Stilbene derivative and preparation method thereof

Abstract

This invention relates to a stilbene derivative and a method of preparing the same, and more particularly to a novel stilbene derivative for inhibiting the function of cyclophilin, which is effective at the prevention of cyclophilin-related diseases or at the treatment of symptoms of such diseases, and to a method of preparing the same.

Description

[Title of Invention] STILBENE DERIVATIVE AND PREPARATION METHOD THEREOF [Technical Field]

[0001] The present invention relates to a novel stilbene derivative for inhibiting the function of cyclophilin, which has an improved pharmaceutical profile, and to a method of preparing the same. [Background of the Invention]

[0002] Cyclophilin is known to be an effective drug target for many diseases, including viral infection diseases such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza virus, etc.; 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] Cyclophilin (CyP), which is a protein belonging to the immunophilin family, is found in all cells of all organisms, both prokaryotes and eukaryotes, and has been structurally well preserved throughout evolution. A human contains a total of 16 intrinsic proteins present therein, including seven main CyPs, namely CyP A, CyP B, CyP C, CyP D, CyP E, CyP 40, and CyP NK.

[0004] Cyclophilin is found in most cells in the human body, and CyP A and CyP 40 in mammals have cytoplasmic signal sequences, whereas CyP B and CyP C have Nterminal signal sequences that target to the endoplasmic reticulum. CyP D has a signal sequence that directs to mitochondria, CyP E has an amino-terminal RNA binding domain and is located in the nucleus, and CyP 40 has a TPR and is located in the cytoplasm. Human CyP NK is the largest CyP, with a large hydrophilic and positively charged carboxyl end, and is located in the cytoplasm.

[0005] Cyclophilin is a multifunctional protein involved in cellular processes and is responsible for essential functions in cells. Cyclophilin has been proven to have enzymatic properties of catalyzing cis-trans isomerization of peptidyl-prolyl bonds. Thus, cyclophilin is referred to as peptidyl prolyl cis-trans isomerase (PPIase), which may act as an acceleration factor in proper folding of newly synthesized proteins. PPIase is also involved in repairing damaged proteins due to environmental stresses, including thermal stress, ultraviolet radiation, changes in the pH of the cellular environment, and oxidant treatment. This function is known as molecular chaperone 1 Date ReQue / Date Received 2024-01-11activity. The PPIase activity of cyclophilin has also been proven to be involved in intracellular protein trafficking, mitochondrial function and pre-mRNA processing.

[0006] Cyclosporine, one of available cyclophilin inhibitors, binds in the hydrophobic pocket of CyP A to thus inhibit PPIase activity. CyP A is a prototype of the cyclophilin family, and shows very high sequence homology with CyP B, CyP C, and CyP D in humans. The binding pockets of all cyclophilins are formed by approximately 109 amino acids, corresponding to highly conserved regions, and the sequence homology between CyP A and CyP D is 100%. Therefore, CyP A binding affinity is the best predictor of CyP D binding affinity and vice versa.

[0007] Such sequence homology between cyclophilins suggests that not only CyP D but also all cyclophilins are potential targets for functional inhibitors having binding affinity to CyP A, indicating that functional inhibitors of CyP A may be useful for the treatment of many diseases caused by numerous intracellular processes to which cyclophilins are related. [Summary] [0007a] Certain exemplary embodiments provide a compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, A is CRa, B is CRb, G is CRe, JisCRf, M is CRg, D, E, and L are CRh, Rx is H, Ra is hydrogen, or a C1-C5 alkyl group, Rb is hydrogen, 2 Date ReQue / Date Received 2024-01-11Rc is -CH2C(CH3)3, Rd is COOH or -COOR5, wherein R5 is a C1-C10 alkyl group or a C3-C10 cycloalkyl group, wherein the Cl-CIO alkyl group may optionally be substituted with at least one substituent each independently being amine, a C6-C12 aryl, a C5-C10 heterocyclic group in which nitrogen is included as a hetero atom, or a C3-C10 cycloalkyl group, Re is hydrogen, NH2, OH, or a Cl-CIO alkyl group, Rf is hydrogen, NH2, OH, or a C1-C4 alkyl group, Rg is hydrogen, NH2, OH, a C1-C10 alkyl group, or -COORz, wherein Rz is a C1-C10 alkyl group, and Rh is hydrogen, NH2, OH, or a C1-C5 alkyl group. [0007b] Other exemplary embodiments provide a compound represented by Chemical Formula 1 below or the pharmaceutically acceptable salt thereof: [Chemical Formula 1] wherein the compound is one or more of Compounds 64-77, 124, 134-140, 142, or 149- 155 below: Compound A=CRa, B=CRb, G=CRe, J=CRf, D 1. 1. M Cl 1 Rx Ra Rb Rc Rd Re Rf 64 H H H CH2C(CH3)3 COO(CH2)3CH3 H H 65 H H H CH2C(CH3)j COO(CH2)3CH3 CH3 H 66 H H H CH2C(CH3)3 COO(CH2)3CH3 ch2ch3 H 67 H CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H 68 H CII2CII3 H CH2C(CH3)3 COO(CH2)3CH3 H H 69 H H H CH2C(CH3)3 COO(CH2)3CH3 H Cft 70 H H H CH2C(CH3)j COO(CH2)3CH3 Clh CH3 71 H H H CH2C(CH3)3 COO(CH2)2CH3 H H 72 H H H CII2C(CII3), COO(CH2)4CH3 H H 73 H H H CH2C(CH3)3 COOCH(CH3)2 H H 74 H H H CH2C(CH3)3 *4° H H 75 H H H CH2C(CH3)3 a Hit ) H H 76 H H H CH2C(CH3)s COOCHaPh H H 3 Date ReQue / Date Received 2024-01-1177 H H H CH2C(CH3)3 H H 124 H H H CH2C(CH3)3 COOCHs H H 134 H H H CH2C(CH3)s COOH H H 135 H H H CH2C(CH3)3 COOH OH H 136 H H H CH2C(CH3)5 COOH H OH 137 H H H CH2C(CH3)3 COOH NIL H 138 H H H CH2C(CH3>! COOH H NHz 139 H H H CH2C(CH3)5 COOH CH3 H 140 H H H OLQCHib COOH H CH3 142 A CRa. B CRb, 6 CRc. I) 1: M CI 1 Rx Ra Rb Rc Rd Re Fused ring formation of J andL H H H CH2C(CH3)3 COO(CH2)3CH3 H -p A=CRa, B=CRb, G=CRe, J=CRf, M=CRg, D=E=L=CH - Rx Ra Rb Rc Rd Re Rf Rg 149 H H H CH2C(CH3)3 COO(CH2)3CH3 H H COO(CH2)3CH3 150 H H H CH2C(CH3)3 COOH H H OH 151 H H H CHzC(CH3)3 COOH H H NHz 152 H H H CII2C(CIh)3 COOH H H CH3 A=CRa, B=CRb, G=CRe, J=CRf, L=CRh, 1) E M CH - Rx Ra Rb Rc Rd Re Rf Rh 153 H H H CH2C(CH3)3 COOH H H OH 154 H H H CH2C(CH3)3 COOH H H NH2 155 H H H CH2C(CH3)3 COOH H H ch3 [0007c] Yet other exemplary embodiments provide use, to inhibit one or more activities of cyclophilin in a subject of a compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof, or of a composition comprising the compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof together with one or more excipient, carrier or diluent: [Chemical Formula 1] Date ReQue / Date Received 2024-01-11in Chemical Formula 1, A is CRa, B is CRb, G is CRe, JisCRf, M is CRg, D, E, and L are CRh, Rx is H, Ra is hydrogen, or a C1-C5 alkyl group, Rb is hydrogen, Re is -CH2C(CH3)3, Rd is COOH or -COOR5, wherein R5 is a C1-C10 alkyl group or a C3-C10 cycloalkyl group, wherein the Cl-CIO alkyl group may optionally be substituted with at least one substituent each independently being amine, a C6-C12 aryl, a C5-C10 heterocyclic group in which nitrogen is included as a hetero atom, or a C3-C10 cycloalkyl group, Re is hydrogen, NH\ OH, or a Cl-CIO alkyl group, Rf is hydrogen, NH2, OH, or a C1-C4 alkyl group, Rg is hydrogen, NH2, OH, a C1-C10 alkyl group, or -COORz, wherein Rz is a C1-C10 alkyl group, and Rh is hydrogen, NH2, OH, or a C1-C5 alkyl group. [Detailed Description of the Invention]

[0008] Accordingly, the present invention is intended to provide a compound for inhibiting the function of cyclophilin, which has an improved pharmaceutical profile so as to prevent diseases, including viral infection diseases such as HBV, HCV, HIV, influenza and the like, cardiovascular diseases, rheumatoid arthritis, sepsis, asthma, periodontitis, aging, alopecia, neurodegenerative diseases, cancer, etc. or to treat symptoms of such diseases, and also to provide a method of preparing the same.

[0009] Therefore, the present invention provides a compound that is capable of inhibiting the function of cyclophilin. The present invention provides a stilbene derivative, represented by Chemical Formula 1 below, a pharmaceutically acceptable salt, a hydrate, a hydrated salt, a polymorphic crystal structure, a racemate, a diastereoisomer, or an enantiomer thereof. It is used for the prevention of cyclophilinrelated diseases or for the treatment of symptoms of such diseases.

[0010] [Chemical Formula 1] 5 Date ReQue / Date Received 2024-01-11In Chemical Formula 1, A is CRa or N, B is CRb or N, Gis CReorN, Jis CRforN, M is CRg or N, D, E, and L are CRh or N, Rx is H, CH3, CN, NH2, F, Cl, Br or I, wherein when Rx is H, CH3, NH2, F, Cl, Br or I, Ra is hydrogen, NO2, CN, OH, a C1-C5 alkyl group, a C2-C10 alkenyl group, a C1-C2 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), Rb is hydrogen, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), Rc is OH, NO2, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C2-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6- C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5- C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-Cl2 heterocyclic group), Rd is halogen, NO2, COOH, CN, a C2-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at 6 Date ReQue / Date Received 2024-01-11least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3- C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3- C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), Re is hydrogen, NH2, OH, CN, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group) or -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), Rf is hydrogen, NH2, OH, NO2, a C1-C4 alkyl group, a C2-C10 alkenyl group, a C1-C4 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NHR11 (Rll is a C1-C2 alkyl group), -COOR12 (R12 is a C1-C2 alkyl group), -OCOR13 (R13 is a ClC2 alkyl group), or -CORM (R14 is a C1-C2 alkyl group), Rg is hydrogen, NH2, OH, halogen, NO2, COOH, CN, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl or a C6- C12 aryl, R4 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6- C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), and Rh is hydrogen, NH2, OH, a C1-C5 alkyl group or a C2-C10 alkenyl group, when Rx is CN, Ra is hydrogen, Rb is hydrogen, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), 7 Date ReQue / Date Received 2024-01-11Rc is OH, NO2, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C2-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6- C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -0C0R6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5- C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group, or a C5-C12 heterocyclic group), Rd is hydrogen, halogen, NO2, COOH, CN, a C2-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6- C12 aryl or a C5-C12 heterocyclic group), or CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), Re is hydrogen, CN, a C2-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3- C10 cycloalkyl group or a C5-C12 heterocyclic group) or -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), Rf and Rg are each hydrogen, and Rh is hydrogen, a C1-C5 alkyl group or a C2-C10 alkenyl group, the hetero atom of the heterocyclic group may be at least one selected from the group consisting of nitrogen, oxygen and sulfur, the alkyl group may be substituted with at least one substituent selected from the group consisting of OH, amine, a C6-C12 aryl, a C5-C10 heterocyclic group and a C3- C10 cycloalkyl group, 8 Date ReQue / Date Received 2024-01-11the alkoxy group may be substituted with at least one substituent selected from the group consisting of halogen, a C6-C12 aryl, a C3-C10 cycloalkyl group, amine and an aminocarbonyl group, the heterocyclic group may be substituted with at least one substituent selected from the group consisting of an alkyl group, an amine-substituted alkyl group, amine, an amide group and a carboxyl group, the aryl may be substituted with at least one substituent selected from the group consisting of halogen, an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group, A, B, D, E, G, J, L and M may be linked with an adjacent group to form a fused ring, and Rd cannot be NO2 when Rb is CH3.

[0011] According to the present invention, stilbene derivatives are effective at inhibiting the function of cyclophilin, and are thus useful for the prevention of cyclophilin-related diseases, including viral infection 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, etc., or for the treatment of symptoms of such diseases. Moreover, the stilbene derivatives of the invention can be used in combination with existing therapeutic agents to thus increase the therapeutic effects. [Description of the Specific Embodiments]

[0012] Hereinafter, a detailed description will be given of the present invention.

[0013] The present invention addresses a stilbene derivative represented by Chemical Formula 1 below. The stilbene derivative of the present invention has a structure appropriate for binding to an active pocket that is maintained in any protein having the function of cyclophilin and is thus useful as a cyclophilin inhibitor.

[0014] [Chemical Formula 1] In Chemical Formula 1, A is CRa or N, Date ReQue / Date Received 2024-01-11Bis CRborN, G is CRe or N J is CRf orN, M is CRg or N, D, E, and L are CRh or N, Rx is H, CH3, CN, NH2, F, Cl, Br or I, wherein when Rx is H, CH3, NH2, F, Cl, Br or I, Ra is hydrogen, NO2, CN, OH, a C1-C5 alkyl group, a C2-C10 alkenyl group, a C1-C2 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), Rb is hydrogen, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), Rc is OH, NO2, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C2-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6- C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -0C0R6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5- C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), Rd is halogen, NO2, COOH, CN, a C2-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3- C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3- C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), 10 Date ReQue / Date Received 2024-01-11Re is hydrogen, NH2, OH, CN, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group) or -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), Rf is hydrogen, NH2, OH, NO2, a C1-C4 alkyl group, a C2-C10 alkenyl group, a C1-C4 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NHR11 (Rll is a C1-C2 alkyl group), -COOR12 (R12 is a C1-C2 alkyl group), -OCOR13 (R13 is a ClC2 alkyl group), or -CORM (R14 is a C1-C2 alkyl group), Rg is hydrogen, NH2, OH, halogen, NO2, COOH, CN, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl or a C6- C12 aryl, R4 is hydrogen, a C1-C20 alkyl or a C6-C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6- C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), and Rh is hydrogen, NH2, OH, a C1-C5 alkyl group or a C2-C10 alkenyl group, when Rx is CN, Ra is hydrogen, Rb is hydrogen, a C1-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy group, -COORI (RI is hydrogen or a C1-C5 alkyl group) or -OCOR2 (R2 is a C1-C5 alkyl group), Re is OH, NO2, a C1-C20 alkyl group, a C3-C10 cycloalkyl group, a C2-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6- C12 aryl, and R3 and R4 may be linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5- 11 Date ReQue / Date Received 2024-01-11C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or -CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group, or a C5-C12 heterocyclic group), Rd is hydrogen, halogen, NO2, COOH, CN, a C2-C20 alkyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR3R4 (R3 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, R4 is hydrogen, a C1-C20 alkyl group or a C6-C12 aryl, and R3 and R4 are linked to form a heterocycle, further containing at least one hetero atom), -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -OCOR6 (R6 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), or CORIO (RIO is a C1-C20 alkyl group, a C6-C12 aryl, a C3-C10 cycloalkyl group or a C5-C12 heterocyclic group), Re is hydrogen, CN, a C2-C20 alkyl group, a C2-C10 alkenyl group, a C1-C10 alkoxy, a C6-C12 aryl, a C5-C12 heterocyclic group, -NR7CYR8 (Y is O or S, R7 is hydrogen or a C1-C5 alkyl group, and R8 is a C1-C20 alkyl group, a C6-C12 aryl, a C3- C10 cycloalkyl group or a C5-C12 heterocyclic group) or -NHS(O)2R9 (R9 is a C6-C12 aryl or a C5-C12 heterocyclic group), Rf and Rg are each hydrogen, and Rh is hydrogen, a C1-C5 alkyl group or a C2-C10 alkenyl group, the hetero atom of the heterocyclic group may be at least one selected from the group consisting of nitrogen, oxygen and sulfur, the alkyl group may be substituted with at least one substituent selected from the group consisting of OH, amine, a C6-C12 aryl, a C5-C10 heterocyclic group and a C3- C10 cycloalkyl group, the alkoxy group may be substituted with at least one substituent selected from the group consisting of halogen, a C6-C12 aryl, a C3-C10 cycloalkyl group, amine and an aminocarbonyl group, the heterocyclic group may be substituted with at least one substituent selected from the group consisting of an alkyl group, an amine-substituted alkyl group, amine, an amide group and a carboxyl group, the aryl may be substituted with at least one substituent selected from the group consisting of halogen, an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an ester group, a nitro group and an amine group, 12 Date ReQue / Date Received 2024-01-11A, B, D, E, G, J, L and M may be linked with an adjacent group to form a fused ring, and Rd cannot be NO2 when Rb is CH3.

[0015] The compound of the present invention may be synthesized via a variety of methods, and typically the synthesis process of the case where Rx of Chemical Formula 1 is CN may be different from those of the other cases.

[0016] When Rx is CN, the stilbene derivative represented by Chemical Formula 1 may be prepared by reacting a phenylacetonitrile derivative represented by Chemical Formula 2 below with a benzaldehyde derivative represented by Chemical Formula 3 below.

[0017] The phenylacetonitrile derivative represented by Chemical Formula 2 and the benzaldehyde derivative represented by Chemical Formula 3 may be commercially available products, or may be used after being prepared through methods known in the art.

[0018] The above reaction may be carried out in the presence of an organic solvent, or without any solvent. In this case, the reaction time may be reduced and the yield may be increased using microwaves.

[0019] The organic solvent is not limited, but preferably includes an alcohol, and more preferably butanol, methanol, ethanol, or propanol. A catalyst such as triphenylphosphine, piperidine or the like may be added to promote the reaction.

[0020] [Chemical Formula 1] Rx = CN

[0021] [Chemical Formula 2] Date ReQue / Date Received 2024-01-11

[0022] [Chemical Formula 3] In Chemical Formulas 2 and 3, A, B, D, E, G, J, L, M, Rc and Rd are as defined in A, B, D, E, G, J, L, M, Rc and Rd of Chemical Formula 1.

[0023] When Rx is H, CFG, NH2, F, Cl, Br or I, the stilbene derivative represented by Chemical Formula 1 may be prepared by reacting an olefin derivative represented by Chemical Formula 4 below with an organic halide derivative represented by Chemical Formula 5 below.

[0024] The olefin derivative represented by Chemical Formula 4 and the organic halide derivative represented by Chemical Formula 5 may be commercially available products, or may be used after being prepared through processes known in the art.

[0025] The above reaction is preferably carried out using a triethanolamine organic solvent in the presence of a palladium (II) acetate catalyst.

[0026] [Chemical Formula 1] Rx = H, CH3, NH2, F, Cl, Br, I

[0027] [Chemical Formula 4] Rx 14 Date ReQue / Date Received 2024-01-11

[0028] [Chemical Formula 5] In Chemical Formulas 4 and 5, Rx is hydrogen, CH3, NH2, F, Cl, Br or I, X is F, Cl, Br or I, and A, B, D, E, G, J, L, M, Rc and Rd are as defined in A, B, D, E, G, J, L, M, Rc and Rd of Chemical Formula 1.

[0029] The stilbene derivative represented by Chemical Formula 1 according to the present invention may be used as a preventative or therapeutic agent of cyclophilinrelated diseases along with a pharmaceutically acceptable carrier.

[0030] Also, the stilbene derivative represented by Chemical Formula 1 according to the present invention may be used as a reference material for comparison of efficacy of therapeutic agents for cyclophilin-related diseases.

[0031] In the present invention, the alkyl group or alkenyl group may be linear or branched.

[0032] As used herein, the term “halogen atom” may refer to fluorine, chlorine, bromine or iodine.

[0033] In the present invention, when A, B, D, E, G, J, L and M are linked with an adjacent group to form a fused ring, the fused ring is preferably a six-membered ring or a five-membered ring. Furthermore, the fused ring may contain at least one of hetero atoms such as N, O and S. The fused ring may be furan or thiophene.

[0034] In an embodiment of the present invention, A is preferably CRa or N, B is preferably CRb, G is preferably CRe, J is preferably CRf, M is preferably CRg or N, and D, E and L are preferably CH, but the present invention is not limited thereto.

[0035] In another embodiment of the present invention, Rb is preferably hydrogen or a C1-C8 alkyl group, but the present invention is not limited thereto.

[0036] In still another embodiment of the present invention, Rc is preferably a C1-C20 alkyl group, a C2-C10 alkoxy group, a phenylalkyl group, a nitro group, a C3-C10 cycloalkyl group, a C5-C12 heterocyclic group or a C1-C10 alkylketone, but the present invention is not limited thereto.

[0037] In yet another embodiment of the present invention, Rd is preferably a C2-C20 alkyl group; a C3-C10 ester group; a C3-C10 cycloalkyl group; a cycloalkyl-group- 15 Date ReQue / Date Received 2024-01-11substituted methoxy; an amine-group-substituted ethoxy; a carboxyl group; a phenylgroup-substituted C2-C20 alkyl group, the phenyl group being unsubstituted or substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or an amine group; amine; N-methylpiperazine; piperidine; morpholine; or -COOR5 (R5 is a C1-C20 alkyl group, a C6-C12 aryl or a C3-C10 cycloalkyl group), but the present invention is not limited thereto.

[0038] In still yet another embodiment of the present invention, Re is preferably hydrogen, OH, a C1-C20 alkyl group, or a C1-C10 alkoxy group, but the present invention is not limited thereto.

[0039] In a furflier embodiment of the present invention, Rg is preferably hydrogen, OH, a C1-C20 alkyl group; a C3-C10 ester group; a C3-C10 cycloalkyl group; a cycloalkyl-group-substituted methoxy; an amine-group-substituted ethoxy; a phenylgroup-substituted C2-C20 alkyl group, the phenyl group being unsubstituted or substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a carboxyl group or an amine group; amine; N-methylpiperazine; piperidine; morpholine; or a carboxyl group, but the present invention is not limited thereto.

[0040] In still a further embodiment of the present invention, Rh is preferably hydrogen, but the present invention is not limited thereto.

[0041] In the present invention, the alkyl group may be a 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, - —' or but the present invention is not limited thereto.

[0042] In the present invention, the alkoxy group may be a substituted or unsubstituted alkoxy group, such as -OCH3, -OCF3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, Date ReQue / Date Received 2024-01-11-OCH(CH3)CH2CH3, -OCH2CONH2, -OCH2CH2N(CH3)2, •

[0043] In the present invention, the heterocyclic group may be or thereto.

[0044] In the present invention, the -NR3R4 may be -NH2, -NHCH3, -N(CH3)2, or , but the oCOO(CH2)2CH3, -COO(CH2)3CH3, COO(CH2)4CH3, COOCH(CH3)2, or , but the present invention is not limited thereto.

[0046] In the present invention, -OCOR6 may or but the present invention is not limited thereto. is not limited thereto. present invention is not limited thereto.

[0045] In the present invention, -COOR5 may be COOCH3, -COOCH2CH3, • O 1 or but the present invention is not limited thereto. or.JhO , but the present invention

[0047] In the present invention, the -NR7CYR8 group may be •- 0 v-x but the present invention is not limited 17 Date ReQue / Date Received 2024-01-11limited thereto.

[0049] In tiie present invention, CORIO may be COC(CH3)3, but the present invention is not limited thereto.

[0050] As used herein, the term “pharmaceutically acceptable carrier” may be defined as a carrier or diluent that does not impair the biological activity or properties of the composition.

[0051] The pharmaceutically acceptable carrier or additive may include at least one of diluents or excipients such as a stabilizer, a filler, an extender, a wetting agent, a disintegrant, a lubricant, a binder, a surfactant, and the like, which are typically used.

[0052] The disintegrant may include agar, starch, alginic acid or a sodium salt thereof, anhydrous calcium hydrogen phosphate, and the like. The lubricant may include silica, talc, stearic acid or a magnesium salt or calcium salt thereof, polyethylene glycol, magnesium aluminometasilicate, and the like. The binder may include magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, and the like.

[0053] In addition thereto, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycine may be used as the diluent. In some cases, commonly known boiling salts, absorbents, coloring agents, flavoring agents, sweetening agents and the like may be used therewith.

[0054] Also, the stabilizer may include a sodium (Na)-free stabilizer, examples of which include magnesium aluminometasilicate, magnesium aluminosilicate, magnesium aluminate, dried aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, L-arginine, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride, aluminum chloride, and the like, which may be used alone or in combinations of two or more thereof.

[0055] A pharmaceutical composition, containing the stilbene derivative of Chemical Formula 1 of the present invention, may be administered in a variety of ways that facilitate administration of the compound into the organism. The pharmaceutical 18 Date ReQue / Date Received 2024-01-11composition containing the compound of the present invention may 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.

[0056] The pharmaceutical composition, containing the compound of the present invention, may be provided in a dosage form of a tablet, capsule, powder, dropping pill, pulvis, bolus, tincture or cataplasm. The preferred tablet may be a typical tablet, coated tablet, dispersible tablet, effervescent tablet, etc., or may be a multi-compressed tablet, such as a double tablet, a tablet-in-tablet, a multilayer tablet, etc.

[0057] The preferred administration amount of the stilbene derivative or pharmaceutically acceptable salt thereof included in the pharmaceutical composition containing the compound of the present invention varies depending on the status and body weight of a patient, the severity of disease, the type of drug, the administration route and duration, but may be appropriately selected by those skilled in the art.

[0058] A better understanding of the present invention may be achieved via the following non-limiting examples, which are merely set forth to illustrate but are not to be construed as limiting the scope of the present invention. The following examples may be appropriately modified and altered within the scope of the present invention.

[0059] Example 1. Preparation of stilbene derivative in which Rx is CN

[0060] 1) Use of solvent

[0061] 1 eq. of a phenylacetonitrile derivative of Chemical Formula 2 and 1.3 eq. of a benzaldehyde derivative of Chemical Formula 3 were refluxed with 0.2 eq. of triphenylphosphine in a butanol solvent, followed by a Knoevenagel condensation reaction, thus yielding a compound of Chemical Formula 1.

[0062] 2) Use of microwaves

[0063] 1 eq. of a phenylacetonitrile derivative of Chemical Formula 2, 1.3 eq. of a benzaldehyde derivative of Chemical Formula 3 and 0.2 eq. of triphenylphosphine were treated with microwaves, thus yielding a compound of Chemical Formula 1. When the microwaves are used, the reaction time may be shortened and the yield may be increased. 19 Date ReQue / Date Received 2024-01-11

[0064] [Scheme 1] [Chemical Formula 2][Chemical Formula 3] [Chemical Formula 1]

[0065] Example 2. Preparation of derivative in which Rx is hydrogen. CH3, NH2. F. CL Br. I

[0066] 1 eq. of an olefin derivative of Chemical Formula 4 and 1 eq. of an organic halide derivative of Chemical Formula 5 were refluxed with 0.01 eq. of palladium (II) acetate in a triethanolamine solvent, followed by a Heck olefination reaction, thus yielding a compound of Chemical Formula 1.

[0067] [Scheme 2] X = F, Cl, Br, I Rx = H, CH3, NH2, F, Cl, Br, I [Chemical Formula 4][Chemical Formula 5] [Chemical Formula 1]

[0068] Test Example 1. Evaluation of cis-trans isomerase inhibitory activity of stilbene derivative

[0069] Chymotrypsin cleaves a trans-type alanine-proline peptide bond. When SucAAPF-pNA (a peptide substrate) and chymotrypsin are mixed, the trans-type peptide substrate is cleaved and the cis-type peptide substrate remains. The remaining cis-type peptide substrate is converted into a trans form by a cis-trans isomerase and is then cleaved again by chymotrypsin. When the cis-trans isomerase is present, chymotrypsin is able to cleave a larger amount of trans-type peptide substrate within a predetermined period of time, from which the activity of the cis-trans isomerase may be determined. The amount of the cleaved trans-type peptide substrate is measured using absorbance at 390 nm.

[0070] Cyclophilin has cis-trans isomerase activity, and accelerates the cleavage of trans-type peptide substrate by chymotrypsin. When the stilbene derivatives of the 20 Date ReQue / Date Received 2024-01-11present invention were treated together with cyclophilin, the cleavage of the peptide substrate by chymotrypsin was not observed to accelerate. Thereby, the stilbene derivatives of the invention can be concluded to inhibit the activity of cyclophilin.

[0071] Compounds 1 to 155 (Tables 1 to 10) below may be grouped as follows based on the cis-trans isomerase inhibitory activity (IC50) values: Group A (Ga): IC50 of 2000 nM or less but exceeding 200 nM, Group B (Gb): IC50 of 200 nM or less but exceeding 20 nM, and Group C (Gc): IC50 of 20 nM or less. [Table 1] Compound A CRa, B CRb. G CRe, J CRf. D=E=L=M=CH Rx Ra Rb Rc Rd Re Rf Test Example 1 3 4 1 CN H H CH3 N(CH3)2 H H Ga Gd Gg 2 CN H H ch2ch3 COOH H H Ga Gd Go 3 CN H H ch2ch3 N(CH3)2 H H Ga Gd Gg 4 CN H H i-Pr Cl H H Ga Gd Gg 5 CN H H i-Pr COOH H H Ga Gd Gg 6 CN H H i-Pr OCRs H H Ga Gd Gg 7 CN H H NO2 NICH^ H H Ga Gd Gg 8 CN H H CH2CH2CH2CH3 COOH H H Gb Ge Gh 9 CN H H CH(CH3)CH2CH3 COOH H H Gb Ge Gh 10 CN H H t-Bu COOH H H Gb Ge Gh 11 CN H H t-Bu OCRs H H Ga Gd Gg 12 CN H CH3 CH3 OCH3 H H Ga Gd Gg 13 CN H ch3 ch3 COOH H H Ga Gd Gg 14 CN H H COC(CH3)3 OCH3 H H Gb Ge Gh 15 CN H H COC(CH3)3 COOH H H Ga Gd Gg 16 CN H H OCEbCHs OCRs H H Ga Gd Gg 17 CN H H OC&CHs COOH H H Ga Gd Gg 18 CN H H OCH2CH2CH2CH3 OCH3 H H Gb Ge Gh 19 CN H H OCaCftCIhCHs COOH H H Gb Ge Gh 20 CN H H CH2Ph OCH3 H H Gc Ge Gi 21 CN H H CH2Ph COOH H H Gc Gf Gi 22 CN H H NO2 CH2CH3 H H Ga Gd Gg 23 CN H H no2 i-Pro H H Ga Gd Gg 24 CN H H no2 NH2 H H Ga Gd Gg 25 CN H H no2 •—rX \i H H Ga Gd Gg 26 CN H H no2 OCH(CH3)CH2CH3 H H Ga Gd Gg 27 CN H H no2 * 0 H H Gb Ge Gh 28 CN H H no2 OCIhCIhNfCIhE H H Ga Gd Gg 29 CN H H no2 -O H H Ga Gd Gg 30 CN H H no2 * N O V J H H Ga Gd Gg 31 CN H H no2 — H H Gb Ge Gh 32 CN H H no2 H OCH2CH2CH(CH3)2 H Ga Gd Gg 21 Date ReQue / Date Received 2024-01-1133 CN H H NO2 H OCH2CH2CH2N(CH3)2 H Ga Gd Gg 34 CN H H NO2 CH2CH(CH3)2 H H Ga Gd Gg 35 CN H H NO2 CH2C(CH3)3 H H Gb Ge Gh 36 CN H H NO2 CH2CH2CH(CH3)2 H H Gb Gb Gh 37 CN H H NO2 * \ / Cl H H Gb Gb Gh 38 CN H H NO2 CH2CH2P11 H H Gb Ge Gh 39 CN H H NO2 / — —( H H Gc Gf Gi 40 CN H H NO2 > H H Gc Gf Gi 41 CN H H NO2 J > H H Gc Gf G 42 CN H H NO2 CH2CH2CH2P11 H H Ga Gd Gg 43 CN H H NO2 CHzCHzCfCHsjs H H Gb Ge Gh 44 CN H H NO2 H H H Gb Ge Gh 45 CN H H NO2 AH H H Gb Ge Gh 46 CN H H NO2 H H Gb Ge Gh 47 CN H H NO2 H H Gb Gb Gh 48 CN H H NO2 H H Gb Ge Gh 49 CN H H NO2 ' H H Ga Gd Gg 51 CN H H NO2 _ / % / H H Ga Gd Gg 52 CN H H NO2 H H Gb Ge Gh 53 CN H H NO2 . r'': H H Gb Gb Gh 54 CN H H CH2C(CH3)3 COOH H H Gc Gf Gi 55 CN H H \ COOH H H Gb Ge Gh 56 CN H H V COOH H H Gb Gb Gh 57 CN H H COOH H H Gc Gf Gi 58 CN H H COOH H H Gb Ge Gh 59 CN H H COOH H H Gc Gf Gi 60 CN H H _J— COOH H H Gc Gf Gi 61 CN H H J COOH H H Gc Gf Gi 62 CN H H COOH H H Gc Gf Gi 63 CN H H £ COOH H H Gb Ge Gh 64 H H H CH2C(CH3)3 COO(CH2)3CH3 H H Gc Gf Gi 65 H H H CH2C(CH3)3 COO(CH2)3CH3 CH3 H Gb Ge Gh 66 H H H CH2C(CH3)3 COO(CH2)3CH3 CH2CH3 H Gb Ge Gh 22 Date ReQue / Date Received 2024-01-1167 H ch3 H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh 68 H ch2ch3 H CH2C(CH3)3 COO(CH2)3CH H H Gb Ge Gh 69 H H H CHC(CH3)3 COO(CH2)3CH3 H CH3 Gb Ge Gh 70 H H H CH2C(CH3)3 COO(CH2)3CH3 01 ch3 Gb Ge Gh 71 H H H CH2C(CH3)3 C00(CH)2CH H H Gc Gf Gi 72 H H H CH2C(CH3)3 COO(CH2)4CH3 H H Gc Ge Gi 73 H H H CH2C(CH3)3 COOCH(CH3)2 H H Gc Gf Gi 74 H H H CH2C(CH3)3 *b 'b H H Gc Gf Gi 75 H H H CH2C(CH3)3 *^PP H H Gb Ge Gh 76 H H H CH2C(CH3)3 COOCHPh H H Gc Gf Gi 77 H H H CHzC(CH3)3 •^3 H H Gb Ge Gh 78 H H H CH2CH(CH3)CHCH3 COO(CH2)3CH3 H H Gb Ge Gh 79 H H H COO(CH2)3CH H H Gb Ge Gh 80 H H H COO(CH2)3CH H H Gb Ge Gh 81 H H H COO(CH2)3OI3 H H Gb Ge Gh 82 OI3 H H CH2C(CH3)3 COO(CH2)3CH H H Gb Ge Gh 83 Oh H H CHC(CH3)3 COO(CH2)3CH3 CH3 H Gb Ge Gh 84 ch3 CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh 85 ch3 H H CH2C(CH3)3 COO(CH2)3CH3 H CH3 Gb Ge Gh 86 Oh H H CH2C(CH3)3 COO(CH2)3ai ch3 CH Gb Ge Gh 87 CH3 H H CH2C(CH3)3 COO(CH2)201 H H Gb Ge Gh 88 CH H H CH2C(CH3)3 COO(CH2)4CH3 H H Gb Ge Gh 89 ch3 H H CH2C(CH3)3 COOCH(CH3)2 H H Gb Ge Gh 90 CH H H CH2C(CH3)3 •b 0 \ H H Gb Ge Gh 91 CH H H CH2C(CH3)3 a hn ) H H Gb Ge Gh 92 Oh H H CH2C(CH3)3 COOCHPh H H Gb Ge Gh 93 CH H H CH2C(CH3)3 P33 H H Gb Ge Gh 94 ch3 H H CH2CH(CH3)CHCH3 COO(CH2)3CH3 H H Gb Ge Gh 95 Oh H H *— COO(CH2)3ai H H Gb Ge Gh 96 CH H H COO(CH2)3CH3 H H Gb Ge Gh 97 ch3 H H .p COO(CH2)3ai H H Gb Ge Gh 98 NH2 H H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh 99 NH2 H H CH2C(CH3)3 C00(CH2)3Ol CH3 H Gb Ge Gh 100 NH CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh 101 NH H H CH2C(CH3)3 COO(CH2)3ai H CH Gb Ge Gh 23 Date ReQue / Date Received 2024-01-11102 Nib H H CH2C(CH3)3 COO(CH2)3CIb ch3 CIb Gb Ge Gh 103 Nib H H CH2C(CH3)3 COO(CH2)4CH3 H H Gb Ge Gh 104 NH2 H H CH2C(CH3)3 COOCH(CH3)2 H H Gb Ge Gh 105 Nib H H CH2C(CH3)3 T) H H Gb Ge Gh 106 nh2 H H CH2C(CH3)3 COOClbPh H H Gb Ge Gh 107 nh2 H H CH2C(CH3)3 ^0 H H Gb Ge Gh 108 Nib H H cn2cii(cn3)cii2cii3 COOfCIhhCIh H H Gb Ge Gh 109 Nib H H * COO(CH2)3CH3 H H Gb Ge Gh 110 nh2 H H COO(CH2)3CIb H H Gb Ge Gh 111 Nib H H COOCC&hCft H H Gb Ge Gh 112 F H H CH2C(CH3)3 COO(CH2)3CH3 H H Gc Gf Gi 113 Cl H H CH2C(CH3)3 COO(CH2)3CIb CH3 H Gc Ge Gi 114 Br ch3 H CH2C(CH3)3 COOfCIhhCIh H H Gc Gf Gi 115 I H H CH2C(CH3)3 COO(CH2)3CH3 H CH3 Gc Gf Gi 116 F H H CH2C(CH3)3 COO(CH2)3CH3 CH3 CIb Gc Gf & 117 Cl H H CH2C(CH3)3 COO(CH2)4CH3 H H Gc Gf Gi 118 Br H H CH2C(CH3)3 COOCH(CH3)2 H H Gc Gf Gi 119 I H H CH2C(CH3)3 H H Gc Gf Gi 120 F H H CIbC(CH3)3 COOClbPh H H Gc Gf Gi 121 Cl H H CH2C(CH3)3 H H Gc Gf Gi 122 Br H H CHsCHCCFDCILCH3 COO(CH2)3CH3 H H Gb Ge Gh 123 I H H Cl COO(CH2)3CIb H H Gb Ge Gh 124 H H H CH2C(CH3)3 COOCHs H H Gc Gf Gi 125 H H H CH2CH(CH3)CH2CH3 COOClb H H Gb Ge Gh 126 H H H COOClb H H Gb Ge Gh 127 H H H COOClb H H Gb Ge Gh 128 H H H p COOClb H H Gb Ge Gh 129 H H H \. COOClb H H Gb Ge Gh 130 H H H CH2(CHz)3CH3 COOClb H H Gc Gf Gi 131 H H H \ COO(CH2)3CIb H H Gc Gf Gi 132 H H H CH2(CH2)3CH3 COO(CH2)3CIb H H Gc Gf Gi 133 H H H CH2C(CH3)3 c H H Gb Ge Gh 134 H H H CH2C(CH3)3 COOH H H Gc Gf Gi 135 H H H CH2C(CH3)3 COOH OH H Gc Gf Gi 24 Date ReQue / Date Received 2024-01-11[Table 2 136 H H H CH2C(CH3)3 COOH H OH Gc Gf Gi 137 H H H CH2C(CH3)3 COOH NH2 H Gc Gf Gi 138 H H H CH2C(CH3)3 COOH H NHz Gc Gf Gi 139 H H H CH2C(CH3)3 COOH CHj H Gc Gf Gi 140 H H H CH2C(CH3)3 COOH H CH3 Gc Gf Gi 141 H H H CH2C(CH3)3 CONH2 H H Gc Gf Gi [Table 3] Compound A CRa, B CRb, G CRe, D=E=M=CH Rx Ra Rb Ra Ra Re Fused ring formation of J andL Test Example 1 3 4 142 H H H CH2C(CH3)3 COO(CH2)3CH3 H Gb Gb Gh [Table 4] Compound A=N, B=CRb, G=CRe, J=CRf, D=E=L=M=CH Rx Rb Rc Ra Re Rf Test Example 1 3 4 143 H H CH2C(CH3)3 COO(CH2)jCH3 H H Gb Gb Gh [Table 5] Compound A=CRa, B=N, G=CRe, J=CRf, D=E=L=M=CH Rx Ra Ra Rd Re Rf Test Example 1 3 4 144 H H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh [Table 6] Compound A CRa, B CRb, G=N, J CRf, D E I. M CH Rx Ra Rb Re Rd Rf Test Example 1 3 4 145 H H H CH2C(CH3)3 COO(CH2)3CH3 H Gb Gb Gh [Table 7] Compound A CRa, B CRb, G CRe, J N, D 1. I. M CH Rx Ra Rb Rc Rd Re Test Example 1 3 4 146 H H H CH2C(CH3)3 COO(CH2)3CH3 H Gb Gb Gh [Table 8] Compound A CRa, B CRb, G CRe, J CRf, D 1. M CH, L=N Rx Ra Rb Rc Rd Re Rr Test Example 1 3 4 147 H H H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh [Table 9] Compound A CRa. B CRb. G CRe. J CRf. D=E=L=CH, MN Rx Ra Rb Rc Rd Re Rf Test Example 1 3 4 148 H H H CH2C(CH3)3 COO(CH2)3CH3 H H Gb Ge Gh Compound A=CRa, B CRb, G=CRe, J=CRf, M CRg. 1) 1, 1. CH Rx Ra Rb Rc Rd Re Rf Rg Test Example 1 3 4 149 H H H CH2C(CH3)3 COO(CH2)3CH3 H H COO(CH2)3CH3 Gb Ge Gh 150 H H H CH2C(CH3)3 COOH H H OH Gc Gf Gi 151 H H H CH2C(CH3)3 COOH H H nh2 Gc Gf Gi 152 H H H CH2C(CH3)3 COOH H H ch3 Gc Gf Gi 25 Date ReQue / Date Received 2024-01-11[Table 10]

[0072] Test Example 2, Evaluation of cytotoxicity of stilbene derivative Compound A CRa, B CRb, G CRe, J=CRf, L=CRh, I) 1 M ClI Rx Ra Rb Re Rd Re Rf Rh Test Example 1 3 4 153 H H H CH2C(CH3)3 COOH H H OH Gb Ge Gh 154 H H H CH2C(CH3)3 COOH H H NH2 Gb Ge Gh 155 H H H CH2C(CH3)3 COOH H H ch3 Gb Ge Gh

[0073] The cytotoxicity of the stilbene derivatives was measured. Replicon cells that stably replicate a hepatitis C virus genome were attached to a 96-well plate and cultured in a CO2 incubator at 37°C for 24 hr. The replicon cells cultured for one day were washed with a phosphate buffered saline (PBS) solution, treated with the compounds of the present invention, and then cultured for 72 hr. Thereafter, through the MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity test, CC50 values of the compounds of the present invention were measured. The CC50 values of the compounds of the present invention were 200 pM or more. For example, Compound 64 had a CC50 of 320 pM, Compound 65 had a CC50 of 284 pM, and Compound 66 had a CC50 of 245 pM. Accordingly, the compounds of Chemical Formula 1 of the present invention exhibited no cytotoxicity.

[0074] Test Example 3, Evaluation of antiviral activity of stilbene derivative

[0075] The antiviral activity of the stilbene derivatives on hepatitis C virus was measured. The replicon cells that stably replicate the hepatitis C virus genome were attached to a culture plate and cultured in a CO2 incubator at 37°C for 24 hr. The replicon cells cultured for one day were washed with a PBS solution, treated with the compounds of the present invention, and then cultured for 72 hr. The stilbene derivative-treated replicon cells were washed with a cold PBS solution and added with 20 pL of a cell lysis solution so that the cells were lysed in ice for 20 min. 100 pL of a Renilla luciferase substrate was added thereto, after which the luminescence thereof was measured and thus the amount of the hepatitis C virus genome was estimated. The amount of the hepatitis C virus genome in the stilbene derivative-treated replicon cells according to the present invention relative to the amount of the hepatitis C virus genome in dimethylsulfoxide (DMSO)-treated replicon cells is shown.

[0076] Compounds 1 to 155 of Tables 1 to 10 may be grouped as follows based on the antiviral activity (EC50) values:

[0077] Group D (Gd): EC50 of 50 pM or less but exceeding 5 pM,

[0078] Group E (Ge): EC50 of 5 pM or less but exceeding 0.5 pM, and

[0079] Group F (Gf): EC50 of 0.5 pM or less. 26 Date ReQue / Date Received 2024-01-11

[0080] Thus, the compounds of Chemical Formula 1 of the present invention exhibited antiviral effects.

[0081] Test Example 4, Inhibitory activity test on mitochondrial swelling

[0082] Cyclophilin is a key protein for forming permeability transition pores (PTP) in mitochondria. When permeability transition pores are formed, mitochondria swell, whereby the outer membrane thereof ruptures and thus cell death progresses. Such mitochondrial dysfunction causes many diseases including neurodegenerative diseases, cancer, and the like. Cyclosporine, a known cyclophilin inhibitor, is capable of preventing the formation of permeability transition pores to thus suppress mitochondrial swelling.

[0083] The mitochondrial swelling test was performed as follows. Specifically, the hepatocytes were disrupted using a Dounce tissue grinder. The disrupted cells were centrifuged at 700 x g for 10 min and the supernatant was transferred into a new tube. The supernatant was centrifuged at 12,000 x g for 15 min, thereby obtaining mitochondria.

[0084] When the extracted mitochondria were added with calcium, they swelled, which may be observed by measuring the absorbance at 520 nm. The stilbene derivatives are effective at inhibiting mitochondrial swelling due to calcium.

[0085] The activity of Compounds 1 to 155 of Tables 1 to 10 on inhibiting mitochondrial swelling may be determined based on ICso values, and may be grouped as follows:

[0086] Group G (Gg): ICso of 500 pM or less but exceeding 50 pM,

[0087] Group H (Gh): ICso of 50 pM or less but exceeding 5 pM, and

[0088] Group I (Gi): ICso of 5 pM or less.

[0089] The results of NMR analysis and LCMS analysis of Compounds 1 to 155 corresponding to the stilbene derivatives prepared in Examples 1 and 2 are as follows.

[0090] Compound 1: NMR (400MHz, CDC13): 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) LCMS: MH+ = 263.1

[0091] Compound 2: 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) LCMS: MH+ = 260.1 27 Date ReQue / Date Received 2024-01-11

[0092] Compound 3: NMR (400MHz, CDC13): 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) LCMS: MNa+ = 300.1

[0093] Compound 4: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 282.0

[0094] Compound 5: NMR (400MHz, CDCI3): 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) LCMS: MNa+ = 314.1

[0095] Compound 6: NMR (400MHz, CDCI3): 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) LCMS: MH ' = 278.1

[0096] Compound 7: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 294.1

[0097] Compound 8: 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) LCMS: MH+ = 304.1

[0098] Compound 9: NMR (400MHz, CDCI3): 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) LCMS: MNa+ = 288.1

[0099] Compound 10: NMR (400MHz, CDCI3): 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) LCMS: MNa+ = 328.3

[00100] Compound 11: NMR (400MHz, CDCI3): 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) 28 Date ReQue / Date Received 2024-01-11LCMS: MH' = 292.2

[00101] Compound 12: NMR (300MHz, CDCh): 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) LCMS: MH+ = 264.1

[00102] Compound 13: NMR (300MHz, CDCh): 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) LCMS: MNa+ = 299.1

[00103] Compound 14: NMR (300MHz, CDCh): 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) LCMS: MH ' = 320.2

[00104] Compound 15: NMR (300MHz, CDCh): 7.75 (d, 1H), 7.72 (m, 2H), 7.65 (d, 2H), 7.61 (d, 1H) 7.43 (d, 2H), 7.39 (s, 1H), 1.37 ppm (s, 9H) LCMS: MNa+ = 355.1

[00105] Compound 16: NMR (300MHz, CDCh): 7.83 (d, 1H), 7.80 (s, 1H), 7.75 (d, 2H), 7.60 (m, 1H) 7.25 (d, 1H), 7.19 (m, 1H), 7.08 (d, 2H), 4.12 (m, 2H), 3.89 (s, 3H), 1.42 ppm (m, 3H) LCMS: MH+ = 280.1

[00106] Compound 17: NMR (300MHz, CDCh): 7.94 (d, 1H), 7.90 (s, 1H), 7.83 (d, 2H), 7.65 (m, 1H) 7.30 (d, 1H), 7.22 (m, 1H), 7.14 (d, 2H) 4.17 (m, 2H), 1.43 ppm (m, 3H) LCMS: MNa+ = 315.1

[00107] Compound 18: NMR (300MHz, CDCh): 7.82 (d, 1H), 7.67 (s, 1H), 7.55 (m, 1H), 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) LCMS: MH+ = 308.2

[00108] Compound 19: NMR (300MHz, CDCh): 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) LCMS: MNa+ = 343.1 29 Date ReQue / Date Received 2024-01-11

[00109] Compound 20: NMR (300MHz, CDC13): 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) LCMS: MH+ = 326.2

[00110] Compound 21: NMR (300MHz, CDCI3): 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) LCMS: MNa+ = 361.1

[00111] Compound 22: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 279.1

[00112] Compound 23: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 293.1

[00113] Compound 24: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 266.1

[00114] Compound 25: NMR (300MHz, CDCI3): 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 (broad s, 4H), 2.41 ppm (s, 3H) LCMS: MH+ = 349.2

[00115] Compound 26: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 323.1

[00116] Compound 27: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 339.1 30 Date ReQue / Date Received 2024-01-11

[00117] Compound 28: NMR (300MHz, CDC13): 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) LCMS: MH+ = 338.1

[00118] Compound 29: NMR (300MHz, CDCI3): 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) LCMS: MH+- 334.2

[00119] Compound 30: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 336.1

[00120] Compound 31: NMR (300MHz, CDCI3): 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) LCMS: MH ' = 333.2

[00121] Compound 32: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 337.2

[00122] Compound 33: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 352.2

[00123] Compound 34: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 307.1

[00124] Compound 35: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 321.2

[00125] Compound 36: NMR (300MHz, CDCh): 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) LCMS: MH =321.2 31 Date ReQue / Date Received 2024-01-11

[00126] Compound37: NMR (400MHz, CDC13): 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) LCMS: MH+ = 409.0

[00127] Compound 38: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 355.1

[00128] Compound 39: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 361.2

[00129] Compound 40: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 375.2

[00130] Compound 41: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 347.2

[00131] Compound 42: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 369.2

[00132] Compound 43: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 335.2

[00133] Compound 44: LCMS MH ' = 385.2

[00134] Compound 45: LCMS MH+ = 411.2

[00135] Compound 46: LCMS MH+ = 389.1

[00136] Compound 47: LCMS MH+ = 389.1

[00137] Compound 48: LCMS MH+ = 389.1

[00138] Compound 49: LCMS MH+ = 385.2 32 Date ReQue / Date Received 2024-01-11

[00139] Compound 50: LCMS: MH == 385.2

[00140] Compound 51: LCMS: MNa+ = 420.1

[00141] Compound 52: LCMS: MH+ = 369.2

[00142] Compound 53: LCMS: MH =370.2

[00143] Compound 54: NMR (300MHz, CDCh): 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) LCMS: MH+ = 320.1

[00144] Compound 55: NMR (300MHz, CDCh): 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) LCMS: MH+ = 320.1

[00145] Compound 56: NMR (300MHz, CDCh): 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) LCMS: MH+ = 334.1

[00146] Compound 57: NMR (300MHz, CDCI3): 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) LCMS: MH+ = 334.1

[00147] Compound 58: NMR (300MHz, CDCh): 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) LCMS: MH+ = 334.1

[00148] Compound 59: NMR (300MHz, CDCh): 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) LCMS: MH+ = 346.1

[00149] Compound 60: NMR (300MHz, CDCh): 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) LCMS: MH+ = 360.1 33 Date ReQue / Date Received 2024-01-11

[00150] Compound 61: NMR (300MHz, CDCh): 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) LCMS: MH+ = 304.1

[00151] Compound 62: NMR (300MHz, CDCh): 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) LCMS: MH+ = 318.1

[00152] Compound 63: NMR (300MHz, CDCh): 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) LCMS: MH+ = 360.1

[00153] Compound 64: NMR (400MHz, CDCh): 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), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H) LCMS: MH+ = 351.2

[00154] Compound 65: NMR (400MHz, CDCh): 7.93 (d, 1H), 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), 2.46 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H) LCMS: MH+ = 365.2

[00155] Compound 66: NMR (400MHz, CDCh): 7.93 (d, 1H), 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), 2.60 (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) LCMS: MH+ = 379.2

[00156] Compound 67: NMR (400MHz, CDCh): 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), 2.48 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.99 (m, 3H), 0.98 ppm (s, 9H) LCMS: MH ' = 365.2 34 Date ReQue / Date Received 2024-01-11

[00157] Compound 68: NMR (400MHz, CDCh): 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) LCMS: MH+ = 379.2

[00158] Compound 69: NMR (400MHz, CDCh): 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) LCMS: MH+ = 365.2

[00159] Compound 70: NMR (400MHz, CDCh): 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) LCMS: MH ' = 379.2

[00160] Compound 71: NMR (400MHz, CDCh): 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) LCMS: MH+ = 337.2

[00161] Compound 72: NMR (400MHz, CDCh): 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) LCMS: MH+ = 351.2

[00162] Compound 73: NMR (400MHz, CDCh): 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) LCMS: MH+ = 337.2

[00163] Compound 74: NMR (400MHz, CDCh): 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) LCMS: MH = 391.2 35 Date ReQue / Date Received 2024-01-11

[00164] Compound 75: NMR (400MHz, CDCh): 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, 1H4.46 (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) LCMS: MH+ = 392.2

[00165] Compound 76: NMR (400MHz, CDCh): 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) LCMS: MH+ = 385.2

[00166] Compound 77: NMR (400MHz, CDCh): 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) LCMS: MH+ = 377.2

[00167] Compound 78: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 351.2

[00168] Compound 79: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 363.2

[00169] Compound 80: NMR (400MHz, CDCh): 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) LCMS: MH+ = 377.2

[00170] Compound 81: NMR (400MHz, CDCh): 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) LCMS: MH = 371.2 36 Date ReQue / Date Received 2024-01-11

[00171] Compound 82: 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, 5H), 1.80 (m, 2H), 1.45 (m, 2H), 0.94 (s, 9H), 0.90ppm (m, 3H) LCMS: MH+ = 365.2

[00172] Compound 83: NMR (400MHz, CDCI3): 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), 0.90ppm (m, 3H) LCMS: MH+ = 379.2

[00173] Compound 84: NMR (400MHz, CDCI3): 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), 0.90ppm (m, 3H) LCMS: MH = 379.2

[00174] Compound 85: NMR (400MHz, CDCI3): 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), 0.90ppm (m, 3H) LCMS: MH+ = 379.2

[00175] Compound 86: NMR (400MHz, CDCI3): 7.92 (m, 1H), 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), 0.90ppm (m, 3H) LCMS: MH+ = 393.2

[00176] Compound 87: NMR (400MHz, CDCI3): 77.94 (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), 0.90ppm (m, 3H) LCMS: MH+ = 351.2

[00177] Compound 88: NMR (400MHz, CDCI3): 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), 0.90ppm (m, 3H) LCMS: MH ' = 379.2 37 Date ReQue / Date Received 2024-01-11

[00178] Compound 89: NMR (400MHz, CDCh): 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) LCMS: MH+ = 351.2

[00179] Compound 90: NMR (400MHz, CDCh): 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) LCMS: MH+ = 405.2

[00180] Compound 91: NMR (400MHz, CDCh): 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) LCMS: MH+ = 406.3

[00181] Compound 92: NMR (400MHz, CDCh): 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) LCMS: MH+ = 399.2

[00182] Compound 93: NMR (400MHz, CDCh): 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) LCMS: MH+ = 391.3

[00183] Compound 94: NMR (400MHz, CDCh): 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), 0.90ppm (m, 6H) LCMS: MH+ = 365.2

[00184] Compound 95: NMR (400MHz, CDCh): 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), 0.90ppm (m, 3H) LCMS: MH+ = 377.2 38 Date ReQue / Date Received 2024-01-11

[00185] Compound 96: NMR (400MHz, CDCh): 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), 0.90ppm (m, 3H) LCMS: MH+ = 391.2

[00186] Compound 97: NMR (400MHz, CDCh): 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) LCMS: MH+ = 385.2

[00187] Compound 98: NMR (400MHz, CDCh): 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) LCMS: MH+ = 366.2

[00188] Compound 99: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 380.2

[00189] Compound 100: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 380.3

[00190] Compound 101: NMR (400MHz, CDCh): 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) LCMS: MH+ = 380.3

[00191] Compound 102: NMR (400MHz, CDCh): 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) LCMS: MH ' = 394.3 39 Date ReQue / Date Received 2024-01-11

[00192] Compound 103: NMR (400MHz, CDCh): 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) LCMS: MH+ = 380.3

[00193] Compound 104: NMR (400MHz, CDCh): 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) LCMS: MH+ = 352.2

[00194] Compound 105: NMR (400MHz, CDCh): 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) LCMS: MH+ = 406.3

[00195] Compound 106: NMR (400MHz, CDCI3): 7.98 (m, 2H), 7.63 (m, 1H), 7.49 (m, 4H), 7.36 (m, 4H), 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) LCMS: MH+ = 400.2

[00196] Compound 107: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 392.3

[00197] Compound 108: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 366.2

[00198] Compound 109: NMR (400MHz, CDCh): 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) LCMS: MH ' = 378.2 40 Date ReQue / Date Received 2024-01-11

[00199] Compound 110: NMR (400MHz, CDCh): 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) LCMS: MH+ = 392.3

[00200] Compound 111: NMR (400MHz, CDCh): 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) LCMS: MH+ = 386.2

[00201] Compound 112: NMR (400MHz, CDCh): 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) LCMS: MH+ = 369.2

[00202] Compound 113: NMR (400MHz, CDCI3): 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) LCMS: MH = 399.2

[00203] Compound 114: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 443.2

[00204] Compound 115: NMR (400MHz, CDCh): 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) LCMS: MH+ = 491.1

[00205] Compound 116: NMR (400MHz, CDCh): 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) LCMS: MH ' = 397.3 41 Date ReQue / Date Received 2024-01-11

[00206] Compound 117: NMR (400MHz, CDCh): 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) LCMS: MH+ = 399.2

[00207] Compound 118: NMR (400MHz, CDCh): 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) LCMS: MH+ = 415.1

[00208] Compound 119: NMR (400MHz, CDCh): 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) LCMS: MH+ = 517.2

[00209] Compound 120: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 403.2

[00210] Compound 121: NMR (400MHz, CDCh): 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) LCMS: MH+ = 411.2

[00211] Compound 122: NMR (400MHz, CDCh): 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) LCMS: MH+ = 429.1

[00212] Compound 123: NMR (400MHz, CDCh): 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) LCMS: MH+ = 497.1 42 Date ReQue / Date Received 2024-01-11

[00213] Compound 124: NMR (400MHz, CDCh): 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), 3.96 (s, 3H), 2.53 (s, 2H), 0.94 ppm (m, 9H) LCMS: MH+ = 309.2

[00214] Compound 125: NMR (400MHz, CDCh): 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) LCMS: MH+ = 309.2

[00215] Compound 126: NMR (400MHz, CDCh): 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) LCMS: MH =321.2

[00216] Compound 127: NMR (400MHz, CDCh): 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) LCMS: MH+ = 335.2

[00217] Compound 128: NMR (400MHz, CDCh): 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) LCMS: MH' = 329.2

[00218] Compound 129: NMR (400MHz, CDCh): 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) LCMS: MH+ = 295.2

[00219] Compound 130: NMR (400MHz, CDCh): 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) LCMS: MH+ = 309.2 43 Date ReQue / Date Received 2024-01-11

[00220] Compound 131: NMR (400MHz, CDCh): 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) LCMS: MH+ = 337.2

[00221] Compound 132: NMR (400MHz, CDCh): 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) LCMS: MH+ = 351.2

[00222] Compound 133: NMR (400MHz, CDCh): 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), 2.53 (s, 2H), 3.27 (m, 4H), 1.92 (m, 4H), 0.96 ppm (s, 9H) LCMS: MH+ = 364.2

[00223] Compound 134: NMR (400MHz, CDCI3): 8.11 (m, 2H), 7.78 (d, 1H), 7.65 (m, 1H), 7.52 (d, 2H), 7.37 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH+ = 295.2

[00224] Compound 135: NMR (400MHz, CDCh): 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) LCMS: MH+ = 311.2

[00225] Compound 136: NMR (400MHz, CDCh): 8.09 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.07 (m, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH+ = 311.2

[00226] Compound 137: NMR (400MHz, CDCh): 8.07 (d, 1H), 7.78 (d, 1H), 7.60 (m, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.13 (m, 1H), 7.06 (d, 1H), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH+ = 310.2

[00227] Compound 138: NMR (400MHz, CDCh): 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) LCMS: MH+ = 310.2 44 Date ReQue / Date Received 2024-01-11

[00228] Compound 139: NMR (400MHz, CDC13): 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) LCMS: MH+ = 309.2

[00229] Compound 140: NMR (400MHz, CDCI3): 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) LCMS: MH+- 309.2

[00230] Compound 141: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 294.2

[00231] Compound 142: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 401.2

[00232] Compound 143: NMR (400MHz, CDCI3): 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) LCMS: MH' = 352.2

[00233] Compound 144: NMR (400MHz, CDCI3): 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) LCMS: MH+ = 352.2

[00234] Compound 145: NMR (400MHz, CDCh): 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) LCMS: MH+ = 352.2 45 Date ReQue / Date Received 2024-01-11

[00235] Compound 146: NMR (400MHz, CDCh): 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) LCMS: MH+ = 352.2

[00236] Compound 147: NMR (400MHz, CDCh): 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) LCMS: MH+ = 352.2

[00237] Compound 148: NMR (400MHz, CDCh): 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) LCMS: MH+ = 352.2

[00238] Compound 149: NMR (400MHz, CDCh): 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) LCMS: MH+ = 451.3

[00239] Compound 150: NMR (400MHz, CDCh): 8.15 (d, 1H), 7.78 (d, 1H), 7.52 (d, 2H), 7.31 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 7.12 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH+ = 311.2

[00240] Compound 151: NMR (400MHz, CDCh): 8.15 (d, 1H), 7.78 (d, 1H), 7.52 (d, 2H), 7.41 (m, 1H), 7.32 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 6.55 (s, 2H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH+ = 310.2

[00241] Compound 152: NMR (400MHz, CDCh): 8.15 (d, 1H), 7.78 (d, 1H), 7.52 (d, 2H), 7.49 (m, 1H), 7.29 (m, 1H), 7.17 (d, 2H), 7.06 (d, 1H), 2.54 (s, 2H), 2.48 (s, 3H), 0.96 ppm (s, 9H) LCMS: MH+ = 309.2

[00242] Compound 153: NMR (400MHz, CDCh): 8.09 (m, 2H), 7.78 (d, 1H), 7.52 (d, 2H), 7.17 (d, 2H), 7.06 (d, 1H), 6.81 (m, 1H), 2.54 (s, 2H), 0.96 ppm (s, 9H) LCMS: MH = 311.2 46 Date ReQue / Date Received 2024-01-11

[00243] Compound 154: NMR (400MHz, CDCh): 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) LCMS: MH+ = 310.2

[00244] Compound 155: NMR (400MHz, CDC13): 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) LCMS: MH+ = 309.2 [Industrial Applicability]

[00245] The novel stilbene derivatives of the present invention can be used as an inhibitor of the function of cyclophilin, which has an improved pharmaceutical profile. 47 Date ReQue / Date Received 2024-01-11

Claims

Claims 1. A compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] in Chemical Formula 1, A is CRa, B is CRb, G is CRe, JisCRf, M is CRg, D, E, and L are CRh, Rx is H, Ra is hydrogen, or a C1-C5 alkyl group, Rb is hydrogen, Rc is -CH2C(CH3)3, Rd is COOH or -COOR5, wherein R5 is a C1-C10 alkyl group or a C3-C10 cycloalkyl group, wherein the Cl-CIO alkyl group may optionally be substituted with at least one substituent each independently being amine, a C6-C12 aryl, a C5-C10 heterocyclic group in which nitrogen is included as a hetero atom, or a C3-C10 cycloalkyl group, Re is hydrogen, NH2, OH, or a C1-C10 alkyl group, Rf is hydrogen, NH2, OH, or a C1-C4 alkyl group, Rg is hydrogen, NH2, OH, a C1-C10 alkyl group, or -COORz, wherein Rz is a C1-C10 alkyl group, and Rh is hydrogen, NH2, OH, or a C1-C5 alkyl group.

2. A compound represented by Chemical Formula 1 below or the pharmaceutically acceptable salt thereof: 48 Date ReQue / Date Received 2024-01-11[Chemical Formula 1] wherein the compound is one or more of Compounds 64-77, 124, 134-140, 142, or 149-155 below: Compound A=CRa, B=CRb, G=CRe, J=CRf, D=E=L=M=CH Rx Ra Rb Rc Rd Re Rf 64 H H H CH2C(CH3)3 COO(CH2)3CH3 H H 65 H H H CH2C(CH3)3 COO(CH2)3CH3 CHs H 66 H H H CH2C(CH3)3 COO(CH2)3CH3 ch2ch3 H 67 H CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H 68 H CH2CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H 69 H H H CH2C(CH3)3 COO(CH2)3CH3 H Cft 70 H H H CH2C(CH3)3 COO(CH2)3CH3 CHs CHs 71 H H H CH2C(CH3)3 COO(CH2)3CH3 H H 72 H H H CH2C(CH3)3 COO(CH2)3CH3 H H 73 H H H CH2C(CH3)3 COOCH(CH3)2 H H 74 H H H CH2C(CH3)3 •4° T) H H 75 H H H CH2C(CH3)3 H H 76 H H H cii2acii3)3 COOCH2Ph H H 77 H H H CH2C(CH3)3 H H 124 H H H CH2C(CH3)3 COOCHs H H 134 H H H CH2C(CH3)3 COOH H H 135 H H H CH2C(CH3)3 COOH OH H 136 H H H CH2C(CH3)3 COOH H OH 137 H H H CH2C(CH3)3 COOH NHz H 138 H H H C&CfC&b COOH H NHz 139 H H H CH2C(CH3)3 COOH CH3 H 140 H H H cii2acii3)3 COOH H CH3 142 A=CRa, B=CRb, GCRe, I) E M Cl 1 Rx R» Ra Rc Rd Rc Fused ring formation of J andL H H H CHzC(CH3)3 COO(CH2)3CH3 H 49 Date ReQue / Date Received 2024-01-11A=CRa, B=CRb, G=CRe, J=CRf, M=CRg, D=E=L=CH - Rx Ra Rb Rc Rd Re Rf Rg 149 H H H CH2C(CH3)3 COO(CH2)3CH3 H H COO(CH2)3CH3 150 H H H CH2C(CH3)3 COOH H H OH 151 H H H CH2C(CH3)3 COOH H H NH2 152 H H H CH2C(CH3)3 COOH H H CH3 A=CRa, B=CRb, G=CRe, J=CRf, L=CRh, D E M CI1 - Rx Ra Rb Rc Rd Re Rf Rh 153 H H H CH2C(CH3)3 COOH H H OH 154 H H H CH2C(CH3)3 COOH H H NH2 155 H H H CH2C(CH3)3 COOH H H ch3 3. Use, to inhibit one or more activities of cyclophilin in a subject of a compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof, or of a composition comprising the compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof together with one or more excipient, carrier or diluent: [Chemical Formula 1] in Chemical Formula 1, A is CRa, B is CRb, G is CRe, J is CRf, M is CRg, D, E, and L are CRh, Rx is H, Ra is hydrogen, or a C1-C5 alkyl group, Rb is hydrogen, Rc is -CH2C(CH3)3, Rd is COOH or -COOR5, wherein R5 is a Cl-CIO alkyl group or a C3-C10 cycloalkyl group, wherein the C1-C10 alkyl group may 50 Date ReQue / Date Received 2024-01-114. The use of claim 3, to treat at least one cyclophilin-related disease that is an infectious disease, a cardiovascular disease, rheumatoid arthritis, sepsis, asthma, periodontitis, aging, alopecia, a neurodegenerative disease, or cancer. optionally be substituted with at least one substituent each independently being amine, a C6-C12 aryl, a C5-C10 heterocyclic group in which nitrogen is included as a hetero atom, or a C3-C10 cycloalkyl group, Re is hydrogen, NH2, OH, or a Cl-CIO alkyl group, Rf is hydrogen, NH2, OH, or a C1-C4 alkyl group, Rg is hydrogen, NH2, OH, a C1-C10 alkyl group, or -COORz, wherein Rz is a C1-C10 alkyl group, and Rh is hydrogen, NH2, OH, or a C1-C5 alkyl group.

5. The use of claim 3 or 4, wherein the compound is one or more of Compounds 64-77, 124, 134-140, 142 or 149-155 below: Compound A CRa. B CRb. G CRe. J CRf. D=E=L=M=CH Rx Ra Rb Rc Rd Re Rf 64 H H H CH2C(CH3)3 COO(CH2)3CH3 H H 65 H H H CH2C(CH3)3 COO(CH2)3CH3 CH3 H 66 H H H CH2C(CH3> COO(CH2)3CHj ch2ch3 H 67 H Cft H CH2C(CH3)3 COO(CH2)3CH3 H H 68 H CH2CH3 H CH2C(CH3)3 COO(CH2)3CH3 H H 69 H H H CH2C(CH3)3 COO(CH2)3CH3 H ch3 70 H H H CH2C(CH3)3 COO(CH2)3CH3 CH3 ch3 71 H H H CH2C(CH3> COO(CH2)2CH3 H H 72 H H H CH2C(CH3> COO(CH2)4CH3 H H 73 H H H CH2C(CH3)3 COOCH(CH3)2 H H 74 H H H CH2C(CH3)3 •4° H H 75 H H H ClhCYCIh), H H 76 H H H CH2C(CH3)3 COOCH2Ph H H 77 H H H CH2C(CH3)3 H H 124 H H H CH2C(CH3)3 COOCHs H H 134 H H H CH2C(CH3)3 COOH H H 135 H H H CH2C(CH3)3 COOH OH H 136 H H H cii2cfcn3)3 COOH H OH 137 H H H CHuCCCH^ COOH NH2 H 138 H H H CH2C(CH3)3 COOH H NH2 139 H H H CH2C(CH3)3 COOH CH3 H 140 H H H CH2C(CH3)3 COOH H ch3 Date ReQue / Date Received 2024-01-11142 A=CRa, B=CRb, G=CRe, D=E=M=CH Rx Ra Ro Rc Rd Rc Fused ring formation of J andL H H H CH2C(CH3)3 COO(CH2)3CH3 H A CRa. B CRb, G CRe, J=CR£ M CRg, D=E=L=CH - Rx Ra Rb Rc Rd Re Rf Rg 149 H H H CH2C(CH3)3 COO(CH2)3CH3 H H COO(CH2)3CH3 150 H H H CH2C(CH3)3 COOH H H OH 151 H H H CH2C(CH3)3 COOH H H NH2 152 H H H CH2C(CH3)3 COOH H H CH3 A CRa, B CRb, G CRe, J CRf, 1. CRh, D=E=M=CH - Rx Ra Rb Rc Rd Re Rf Rh 153 H H H CH2C(CH3)3 COOH H H OH 154 H H H CH2C(CH3)3 COOH H H NIE 155 H H H CH2C(CH3)3 COOH H H ch3 6. The compound of claim 1 or 2, for use to inhibit one or more activities of cyclophilin in a subject.

7. The compound for use of claim 6, to treat at least one cyclophilin-related disease that is an infectious disease, a cardiovascular disease, rheumatoid arthritis, sepsis, asthma, periodontitis, aging, alopecia, a neurodegenerative disease, or cancer. 52 Date ReQue / Date Received 2024-01-11