CDCl3): 7.93 (d, IH), 7.74 (d, IH), 7.59 (m, IH), 7.48 (d, 2H), 7.35 (m, IH), 7.13 (d, 2H), 7.00 (d, IH), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0370] LCMS: MH + = 351.2

[0371] Compound 65:

[0372] NMR (400MHz, CDCl3): 7.93 (d, IH), 7.74 (d, IH), 7.59 (m, IH), 7.48 (d, 2H), 7.35 (m, IH), 7.13 (d, 2H), 7.00 (d, IH), 4.36 (m, 2H), 2.53 (s, 2H), 2.46 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0373] LCMS: MH + = 365.2

[0374] Compound 66:

[0375] NMR (400MHz, CDCl3): 7.93 (d, IH), 7.74 (d, IH), 7.59 (m, IH), 7.48 (d, 2H), 7.35 (m, IH), 7.13 (d, 2H), 7.00 (d, IH), 4.36 (m, 2H), 2.60 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.25 (m, 3H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0376] LCMS: MH + = 379.2

[0377] Compound 67:

[0378] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0379] LCMS: MH + = 365.2

[0380] Compound 68:

[0381] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 7.00 (d, 1H), 4.36 (m, 2H), 2.60 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.25 (m, 3H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0382] LCMS: MH + = 379.2

[0383] Compound 69:

[0384] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0385] LCMS: MH + = 365.2

[0386] Compound 70:

[0387] NMR (400MHz, CDCl3): 7.92 (m, 1H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0388] LCMS: MH + = 379.2

[0389] Compound 71:

[0390] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.85 (m, 2H), 1.05 (m, 3H), 0.94 ppm (s, 9H)

[0391] LCMS: MH + = 337.2

[0392] Compound 72:

[0393] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.43 (m, 4H), 0.99 (s, 9H), 0.97 ppm (m, 3H)

[0394] LCMS: MH + = 351.2

[0395] Compound 73:

[0396] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 5.33 (m, 1H), 2.54 (s, 2H), 1.42 (d, 6H), 0.96 ppm (s, 9H)

[0397] LCMS: MH + = 337.2

[0398] Compound 74:

[0399] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.03 (m, 2H), 2.41 (s, 2H), 2.03 (m, 1H), 1.53 (m, 4H), 1.48 (m, 2H), 1.43 (m, 2H), 1.27 (m, 2H), 0.94 ppm (s, 9H)

[0400] LCMS: MH + = 391.2

[0401] Compound 75:

[0402] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.46 (m, 1H), 4.21 (m, 1H), 3.33 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.41 (s, 2H), 1.55 (m, 1H), 1.48 (m, 2H), 1.45 (m, 1H), 0.94 ppm (s, 9H)

[0403] LCMS: MH + = 392.2

[0404] Compound 76:

[0405] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.47 (m, 4H), 7.38 (m, 4H), 7.13 (d, 2H), 7.00 (d, 1H), 5.26 (m, 2H), 2.53 (s, 2H), 0.98 ppm (s, 9H)

[0406] LCMS: MH + = 385.2

[0407] Compound 77:

[0408] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.91 (m, 1H), 2.53 (s, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.48 (m, 2H), 1.43 (m, 2H), 0.94 ppm (s, 9H)

[0409] LCMS: MH + = 377.2

[0410] Compound 78:

[0411] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.63 (m, 1H), 2.38 (m, 1H), 2.04 (m, 1H), 1.80 (m, 2H), 1.55 (m, 2H), 1.45 (m, 2H), 0.96 (m, 3H), 0.90 ppm (m, 6H)

[0412] LCMS: MH + = 351.2

[0413] Compound 79:

[0414] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.54 (m, 2H), 1.89 (m, 1H), 1.80 (m, 2H), 1.60 (m, 2H), 1.56 (m, 2H), 1.46 (m, 4H), 1.35 (m, 2H), 0.90 ppm (m, 3H)

[0415] LCMS: MH + = 363.2

[0416] Compound 80:

[0417] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.29 (m, 2H), 1.81 (m, 1H), 1.53 (m, 4H), 1.48 (m, 2H), 1.44 (m, 2H), 1.27 (m, 2H), 0.90 ppm (m, 3H)

[0418] LCMS: MH + = 377.2

[0419] Compound 81:

[0420] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 3H), 7.23 (m, 3H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.90 ppm (m, 3H)

[0421] LCMS: MH + = 371.2

[0422] Compound 82:

[0423] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0424] LCMS: MH + = 365.2

[0425] Compound 83:

[0426] NMR (400MHz, CDCl3): 7.92 (m, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.48 (s, 3H), 2.42 (m, 5H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0427] LCMS: MH + = 379.2

[0428] Compound 84:

[0429] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.50 (m, 1H), 7.46 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 7.00 (d, 1H), 4.36 (m, 2H), 2.48 (s, 3H), 2.42 (m, 5H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0430] LCMS: MH + = 379.2

[0431] Compound 85:

[0432] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 2.34 (s, 3H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0433] LCMS: MH + = 379.2

[0434] Compound 86:

[0435] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 2.34 (s, 3H), 2.22 (s, 3H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0436] LCMS: MH + = 393.2

[0437] Compound 87:

[0438] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 1.91 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0439] LCMS: MH + = 351.2

[0440] Compound 88:

[0441] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 1.80 (m, 2H), 1.39 (m, 2H), 1.31 (m, 2H), 0.94 (s, 9H), 0.90 ppm (m, 3H)

[0442] LCMS: MH + = 379.2

[0443] Compound 89:

[0444] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 5.33 (m, 1H), 2.54 (s, 2H), 2.42 (m, 3H), 1.42 (d, 6H), 0.96 ppm (s, 9H)

[0445] LCMS: MH + = 351.2

[0446] Compound 90:

[0447] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 5H), 2.03 (m, 1H), 1.53 (m, 4H), 1.43 (m, 2H), 1.27 (m, 2H), 1.48 (m, 2H), 0.94 ppm (s, 9H)

[0448] LCMS: MH + = 405.2

[0449] Compound 91:

[0450] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 3.33 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.42 (m, 5H), 1.55 (m, 1H), 1.48 (m, 2H), 1.45 (m, 1H), 0.94 ppm (s, 9H)

[0451] LCMS: MH + = 406.3

[0452] Compound 92:

[0453] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (m, 4H) 7.36 (m, 4H), 7.13 (d, 2H), 7.00 (d, 1H), 5.26 (m, 2H), 2.53 (s, 2H), 0.98 ppm (s, 9H)

[0454] LCMS: MH + = 399.2

[0455] Compound 93:

[0456] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.91 (m, 1H), 2.42 (s, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.48 (m, 2H), 1.43 (m, 2H), 0.94 ppm (s, 9H)

[0457] LCMS: MH + = 391.3

[0458] Compound 94:

[0459] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.63 (m, 1H), 2.42 (m, 3H), 2.38 (m, 1H), 2.04 (m, 1H), 1.80 (m, 2H), 1.55 (m, 2H), 1.45 (m, 2H), 0.96 (m, 3H), 0.90 ppm (m, 6H)

[0460] LCMS: MH + = 365.2

[0461] Compound 95:

[0462] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.54 (m, 2H), 2.42 (m, 3H), 1.89 (m, 1H), 1.80 (m, 2H), 1.60 (m, 2H), 1.56 (m, 2H), 1.46 (m, 4H), 1.35 (m, 2H), 0.90 ppm (m, 3H)

[0463] LCMS: MH + = 377.2

[0464] Compound 96:

[0465] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.42 (m, 3H), 1.81 (m, 3H), 1.53 (m, 4H), 1.48 (m, 2H), 1.44 (m, 4H), 0.90 ppm (m, 3H)

[0466] LCMS: MH + = 391.2

[0467] Compound 97:

[0468] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.48 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.92 ppm (m, 3H)

[0469] LCMS: MH + = 385.2

[0470] Compound 98:

[0471] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0472] LCMS: MH + = 366.2

[0473] Compound 99:

[0474] NMR (400MHz, CDCl3): 7.94 (m, 1H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.48 (s, 3H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0475] LCMS: MH + = 380.2

[0476] Compound 100:

[0477] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.48 (m, 1H), 7.36 (m, 1H), 7.17 (m, 1H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.48 (s, 3H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0478] LCMS: MH + = 380.3

[0479] Compound 101:

[0480] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0481] LCMS: MH + = 380.3

[0482] Compound 102:

[0483] NMR (400MHz, CDCl3): 7.96 (m, 1H), 7.63 (m, 1H), 7.49 (d, 2H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0484] LCMS: MH + = 394.3

[0485] Compound 103:

[0486] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.02 (s, 2H), 1.79 (m, 2H), 1.50 (m, 4H), 0.98 (s, 9H), 0.96 ppm (m, 3H)

[0487] LCMS: MH + = 380.3

[0488] Compound 104:

[0489] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 5.33 (m, 1H), 2.54 (s, 2H), 2.02 (s, 2H), 1.43 (d, 6H), 0.96 ppm (s, 9H)

[0490] LCMS: MH + = 352.2

[0491] Compound 105:

[0492] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.03 (m, 2H), 2.53 (s, 2H), 2.02 (m, 3H), 1.52 (m, 4H), 1.48 (m, 2H), 1.43 (m, 2H), 1.27 ppm (m, 2H)

[0493] LCMS: MH + = 406.3

[0494] Compound 106:

[0495] NMR (400MHz, CDC13): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 5.26 (m, 2H), 2.53 (s, 2H), 2.02 (s, 2H), 0.98 ppm (s, 9H)

[0496] LCMS: MH + = 400.2

[0497] Compound 107:

[0498] NMR (400MHz, CDC13): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 3.91 (m, 1H), 2.53 (s, 2H), 2.02 (s, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.48 (m, 2H), 1.43 (m, 1H), 0.98 ppm (s, 9H)

[0499] LCMS: MH + = 392.3

[0500] Compound 108:

[0501] NMR (400MHz, CDC13): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.63 (m, 1H), 2.38 (m, 1H), 2.02 (m, 3H), 1.79 (m, 2H), 1.55 (m, 2H), 1.51 (m, 2H), 0.96 (m, 3H), 0.92 ppm (m, 6H)

[0502] LCMS: MH + = 366.2

[0503] Compound 109:

[0504] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (d, 2H), 2.02 (s, 2H), 1.89 (m, 1H), 1.79 (m, 2H), 1.57 (m, 4H), 1.51 (m, 2H), 1.40 (m, 4H), 0.99 ppm (m, 3H)

[0505] LCMS: MH + = 378.2

[0506] Compound 110:

[0507] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 2.53 (d, 2H), 2.02 (s, 2H), 1.80 (m, 3H), 1.51 (m, 6H), 1.48 (m, 2H), 1.43 (m, 2H), 0.98 ppm (m, 3H)

[0508] LCMS: MH + = 392.3

[0509] Compound 111:

[0510] NMR (400MHz, CDCl3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (d, 2H), 7.36 (m, 3H), 7.23 (m, 3H), 7.17 (d, 2H), 6.84 (m, 1H), 4.36 (m, 2H), 3.96 (s, 2H), 2.02 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.98 ppm (m, 3H)

[0511] LCMS: MH + = 386.2

[0512] Compound 112:

[0513] NMR (400MHz, CDCl3): 7.97 (m, 2H), 7.62 (m, 1H), 7.48 (d, 2H), 7.36 (m, 1H), 7.17 (d, 2H), 6.90 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0514] LCMS: MH + = 369.2

[0515] Compound 113:

[0516] NMR (400MHz, CDCl3): 7.92 (m, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.48 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0517] LCMS: MH + = 399.2

[0518] Compound 114:

[0519] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.50 (m, 1H), 7.46 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.48 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0520] LCMS: MH + = 443.2

[0521] Compound 115:

[0522] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0523] LCMS: MH + = 491.1

[0524] Compound 116:

[0525] NMR (400MHz, CDCl3): 7.94 (m, 1H), 7.62 (m, 1H), 7.48 (d, 2H), 7.17 (d, 2H), 6.90 (m, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0526] LCMS: MH + = 397.3

[0527] Compound 117:

[0528] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.54 (s, 2H), 1.79 (m, 2H), 1.48 (m, 4H), 0.98 (s, 9H), 0.96 ppm (m, 3H)

[0529] LCMS: MH + = 399.2

[0530] Compound 118:

[0531] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 5.33 (m, 1H), 2.53 (s, 2H), 1.42 (d, 6H), 0.96 ppm (s, 9H)

[0532] LCMS: MH + = 415.1

[0533] Compound 119:

[0534] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.03 (m, 2H), 2.41 (s, 2H), 2.03 (m, 1H), 1.53 (m, 4H), 1.48 (m, 2H), 1.43 (m, 2H), 1.27 (m, 2H), 0.94 ppm (s, 9H)

[0535] LCMS: MH + = 517.2

[0536] Compound 120:

[0537] NMR (400MHz, CDCl3): 7.97 (m, 2H), 7.62 (m, 1H), 7.47 (m, 4H), 7.37 (m, 4H), 7.17 (d, 2H), 6.90 (m, 1H), 5.26 (m, 2H), 2.42 (s, 2H), 0.94 ppm (s, 9H)

[0538] LCMS: MH + = 403.2

[0539] Compound 121:

[0540] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.91 (m, 1H), 2.53 (s, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.49 (m, 4H), 1.43 (m, 3H), 0.96 ppm (s, 9H)

[0541] LCMS: MH + = 411.2

[0542] Compound 122:

[0543] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.63 (m, 1H), 2.38 (m, 1H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.96 ppm (m, 6H)

[0544] LCMS: MH + = 429.1

[0545] Compound 123:

[0546] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.59 (m, 1H), 7.48 (d, 2H), 7.34 (m, 3H), 7.24 (m, 3H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 3.96 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.98 ppm (m, 3H)

[0547] LCMS: MH + = 497.1

[0548] Compound 124:

[0549] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.95 (s, 3H), 2.63 (m, 1H), 2.38 (m, 1H), 1.65 (m, 1H), 1.21 (m, 2H), 0.94 (m, 3H), 0.87 ppm (d, 3H)

[0550] LCMS: MH + = 309.2

[0551] Compound 125:

[0552] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.95 (s, 3H), 2.63 (m, 1H), 2.38 (m, 1H), 1.65 (m, 1H), 1.21 (m, 2H), 0.94 (m, 3H), 0.87 ppm (d, 3H)

[0553] LCMS: MH + = 309.2

[0554] Compound 126:

[0555] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.95 (s, 3H), 2.63 (m, 2H), 2.11 (m, 1H), 1.65 ppm (m, 6H)

[0556] LCMS: MH + = 321.2

[0557] Compound 127:

[0558] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.92 (s, 3H), 2.48 (d, 2H), 2.14 (m, 1H), 1.24 ppm (m, 10H)

[0559] LCMS: MH + = 335.2

[0560] Compound 128:

[0561] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.34 (m, 3H), 7.25 (m, 3H), 7.13 (d, 2H), 7.00 (d, 1H), 3.92 (s, 3H), 3.89 ppm (s, 2H)

[0562] LCMS: MH + = 329.2

[0563] Compound 129:

[0564] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.93 (s, 3H), 2.48 (d, 2H), 1.88 (m, 1H), 0.91 ppm (d, 6H)

[0565] LCMS: MH + = 295.2

[0566] Compound 130:

[0567] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 3.92 (s, 3H), 2.60 (m, 2H), 1.62 (m, 2H), 1.33 (m, 4H), 0.90 ppm (m, 3H)

[0568] LCMS: MH + = 309.2

[0569] Compound 131:

[0570] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.35 (m, 2H), 2.49 (d, 2H), 1.91 (m, 1H), 1.78 (m, 2H), 1.50 (m, 2H), 0.95 (m, 3H), 0.91 ppm (d, 6H)

[0571] LCMS: MH + = 337.2

[0572] Compound 132:

[0573] NMR (400MHz, CDC13): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H) 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.37 (m, 2H), 2.64 (m, 2H), 1.85 (m, 2H), 1.68 (m, 2H), 1.53 (m, 2H), 1.37 (m, 4H), 098 (m, 3H), 0.92 ppm (m, 3H)

[0574] LCMS: MH + = 351.2

[0575] Compound 133:

[0576] NMR (400MHz, CDCl3): 8.07 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 6.84 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0577] LCMS: MH + = 364.2

[0578] Compound 134:

[0579] NMR (400MHz, CDCl3): 8.07 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 6.84 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0580] LCMS: MH + = 295.2

[0581] Compound 135:

[0582] NMR (400MHz, CDCl3): 8.07 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 6.84 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0583] LCMS: MH + = 311.2

[0584] Compound 136:

[0585] NMR (400MHz, CDCl3): 8.07 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 6.84 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0586] LCMS: MH + = 311.2

[0587] Compound 137:

[0588] NMR (400MHz, CDCl3): 8.06 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.41 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0589] LCMS: MH + = 310.2

[0590] Compound 138:

[0591] NMR (400MHz, CDCl3): 8.06 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.41 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0592] LCMS: MH + = 310.2

[0593] Compound 139:

[0594] NMR (400MHz, CDCl3): 8.07 (d, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.52 (d, 2H), 7.21 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 2.54 (s, 2H), 2.48 (s, 3H), 0.96 ppm (s, 9H)

[0595] LCMS: MH + = 309.2

[0596] Compound 140:

[0597] NMR (400MHz, CDCl3): 8.04 (m, 2H), 7.78 (d, 1H), 7.55 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 2.54 (s, 2H), 2.34 (s, 3H), 0.96 ppm (s, 9H)

[0598] LCMS: MH + = 309.2

[0599] Compound 141:

[0600] NMR (400MHz, CDCl3): 7.72 (d, 1H), 7.59 (m, 2H), 7.47 (m, 1H), 7.46 (d, 2H), 7.32 (m, 1H), 7.13 (d, 2H), 7.07 (d, 1H), 6.60 (s, 1H), 6.10 (s, 1H), 2.53 (s, 2H), 0.95 ppm (s, 9H)

[0601] LCMS: MH + = 294.2

[0602] Compound 142:

[0603] NMR (400MHz, CDCl3): 8.34 (s, 1H), 8.17 (m, 1H), 8.04 (m, 2H), 7.74 (m, 3H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0604] LCMS: MH + = 401.2

[0605] Compound 143:

[0606] NMR (400MHz, CDCl3): 8.37 (s, 1H), 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (m, 1H), 7.35 (m, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0607] LCMS: MH + = 352.2

[0608] Compound 144:

[0609] NMR (400MHz, CDCl3): 8.39 (s, 1H), 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0610] LCMS: MH + = 352.2

[0611] Compound 145:

[0612] NMR (400MHz, CDCl3): 8.61 (m, 1H), 7.92 (m, 1H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0613] LCMS: MH + = 352.2

[0614] Compound 146:

[0615] NMR (400MHz, CDCl3): 9.17 (s, 1H), 8.27 (m, 1H), 7.94 (m, 1H), 7.74 (d, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0616] LCMS: MH + = 352.2

[0617] Compound 147:

[0618] NMR (400MHz, CDCl3): 8.90 (s, 1H), 8.00 (m, 1H), 7.94 (d, 1H), 7.74 (d, 1H), 7.48 (d, 2H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0619] LCMS: MH + = 352.2

[0620] Compound 148:

[0621] NMR (400MHz, CDCl3): 8.76 (m, 1H), 7.94 (m, 1H), 7.74 (d, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 2H), 2.53 (s, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H)

[0622] LCMS: MH + = 352.2

[0623] Compound 149:

[0624] NMR (400MHz, CDCl3): 7.94 (m, 2H), 7.74 (d, 1H), 7.59 (m, 1H), 7.48 (d, 2H), 7.35 (m, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 4.36 (m, 4H), 2.53 (s, 2H), 1.79 (m, 4H), 1.51 (m, 4H), 0.99 (m, 6H), 0.98 ppm (s, 9H)

[0625] LCMS: MH + = 451.3

[0626] Compound 150:

[0627] NMR (400MHz, CDCl3): 8.15 (d, IH), 7.78 (d, IH), 7.52 (d, 2H), 7.31 (m, IH), 7.17 (d, 2H), 7.06 (d, IH), 7.12 (m, IH), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0628] LCMS: MH + = 311.2

[0629] Compound 151:

[0630] NMR (400MHz, CDCl3): 8.15 (d, IH), 7.78 (d, IH), 7.52 (d, 2H), 7.41 (m, IH), 7.32 (m, IH), 7.17 (d, 2H), 7.06 (d, IH), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0631] LCMS: MH + = 310.2

[0632] Compound 152:

[0633] NMR (400MHz, CDCl3): 8.15 (d, IH), 7.78 (d, IH), 7.52 (d, 2H), 7.49 (m, IH), 7.29 (m, IH), 7.17 (d, 2H), 7.06 (d, IH), 2.54 (s, 2H), 2.48 (s, 3H), 0.96 ppm (s, 9H)

[0634] LCMS: MH + = 309.2

[0635] Compound 153:

[0636] NMR (400MHz, CDCl3): 8.09 (m, 2H), 7.78 (d, IH), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, IH), 6.81 (m, IH), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0637] LCMS: MH + = 311.2

[0638] Compound 154:

[0639] NMR (400MHz, CDCl3): 8.10 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.14 (m, 1H), 7.06 (d, 1H), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H)

[0640] LCMS: MH + = 310.2

[0641] Compound 155:

[0642] NMR (400MHz, CDCl3): 8.10 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.21 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 2.54 (s, 2H), 2.34 (s, 3H), 0.96 ppm (s, 9H)

[0643] LCMS: MH + = 309.2

[0644] Industrial applicability

[0645] The novel stilbene derivatives of the present application can be used as functional inhibitors of cyclophilins with improved pharmaceutical profiles.

Claims

1. A stilbene derivative represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In chemical formula 1, A is CRa. B is CRb. G stands for CRe. J is CRf, M is CRg. D and E are CH. L is CRh Rx is H, Ra is hydrogen or a C1-C5 alkyl group. Rb is hydrogen. Rc is CH2C(CH3)3. Rd is either COOH or -COOR5, where R5 is a C1-C20 alkyl group. Re is hydrogen, NH2, OH, or a C1-C20 alkyl group. Rf is hydrogen, NH2, OH, or a C1-C4 alkyl group. Rg is hydrogen, NH2, OH, C1-C20 alkyl, or -COORz, wherein Rz is a C1-C20 alkyl, and Rh is hydrogen, NH2, OH, or a C1-C5 alkyl group.

2. Stilbene derivatives represented by the following chemical formula 1, or pharmaceutically acceptable salts thereof, [Chemical Formula 1] The stilbene derivative is selected from any one of the following groups: 64-67, 124, 134-140, 142, and 149-155.

3. A pharmaceutical composition comprising the stilbene derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. Use of the pharmaceutical composition of claim 3 in the preparation of a medicament for inhibiting the function of cyclic proteins.

5. Use of the pharmaceutical composition of claim 3 in the preparation of a medicament for preventing or treating symptoms of cyclophilin-related diseases, wherein the cyclophilin-related diseases are selected from the group consisting of HBV, HCV, HIV, influenza; cardiovascular disease; rheumatoid arthritis; sepsis; asthma; periodontitis; aging; alopecia; neurodegenerative diseases; and cancer.

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