NOVEL BENZENE DERIVATIVE AND IMMUNOSUPPRESSION-RELATED USE THEREOF

Abstract

The present invention relates to a novel benzene derivative and immunosuppressive-related use thereof. Specifically, it relates to a composition comprising a compound of Formula 1, its stereoisomer, solvate, hydrate, crystalline form, or pharmaceutically acceptable salt. The composition has preventive or therapeutic applications in immune disorders such as autoimmune diseases, transplant rejections, allergic diseases, and inflammatory conditions.

Claims

1. A compound represented by Formula 1, its stereoisomer, solvate, hydrate, crystalline form, or pharmaceutically acceptable salt: ##STR00091## in the Formula 1, among X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5, one or two atoms are nitrogen, and the other atoms are carbon, each R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is independently selected among hydrogen, halogen, C1-C14 alkyl, C2-C14 alkenyl, C2-C14 alkynyl, C5-C14 aryl, C5-C14 arylalkyl, C3-C14 cycloalkyl, C3-C14 cycloalkylalkyl, C3-C14 heteroaryl, C3-C14 heteroarylalkyl, C3-C14 heterocycloalkyl, C3-C14 heterocycloalkylalkyl, C1-C14 alkoxy, C5-C14 aryloxy, C5-C14 heteroaryloxy, NO.sub.2, NR.sub.6, SO.sub.2R.sub.6, SO.sub.2N(R.sub.6).sub.2, CF.sub.3, OH, cyanide, thiol, triazine, triazole, tetrazole, thiazole, diazole, imidazole, alkylamine, cycloalkylamine, heterocycloamine, and biotin, and Y is selected among OH, thiol, phenoxy, cyanide, thiazole, diazole, imidazole, triazine, triazole, tetrazole, CON(R.sub.6).sub.2, NR.sub.6COR.sub.6, SO.sub.2N(R.sub.6).sub.2, NH.sub.2, NO.sub.2, COOR.sub.6, R.sub.7COOR.sub.6, R.sub.7CON(R.sub.6).sub.2, CONHSR.sub.6, CONHR.sub.7SR.sub.6, CONHSSR.sub.6, CONHRSSR.sub.6, CONHR.sub.7SO.sub.2R.sub.6, CONHOR.sub.6, CONHR.sub.7OR.sub.6, CON(R.sub.7).sub.2CON(R.sub.6).sub.2, and CON(R.sub.7).sub.2NR.sub.7COR.sub.6, wherein each R.sub.6 and R.sub.7 is independently selected among hydrogen, C1-C14 alkyl, C2-C14 alkenyl, C2-C14 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkylalkyl, alkylamine, cycloalkylamine, heterocycloamine and biotin, unsubstituted or substituted with one or more of hydrogen, halogen, thiol, phenoxy, cyanide, thiazole, diazole, imidazole, triazine, triazole, tetrazole, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkylalkyl, C1-C6 alkoxy, CF.sub.3, amine, C1-6 alkylamine, and CN.

2. A composition comprising the compound represented by Formula 1, its stereoisomer, solvate, hydrate, crystalline form, or pharmaceutically acceptable salt according to claim 1.

3. The composition according to claim 2, wherein the composition is a pharmaceutical composition for preventing or treating an immune disorder selected from autoimmune disease, transplant rejection, allergic disease, and inflammatory disease.

4. The composition according to claim 2, wherein the composition is a food composition for preventing or alleviating an immune disorder selected from autoimmune disease, transplant rejection, allergic disease, and inflammatory disease.

5. The composition according to claim 2, wherein the composition is a cosmetic composition for preventing or alleviating an immune disorder selected from autoimmune disease, transplant rejection, allergic disease, and inflammatory disease.

6. A method for preventing or treating an immune disorder selected from autoimmune disease, transplant rejection, allergic disease, and inflammatory disease, the method comprising administering to a subject in need there of the composition according to claim 2.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0045] FIG. 1 is a FACS graph to explain the relationship between CFSE fluorescence staining and cell proliferation.

[0046] FIG. 2 is a graph showing cell proliferation read by FACS after administering each compound of the present invention.

[0047] FIG. 3 to FIG. 6 are graphs measuring the secretion levels of IL-2 after 24 hours, and of IFN-, TNF-, and IL-17A after 72 hours, respectively, following drug treatment.

[0048] FIG. 7 to FIG. 9 show the methods and results for evaluating the efficacy of the compounds of the present invention in a psoriasis mouse animal model.

[0049] FIG. 10a to FIG. 10c are graphs depicting the results of evaluating the efficacy of the compounds of the present invention in a psoriasis mouse animal model, specifically regarding the ratio of CD11b granulocytes, B cells, and T cells.

EXAMPLES

[0050] Hereinafter, examples are presented to help the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the scope of the present invention is not limited by the following examples. Those having ordinary skill in the art may make various modifications to the present invention within the scope not departing from the inventive concept. Terms that are not specifically defined in this specification should be understood to have meanings commonly used in the technical field to which the present invention pertains.

Preparation Example

[0051] Compounds belonging to Formula 1 were prepared, for example, according to Scheme 1 or 2 below. Compounds having different substituents were prepared through similar steps, but not all examples are described here. Referring to the following representative examples, those skilled in the art are able to easily prepare compounds of Formula 1.

##STR00002##

[0052] In the Scheme 1, Compound C is obtained by coupling reaction from Compound A and Compound B, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.Math.HCl) and hydroxybenzotriazole (HOBt).

##STR00003##

[0053] In the Scheme 2, Compound C is obtained from Compound A and Compound B.

[0054] Representative examples of compounds prepared in this manner are provided below along with their specific chemical structure. It is noted that all compounds shown in the table are not comprised in Formula 1 according to the present invention.

TABLE-US-00001 NO Chemical structure 1 [00004] 2 [00005] 3 [00006] 4 [00007] 5 [00008] 6 [00009] 7 [00010] 8 [00011] 9 [00012] 10 [00013] 11 [00014] 12 [00015] 13 [00016] 14 [00017] 15 [00018] 16 [00019] 17 [00020] 18 [00021] 19 [00022] 20 [00023] 21 [00024] 22 [00025] 23 [00026] 24 [00027] 25 [00028] 26 [00029] 27 [00030] 28 [00031] 29 [00032] 30 [00033] 31 [00034] 32 [00035] 33 [00036] 34 [00037] 35 [00038] 36 [00039] 37 [00040] 38 [00041] 39 [00042] 40 [00043] 41 [00044] 42 [00045] 43 [00046] 44 [00047] 45 [00048] 46 [00049] 47 [00050] 48 [00051] 49 [00052] 50 [00053] 51 [00054] 52 [00055] 53 [00056] 54 [00057] 55 [00058] 56 [00059] 57 [00060] 58 [00061] 59 [00062] 60 [00063] 61 [00064] 62 [00065] 63 [00066] 64 [00067] 65 [00068] 66 [00069] 67 [00070] 68 [00071] 69 [00072] 70 [00073] 71 [00074] 72 [00075] 73 [00076] 74 [00077] 75 [00078] 76 [00079] 77 [00080] 78 [00081] 79 [00082] 80 [00083] 81 [00084] 82 [00085] 83 [00086] 84 [00087] 85 [00088] 86 [00089] [00090]

[0055] After preparing the compounds, the measured molecular weights, properties, and 1H NMR data thereof are as in Table 1 below.

TABLE-US-00002 TABLE 1 Molecular Molecular formula weights Properties 1H NMR 1 C.sub.12H.sub.9BrN.sub.2O 277.12 White 1H NMR (400 MHz, DMSO) 10.67 (s, solid 1H), 8.88 (s, 1H), 8.69 (d, J = 4.81 Hz, 1H), 7.70-7.67 (m, 2H), 7.63 (dd, J = 4.84, 0.6 Hz, 1H), 7.40- 7.36 (m, 2H), 7.17-7.12 (m, 1H). 2 C.sub.14H.sub.12BrNO 290.16 Pale 1H NMR (400 MHz, DMSO) 9.96 (s, Orange 1H), 7.72 (dd, J = 8.00, 0.96 Hz, solid 1H), 7.58 (dd, J = 7.52, 1.72 Hz, 1H), 7.50 (td, J = 7.45, 1.09 Hz, 1H), 7.44-7.39 (m, 2H), 7.27-7.24 (m, 1H), 7.21 (d, J = 7.61 Hz, 1H), 7.18-7.14 (m, 1H), 2.03 (s, 3H). 3 C.sub.14H.sub.12FNO 229.25 White 1H NMR (400 MHz, DMSO) 9.82 (s, solid 1H), 7.75-7.71 (m, 1H), 7.61-7.56 (m, 1H), 7.47 (d, J = 7.59 Hz, 1H), 7.38-7.32 (m, 2H), 7.27 (d, J = 7.29 Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.14 (m, 1H) 2.27 (s, 3H). 4 C.sub.16H.sub.16BrNO 318.21 White 1H NMR (400 MHz, DMSO) 8.47 (t, J = solid 5.26 Hz, 1H), 7.66-7.64 (m, 1H), 7.45-7.41 (m, 1H), 7.39-7.33 (m, 2H), 7.31-7.28 (m, 2H), 7.25-7.23 (m, 2H), 7.20-7.17 (m, 1H), 3.26- 3.21 (m, 2H), 2.68-2.64 (m, 2H), 1.84-1.77 (m, 2H). 5 C.sub.16H.sub.16FNO 257.31 Liquid 1H NMR (400 MHz, DMSO) 8.37 (s, 1H), 7.57 (td, J = 7.52, 1.76 Hz, 1H), 7.54-7.48 (m, 1H), 7.30-7.24 (m, 4H), 7.23-7.21 (m, 2H), 7.20- 7.15 (m, 1H), 3.28-3.23 (m, 2H), 2.65-2.61 (m, 2H), 1.84-1.77 (m, 2H). 6 C.sub.14H.sub.11Br.sub.2NO 369.06 White 1H NMR (400 MHz, DMSO) 8.99 (t, J = solid 5.96 Hz, 1H), 7.66 (d, J = 7.61 Hz, 1H), 7.54 (d, J = 10.88 Hz, 2H), 4.40 (d, J = 6.03 Hz, 2H). 7 C.sub.14H.sub.10BrN.sub.3O 316.16 White 1H NMR (400 MHz, DMSO) 13.03 (s, solid 1H), 10.48 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.23 (d, J = 7.92 Hz, 1H), 7.58-7.49 (m, 4H), 7.44-7.40 (m, 1H). 8 C.sub.22H.sub.29NO 323.48 White 1H NMR (400 MHz, DMSO) 8.50 (t, J = solid 5.53 Hz, 1H), 7.93 (d, J = 7.34 Hz, 2H), 7.77-7.72 (m, 4H), 7.51-7.48 (m, 2H), 7.42-7.39 (m, 1H), 3.30-3.24 (m, 2H), 1.55-1.51 (m, 2H), 1.29-1.25 (m, 12H) 0.87-0.84 (m, 3H). 9 C.sub.13H.sub.9Br.sub.2NO 355.03 Pale 1H NMR (400 MHz, DMSO) 10.19 (s, Orange 1H), 7.74-7.71 (m, 2H), 7.60 (d, J = solid 7.62 Hz, 2H), 7.52 (t, J = 7.26 Hz, 1H), 7.47-7.42 (m, 2H), 7.23 (t, J = 7.12 Hz, 1H). 10 C.sub.18H.sub.26BrNO 352.32 Liquid 1H NMR (400 MHz, DMSO) 8.19 (t, J = 5.37 Hz, 1H), 7.70-7.64 (m, 3H), 7.44 (t, J = 7.62 Hz, 1H), 7.33- 7.29 (m, 1H), 6.62 (d, J = 15.60 Hz, 1H), 3.19-3.14 (m, 2H), 1.46-1.43 (m, 2H), 1.30-1.25 (m, 12H), 0.87- 0.83 (m, 3H). 11 C.sub.20H.sub.31ClN.sub.2O 329.89 White 1H NMR (400 MHz, CDCl3-d1) 8.48 solid (dd, J = 1.40, 4.52, 1H), 7.84 (dd, J = 1.44, 8.16, 1H), 7.77(s, 1H), 7.38 (dd, J = 4.56, 8.16, 1H), 3.49- 3.44(m, 2H), 1.69-1.62(m, 2H), 1.41- 1.23 (m, 18H), 0.90(t, J = 6.85, 3H). 12 C.sub.20H.sub.13ClN.sub.2O 329.89 White 1H NMR (400 MHz, CDCl3-d1) 8.68 (s, solid 1H), 8.60 (d, J = 4.88, 1H), 7.61(d, J = 4.92, 1H), 6.27 (s, 1H), 3.53- 3.48(m, 2H), 1.69-1.62(m, 2H), 1.44- 1.23 (m, 18H), 0.90(t, J = 6.84, 3H). 13 C.sub.20H.sub.31ClN.sub.2O 329.89 White 1H NMR (400 MHz, CDCl3-d1) 8.46 solid (dd, J = 2.00, 4.72, 1H), 8.12 (dd, J = 2.00, 7.64, 1H), 7.35 (dd, J = 4.76, 7.64, 1H), 6.46(s, 1H), 3.50- 3.46(m, 2H), 1.68-1.61(m, 2H), 1.42- 1.26 (m, 18H), 0.88(t, J = 6.86, 3H). 14 C.sub.30H.sub.31ClN.sub.2O 329.89 White 1H NMR (400 MHz, MeOD-d4) 8.80(s, solid 1H), 8.53(d, J = 5.94, 1H), 8.16(d, J = 8.46. 1H), 7.79-7.77 (m, 1H), 7.73-7.69(m, 1H), 7.62-7.58(m, 1H), 6.60(d, J = 5.94, 1H), 3.48(t, J = 6.90, 2H), 1.72-1.65(m, 2H), 1.47- 1.43(m, 2H), 1.37-1.21 (m, 18H), 0.91(t, J = 7.01, 3H). 15 C.sub.19H.sub.32N.sub.2O 304.48 White 1H NMR (400 MHz, CD3OD-d4) 8.54 (d, solid J = 5.24 Hz, 1H), 7.65 (s, J = 0.00 Hz, 1H), 7.57 (d, J = 5.2 Hz, 1H), 3.39 (t, J = 7.18 Hz, 2H), 2.62 (s, J = 0.00 Hz, 3H), 1.63 (m, J = 1.6574- 1.6071 Hz, 2H), 1.34 (m, J = 1.3805- 1.3043 Hz, 18H), 0.91 (m, J = 0.9284- 0.8945 Hz, 3H). 16 C.sub.26H.sub.34ClNO.sub.2 428.01 White 1H NMR (400 MHz, CD3OD-d4) 8.98 (s, solid 1H), 8.69 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 5.0, 8.1 Hz, 1H), 3.44-3.38 (m, 2H), 1.70-1.61 (m, 2H), 1.41-1.29 (m, 18H), 0.91 (t, J = 6.9 Hz, 3H). 17 C.sub.18H.sub.26BrNO.sub.2 368.32 White 1H NMR (400 MHz, CDCl3) 7.58 (dd, J = solid 1.1, 8.0 Hz, 1H), 7.53 (dd, J = 1.8, 7.6 Hz, 1H), 7.35 (td, J = 3.8, 8.7 Hz, 1H), 7.28 (d, J = 1.8 Hz, 0H), 7.24 (d, J = 1.8 Hz, 0H), 5.96 (s, 1H), 3.46 (dd, J = 7.1, 13.0 Hz, 2H), 2.93-2.88 (m, 1H), 2.74 (dd, J = 4.0, 5.0 Hz, 1H), 2.46 (dd, J = 2.7, 5.0 Hz, 1H), 1.48-1.24 (m, 14H). 18 C.sub.23H.sub.33NO 339.52 White 1H NMR (400 MHz, MeOD) 8.20-8.17 solid (m, 1H), 8.00-7.92 (m, 2H), 7.61- 7.50 (m, 4H), 3.48 (t, J = 7.1 Hz, 2H), 1.75-1.66 (m, 2H), 1.39-1.29 (m, 18H), 0.92 (t, J = 6.9 Hz, 3H). 19 C H N O 290.45 White 1H NMR (400 MHz, MeOD) 8.98 (d, J = solid 1.5 Hz, 1H), 8.70 (dd, J = 1.6, 4.9 Hz, 1H), 8.27-8.23 (s, 1H), 7.56 (ddd, J = 0.8, 4.9, 8.0 Hz, 1H), 1.70- 1.61 (m, 2H), 0.91 (t, J = 6.9 Hz, 3H). 20 C H N O 340. 1 Yellow 1N NMR (400 MHz, MeOD) 8.90 (d, J = oil 8.6 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 5.5 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 3.50 (t, J = 7.2 Hz, 2H), 1.76-1.66 (m, 2H), 1.46 (td, J = 5.8, 21.2 Hz, 3H), 1.34 (dd, J = 9.7, 12.6 Hz, 15H), 0.91 (t, J = 6.8 Hz, 3H). 21 C H N O 356.51 Orange 1H NMR (400 MHz, CDCl3) 8.32 (s, sold 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 0.8, 8.2 Hz, 1H), 7.79- 7.74 (m, 1H), 7.64-7.60 (m, 1H), 3.53 (dd, J = 7.2, 13.4 Hz, 2H), 1.75- 1.66 (m, 2H), 3.48-1.24 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 22 C H N O 340. 1 Yellow 1N NMR (400 MHz, CDCl3) 8.36 (d, J = oil 8.5 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 5.8 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.39 (dd, J = 1.1, 8.3 Hz, 1H), 7.24 (td, J = 4.2, 8.4 Hz, 1H), 3.51 (dd, J = 7.0, 13.7 Hz, 2H), 1.70-1.60 (m, 2H), 0.87 (t, J = 6.9 Hz, 3H). 23 C H N O 354.54 Brown 1N NMR (400 MHz, DMSO) 8.53 (t, J = sold . Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.34 (ddd, J = 1.3, 6.8, 8.2 Hz, 1H), 7.14 (ddd, J = 1.2, 6.8, 8.1 Hz, 1H), 6.95 (s, 1H), 6.07 (s, 2H), 3.25 (dd, J = 6.9, 12.9 Hz, 2H), 0.85 (t, J = 6.8 Hz, 3H). 24 C.sub.19H.sub.32N.sub.2OS 336.54 White 1H NMR (400 MHz, CDCl3) 8.53 (dd, solid J = 1.8, 5.0 Hz, 1H), 7.87 (dd, J = 1.7, 7.6 Hz, 1H), 7.11 (dd, J = 5.0, 7.6 Hz, 1H), 3.46 (dd, J = 7.1, 12.9 Hz, 2H), 2.65 (s, 3H), 1.68-1.59 (m, 2H), 1.36-1.25 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H). 25 C.sub.20H.sub.33NO 303.49 White 1H NMR (400 MHz, CDCl3) 7.39-7.33 solid (m, 2H), 7.32-7.27 (m, 2H), 7.24 (s, 1H), 3.58 (s, 2H), 3.19 (dd, J = 7.0, 13.1 Hz, 2H), 1.41 (q, J = 6.9 Hz, 2H), 1.28-1.20 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H) 26 C.sub.24H.sub.33ClN.sub.2O.sub.2 416.99 White 1H NMR (400 MHz, CDCl3) 8.62 (dd, J = solid 2.0, 7.6 Hz, 1H), 8.19 (dd, J = 2.0, 4.8 Hz, 1H), 7.76 (s, 1H), 7.42 (dd, J = 2.2, 6.7 Hz, 1H), 7.17 (dd, J = 4.8, 7.6 Hz, 1H), 3.49 (dd, J = 7.1, 12.8 Hz, 2H), 1.62 (t, J = 7.2 Hz, 2H), 1.39-1.30 (m, 6H), 1.27- 1.21 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H). 27 C.sub.26H.sub.37NO 379.59 White 1H NMR (400 MHz, MeOD) 7.50-7.31 solid (m, 6H), 7.22 (d, J = 7.8 Hz, 2H), 3.14 (t, J = 6.9 Hz, 2H), 2.39 (s, 3H), 1.34-1.28 (m, 18H), 1.12- 1.04 (m, 2H), 0.92 (t, J = 6.8 Hz, 3H). 28 C.sub.19H.sub.29Cl.sub.2NO.sub.2 374.35 White 1H NMR (400 MHz, CDCl3) 12.95 (s, solid 1H), 7.49 (d, J = 2.4 Hz, 1H), 6.27 (s, 1H), 3.45 (dd, J = 7.2, 13.0 Hz, 2H), 1.36-1.24 (m, 19H), 0.88 (t, J = 6.8 Hz, 3H). 29 C.sub.19H.sub.31ClN.sub.2O 338.92 White 1H NMR (400 MHz, CDCl3) 7.34 (dd, J = solid 1.3, 7.9 Hz, 1H), 7.26 (s, 1H), 7.26-7.21 (m, 1H), 6.62 (t, J = 7.8 Hz, 1H), 3.41 (t, J = 6.9 Hz, 2H), 1.29-1.24 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H). 30 C.sub.18H.sub.28Cl.sub.2N.sub.2O 359.34 White 1H NMR (400 MHz CDCl3) 8.31 (d, J = solid 5.4 Hz, 1H), 7.32 (d, J = 5.4 Hz, 1H), 3.49 (dd, J = 7.0, 13.0 Hz, 2H), 1.30-1.24 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H). 31 C.sub.12H.sub.29N.sub.3O 291.44 White 1H NMR (400 MHz, CDCl3) 9.28 (dd, J = solid 1.8, 5.0 Hz, 1H), 8.34 (dd, J = 1.8, 8.4 Hz, 1H), 7.67 (dd, J = 5.0, 8.4 Hz, 1H), 3.53 (dd, J = 7.1, 13.2, Hz, 2H), 1.29-1.24 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H). 32 C.sub.19H.sub.32N.sub.2O.sub.2 320.48 White 1H NMR (400 MHz, CDCl3) 8.52 (dd, J = solid 2.0, 7.5 Hz, 1H), 8.25 (dd, J = 2.0, 4.8 Hz, 1H), 7.05 (dd, J = 4.8, 7.5 Hz, 1H), 4.10 (s, 3H), 3.46 (dd, J = 7.2, 12.8 Hz, 2H), 1.67-1.58 (m, 2H), 1.36-1.24 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H). 33 C.sub.25H.sub.34F.sub.3N.sub.3O 449.56 White 1H NMR (400 MHz, CDCl3) 10.72 (s, solid 1H), 8.35 (dd, J = 1.6, 4.8 Hz, 1H), 8.06 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.72 (dd, J = 1.6, 7.6 Hz, 1H). 7.42 (t, J = 8.0 Hz, 1H), 6.77 (dd, J = 4.9, 7.7 Hz, 1H), 3.44 (dd, J = 7.2, 13.0 Hz, 2H), 1.28-1.24 (m, 20H) 0.88 (t, J = 6.9 Hz, 3H). 34 C.sub.18H.sub.28F.sub.2N.sub.2O 326.43 White 1H NMR (400 MHz, MeOD) 8.44 (d, J = solid 2.4 Hz, 1H), 7.75-7.69 (m, 1H), 1.68-1.59 (m, 3H), 1.32 (s, 24H), 0.92 (t, J = 6.8 Hz, 4H). 35 C.sub.18H.sub.30BrNO.sub.2S 404.41 Yellow .sup.1H NMR (500 MHz, cdcl.sub.3) 8.15 (dd green J = 7.8, 1.8 Hz, 1H), 7.74 (dd, J = solid 7.6 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.45-7.39 (m, 1H), 5.08 (t, J = 6.1 Hz, 11), 2.90 (q, J = 6.8 Hz, 2H), 1.45 (p, 2H), 1.28-1.19 (m, 19H) 0.88 (t J = 6.9 Hz, 3H). 36 C.sub.18H.sub.32N.sub.2O.sub.2s 340.53 Off- 1H NMR (500 MHz, cdcl.sub.3) 7.91 (td, white to J = 7.6, 1.8 Hz, 1H), 7.62-7.54 (m Ivory 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21 solid (dd, J = 10.2, 8.3 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 2.99 (q, J = 6.7 Hz, 2H), 1.47 (p, J = 7.1 Hz, 2H), 1.33- 1.19 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H). 37 C2OH31NO.sub.3 333.47 Off- 1H NMR (500 MHz, cdcl.sub.3) 8.03 (dd, white to J = 7.4, 1.6 Hz, 1H), 7.56-7.43 (m, Ivory 4H), 3.40 (q, J = 6.8 Hz, 2H), 1.59 solid (p, J = 7.2 Hz, 2H), 1.27 (d, J = 14.8 Hz, 33H), 0.88 (t, J = 6.8 Hz, 6H). 38 C.sub.20H.sub.30NF.sub.3NO 357.46 Off- 1H NMR (500 MHz, cdcl.sub.3) 7.72- white to 7.66 (m, 1H), 7.58 (dd, J = 8.6, 6.2 Ivory Hz, 1H), 7.55-7.49 (m, 2H), 5.77 solid (s, 1H), 3.43 (dd, J = 7.5, 6.0 Hz, 2H), 1.63-1.56 (m, 2H), 1.39-1.27 (m, 9H), 1.26 (s, 10H), 0.88 (t, J = 6.8 Hz, 3H). 39 C.sub.19H.sub.29Cl.sub.2NO 358.35 White 1H NMR (500 MHz, cdcl.sub.3) 7.31 (d, J = solid 7.5 Hz, 2H), 7.28-7.21 (m, 1H), 5.74 (s, 1H), 3.48 (q, J = 6.7 Hz, 2H), 1.68-1.59 (m, 3H), 1.40 (td, J = 10.5, 9.1, 4.8 Hz, 2H), 1.35-1.24 (m, 16H) 0.88 (t, J = 6.8 Hz, 3H). 40 C.sub.18H.sub.29Cl.sub.2NO.sub.2S 394.4 Yellow 1H NMR (500 MHz, cdcl.sub.3) 7.48 (d, J = green 8.0 Hz, 2H), 7.38-7.31 (m, 1H), solid 5.29 (t, J = 6.2 Hz, 1H), 3.04 (q, J = 6.8 Hz, 2H), 1.48 (p, J = 7.1 Hz, 2H), 1.31-1.19 (m, 21H), 0.88 (t, J = 6.9 Hz, 3H). 41 C.sub.21H.sub.37NO.sub.2S 367.59 Off- 1H NMR (500 MHz, cdcl.sub.3) 6.96 (s, white to 2H), 4.46 (q, J = 6.8 Hz, 1H), 2.88 Ivory (q, J = 6.8 Hz, 2H), 2.64 (s, 6H), solid 2.30 (s, 3H), 1.43 (p, J = 7.0 Hz, 2H), 1.23 (dd, J = 22.6, 9.8 Hz, 17H) 0.88 (t, J = 6.9 Hz, 3H). 42 C.sub.18H.sub.28BrNO 354.33 Off- 1H NMR (500 MHz, cdcl.sub.3) 8.37 (d, J = white to 8.3 Hz, 1H), 7.62 (s, 1H), 7.53 Ivory (dd, J = 8.0, 1.5 Hz, 1H), 7.34- solid 7.24 (m, 1H), 6.97 (td, J = 7.7, 1.6 Hz, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H), 1.38 (dt, J = 16.4, 8.2 Hz, 3H), 1.35-1.24 (m, 15H), 0.88 (t, J = 6.9 Hz, 3H). 43 C.sub.19H.sub.30BrNO 367.15 White 1H NMR (500 MHz, cdcl.sub.3) 6 7.55 (d, J = solid 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (td, J = 7.7, 1.7 Hz, 1H), 5.90 (s, 1H), 4.51 (d, J = 6.0 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.68-1.60 (m, 3H), 1.33- 1.23 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H). 44 C.sub.26H.sub.37Br.sub.2N 521.13 Off- 1H NMR (500 MHz, cdcl.sub.3) 7.60 (dd, white to J = 7.8, 1.8 Hz, 1H), 7.50 (dd, J = Ivory 8.0, 1.2 Hz, 1H), 7.30-7.23 (m, solid 2H), 7.07 (td, J = 7.6, 1.7 Hz, 1H), 3.71 (s, 3H), 2.52-2.46 (m, 1H), 1.58-1.51 (m, 2H), 1.33-1.25 (m, 5H), 1.23 (d, J = 9.2 Hz, 10H), 0.88 (t, J = 6.9 Hz, 3H). 45 C.sub.18H.sub.30NO.sub.2S 343.50 Off- 1H NMR (500 MHz, cdcl.sub.3) 7.91 (td, white to J = 7.6, 1.8 Hz, 1H), 7.62-7.54 (m, Ivory 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21 solid (dd, J = 10.2, 8.3 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 2.99 (q, J = 6.7 Hz, 2H), 1.47 (p, J = 7.1 Hz, 2H), 1.33- 1.19 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H). 46 C.sub.18H.sub.32N.sub.2O.sub.2S 340.53 Off- 1H NMR (500 MHz, cdcl.sub.3) 7.71 (d, J = white to 8.0 Hz, 1H), 7.33 (t, J = 7.7 Hz, Ivory 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.77 solid (d, J = 8.1 Hz, 1H), 4.83 (s, 2H), 4.66 (s, 1H), 2.86 (q, J = 6.4 Hz, 2H), 1.40 (p, J = 7.0 Hz, 2H), 1.33- 1.17 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H). 47 C.sub.20H.sub.23BrN.sub.2O.sub.2 403.32 White 1H NMR (500 MHz, cd.sub.3od) 7.64 (d, J = solid 8.0 Hz, 1H), 7.54 (t, J = 8.7 Hz, 2H), 7.50-7.39 (m, 2H), 7.39-7.28 (m, 3H), 4.53 (d, J = 11.8 Hz, 2H), 2.39-2.32 (m, 2H), 1.69 (q, J = 7.3 Hz, 2H), 1.43-1.32 (m, J = 4.8, 3.8 Hz, 4H), 0.97-0.91 (m, 3H) 48 C.sub.20H.sub.23BrN.sub.2O.sub.2 403.32 Off- 1H NMR (500 MHz, cd.sub.3od) 7.87- white to 7.83 (m, 1H), 7.65 (dd, J = 11.8, 8.0 Ivory Hz, 2H), 7.50-7.38 (m, 3H), 7.38- solid 7.27 (m, 2H), 7.24-7.16 (m, 1H), 4.54 (d, J = 6.8 Hz, 2H), 2.49 (td, J = 7.5, 2.1 Hz, 2H), 2.16 (d, J = 1.0 Hz, 2H), 1.76 (q, J = 7.5 Hz, 2H), 1.47-1.37 (m, 4H), 0.94 (q, J = 7.0 Hz, 3H). 49 C.sub.20H.sub.23BrN.sub.2O.sub.2 403.32 Off- 1H NMR (500 MHz, cd.sub.3od) 7.87- white to 7.83 (m, 1H), 7.65 (dd, J = 11.8, 8.0 Ivory Hz, 2H), 7.50-7.38 (m, 3H), 7.38- solid 7.27 (m, 2H), 7.24-7.16 (m, 1H), 4.54 (d, J = 6.8 Hz, 2H), 2.49 (td, J = 7.5, 2.1 Hz, 2H), 2.16 (d, J = 1.0 Hz, 2H), 1.76 (q, J = 7.5 Hz, 2H), 1.47-1.37 (m, 4H), 0.94 (q, J = 7.0 Hz, 3H). 50 C.sub.19H.sub.30N.sub.2O.sub.3 334.25 Off- 1H NMR (500 MHz, cdcl.sub.3) 8.17- white 8.12 (m, 1H), 7.90-7.83 (m, 1H), to 7.75 (q, J = 5.3, 4.2 Hz, 2H), 5.24 Ivory (t, J = 6.1 Hz, 1H), 3.09 (q, J = 6.8 solid Hz, 2H), 1.51 (p, J = 7.1 Hz, 2H), 1.34-1.18 (m, 19H), 0.88 (t, J = 6.9 Hz, 3H). 51 C.sub.27H.sub.40N.sub.2O 408.63 Yellow 1H NMR (500 MHz, cdcl.sub.3) 8.40 (dd, solid J = 8.6, 1.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.77 (ddd, J = 8.5, 6.6, 1.4 Hz, 1H), 7.60 (ddd, J = 7.9, 6.6, 1.2 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 2.90 (s, 3H), 2.57 (s, 3H), 1.39-0.98 (m, 11H), 0.87 (dd, J = 16.2, 9.5 Hz, 5H). 52 C.sub.22H.sub.33N.sub.3O 355.53 Yellow 1H NMR (500 MHz, cdcl.sub.3) 8.09 (t, J = solid 7.6 Hz, 1H), 7.42 (ddd, J = 16.2, 8.1, 1.4 Hz, 2H), 7.38 (d, J = 1.4 Hz, 1H), 7.27 (td, J = 7.5, 1.3 Hz, 2H), 7.09 (s, 3H), 6.95-6.89 (m, 1H), 3.42-3.38 (m, 3H), 1.59-1.57 (m, 2H), 1.36-1.22 (m, 32H), 0.89 (t, J = 6.6 Hz, 4H). 53 C.sub.26H.sub.42N.sub.2O.sub.2 414.63 White 1H NMR (500 MHz, cdcl.sub.3) 7.57 (ddd, solid J = 11.1, 5.8, 3.3 Hz, 2H), 7.44 (dd, J = 5.7, 3.3 Hz, 2H), 6.76-6.70 (m, 1H), 6.53 (d, J = 8.1 Hz, 1H), 3.91 (tdd, J = 10.5, 8.0, 3.9 Hz, 1H), 3.38 (td, J = 7.3, 5.7 Hz, 2H), 1.97 (dq, J = 12.6, 4.1 Hz, 2H), 1.74 (dp, J = 12.3, 4.1 Hz, 2H), 1.65-1.50 (m, 2H), 1.47-1.17 (m, 19H), 0.88 (t, J = 6.9 Hz, 3H) 54 C.sub.18H.sub.29F.sub.2NO.sub.2S 361.19 White 1H NMR (500 MHz, cdcl.sub.3) 7.51 (tt, solid J = 8.5, 6.0 Hz, 1H), 7.03 (t, J = 8.7 Hz, 2H), 4.88 (s, 1H), 3.10 (q, J = 6.8 Hz, 2H), 1.52 (q, J = 7.2 Hz, 2H), 1.28-1.22 (m, 15H), 0.88 (t, J = 6.9 Hz, 3H). 55 C.sub.19H.sub.28F.sub.3NO 343.21 White 1H NMR (500 MHz, cdcl.sub.3) 7.86 (tdd, solid J = 8.4, 5.9, 2.4 Hz, 1H), 7.08 (tdd, J = 9.0, 6.7, 2.0 Hz, 1H), 6.52 (s, 1H), 3.47 (q, J = 6.7 Hz, 2H), 1.63- 1.59 (m, 3H), 1.42-1.24 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H). 56 C.sub.21H.sub.33ClN.sub.2O.sub.2 308.96 Off- 1H NMR (500 MHz, cdcl.sub.3) 8.01 (s, white to 4H), 7.66 (dd, J = 7.6, 1.8 Hz, 1H), Ivory 7.45-7.30 (m, 3H), 7.13 (s, 1H), liquid 6.39 (s, 1H), 4.14 (d, J = 5.3 Hz, 2H), 3.29 (td, J = 7.2, 5.8 Hz, 2H), 1.81 (s, 3H), 1.55-1.49 (m, 2H), 1.33-1.27 (m, 6H), 1.25 (s, 11H), 0.88 (t, J = 6.9 Hz, 3H). 57 C.sub.21H.sub.33NO 354.54 Yellow 1H NMR (500 MHz, cdcl.sub.3) 7.58 (d, J = solid 8.2 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.23-7.12 (m, 2H), 5.92 (s, 4H), 2.86 (t, J = 7.5 Hz, 2H), 1.46 (q, J = 7.6 Hz, 2H), 1.31-1.01 (m, 18H) 0.88 (t, J = 7.0 Hz, 3H). 58 C.sub.18H.sub.30N.sub.2O.sub.4S 370.51 White 1H NMR (500 MHz, cdcl3) 8.17- solid 8.12 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (q, J = 5.3, 4.2 Hz, 2H), 5.24 (s, 1H), 3.09 (q, J = 6.8 Hz, 2H), 1.51 (p, J = 7.1 Hz, 2H), 1.34-1.14 (m, 19H) 0.88 (t, J = 6.9 Hz, 3H). 59 C.sub.20H.sub.30F.sub.3N.sub.2O 357.46 Off- 1H NMR (500 MHz, cdcl3) 7.72- white to 7.66 (m, 1H), 7.58 (dd, J = 8.6, 6.2 Ivory Hz, 1H), 7.53 (d, J = 7.3 Hz, 2H), liquid 5.77 (s, J = 7.1 Hz, 1H), 3.43 (dd, J = 7.5, 6.0 Hz, 2H), 1.63-1.56 (m, 3H), 1.40-1.21 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H). 60 C.sub.19H.sub.19Cl.sub.2N.sub.2O 358.35 White 1H NMR (500 MHz, cdcl3) 7.62 (d, J = solid 8.4 Hz, 1H), 7.42 (s, 1H), 7.30 (dd, J = 8.3, 2.0 Hz, 1H), 3.45 (q, J = 6.7 Hz, 2H), 1.62 (q, J = 7.5 Hz, 3H), 1.42-1.28 (m, 7H), 1.26 (s, 11H), 0.88 (t, J = 6.8 Hz, 3H). 61 C.sub.25H.sub.35NO.sub.2 381.27 White 1H NMR(CDCl.sub.3, 400 MHz) 8.22(dd, J = 7.85, solid 1.68 Hz, 1H), 7.6(s, 1H), 7.3(q, J = 7.44 Hz, 3H), 7.1(m, 2H), 7.0(d, J = 8.39 Hz, 2H), 6.8(d, J8.22 Hz, 1H), 3.4(q, J = 6.35 Hz, 2H), 1.5(t, J = 7.05 Hz, 2H), 1.2(m, 18H), 0.8(t, J = 6.83 Hz, 3H) 62 C.sub.19H.sub.30H.sub.2O.sub.3 334.23 White 1H NMR(CDCl.sub.3, 400 MHz) d solid 8.2(dd, J = 7.85, 1.68 Hz, 1H), 7.6(s, 1H), 7.3(q, J = 7.44 Hz, 1H), 7.1(m, 1H), 7.0(d, J = 8.39 Hz, 1H), 6.8(d, J = 8.22 Hz, 1H), 3.4(q, J = 6.35 Hz, 2H), 1.5(Q, J = 7.05 Hz, 18H), 0.8(q, J = 7.81 Hz, 3H) 63 C H IN O 415.14 White 1H NMR(CDCl.sub.3, 400 MHz) solid d7.8(d, J = 7.90 Hz, 1H), 7.3(m, 2H), 7.0(ddd, J = 7.95, 6.53, 2.60 Hz, 1H), 5.7(s, 1H), 3.4(m, 1H), 1.6(dt, J = 14.62, 7.30 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 6.86 Hz, 3H) J = 7.95, 6.53, 2.60 Hz, 1H), 5.7(s, 1H), 3.4(m, 1H), 1.6(dt, J = 14.62, 7.30 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 6.85 Hz, 3H) 64 C H FN O 352.22 Yellow 1H NMR(CDCl.sub.3, 400 MHz) d 7.8(dd, solid J = 8.24, 0.72 Hz, 1H), 7.5(td, J = 8.35, 5.46 Hz, 1H), 7.4(m, 1H), 5.8(d, J = 3.5 Hz, 1H), 3.4(q, J = 6.58 Hz, 2H), 1.6(q, J = 7.35 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 6.83 Hz, 3H) 65 C H N O 318.27 Light 1H NMR(CDCl.sub.3, 400 MHz) d 7.3(m, 1H), yellow 7.2(m, 2H), 6.6(d, J = 8.16 Hz, 1H), solid 6.5(m, 1H), 5.9(s, 1H), 2.8(d, J = 2.78 Hz, 2H), 1.5(q, J = 9.07 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 10.74 Hz, 3H) 66 C H N O 304.25 White 1H NMR(CDCl.sub.3, 400 MHz) d 7.2(dd, solid J = 7.82, 1.30 Hz, 1H), 7.1(m, 1H), 6.6(m, 2H), 5.9(td, J = 6.51, 2.38 Hz, 1H), 5.4(m, 2H), 3.3(m, 2H), 1.5(m, 2H), 1.3(m, 18H), 0.8(m, 3H) 67 C H N O 305.25 Yellow 1H NMR(DMSO, 400 MHz) d 8.4(m, 1H), solid 7.7(dd, J = 4.23, 1.55 Hz, 1H), 7.1(dd, J = 8.44, 4.22 Hz, 1H), 7.0(dd, J = 8.34, 1.42 Hz, 1H), 6.7(m, 2H), 3.1(q, J = 6.85 Hz, 2H), 1.4(m, 2H), 1.1(dd, J = 23.54, 4.55 Hz, 18H), 0.8(t, J = 6.81 Hz, 3H) 68 C H N O 305.25 Orange 1H NMR(DMSO, 400 MHz) d 8.4(m, 1H), solid 8.0(m, 1H), 7.6(t, J = 5.62 Hz, 1H), 7. (t, J = 5.14 1H), 6.3(m, 2H), 3.1(m, 2H), 1.4(m, 2H), 1.2(m, 18H), 0.8(m, 3H) 69 C H N O 305.25 White 1H NMR(CDCl , 400 MHz) d 8.1 (m, 1H), solid 7.5(dd, J = 7.67, 1.31 Hz, 1H), 6.5(m, 1H), 6.2(s, 2H), 6.0(s, 1H), 3.3(q, J = 6.77 Hz, 2H), 1.5(q, J = 7.22 Hz, 2H), 1.3(dt, J = 16.51, 8.37 Hz, 18H), 0.8(m, 3H) 70 C H N O 306.44 White 1H NMR(DMSO, 400 MHz) d 12.3(dd, solid J = 2.28, 1.48 Hz, 1H), 9.7(m, 1H), 8.2(dd, J = 7.2, 2.24 Hz, 1H), 7.6(dd, J = 6.33, 2.27 Hz, 1H), 3.3(m, 2H), 1.4(m, 2H), 1.2(m, 18H), 0.8(t, J = 6.84 Hz, 3H) 71 C H N O 305.47 Light 1H NMR(DMSO, 400 MHz) d 8.4(s, 1H), yellow 8.3(m, 1H), 7.9(d, J = .78 Hz, 1H), solid 7.0(s, 2H), .5(d, J = .78 Hz, 1H), .1(m, 2H), 1.4(m, 2H), 1.1(m, 18H), 0.80(t, J = 6.66 Hz, 3H) 72 C H N O S 342.5 Light 1H NMR(CDCl.sub.3, 400 MHz) d 12.8(m, 1H), yellow 8.7(s, 1H), 8.0(q, J = 5.92, 2H), solid 6.6(d, J = 7.23 Hz, 1H), 3.3(q, J = 6.50 Hz, 2H), 1.7(tt, J = 17.11, 8.37 Hz, 2H), 1.3(m, 18H), 0.8(d, J = 13.72 Hz, 3H) 73 C H Br O 3 9.35 Light 1H NMR(CDCl.sub.3, 400 MHz) d 8.4(dd, yellow J = 4.46, 1.5 Hz, 1H), 8.0(dd J = 8.06, solid 1.47 Hz, 1H), 7.7(d, J = 0.72 Hz, 1H), 7.2(q, J = 4.17 Hz, 2H) 3.4(q, J = 6.66 Hz, 2H), 1.6(dt, J = 14.53, 7.28 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 6.8 Hz, 3H) 74 C H N O 249.36 white 1H NMR(CDCl , 400 MHz) H NMR(CDCl , solid 400 MHz) d 8.13(dd, J = 4.77, 1.76 Hz, 1H), 7.55(dd, J = 7.68, 1.76 Hz, 6.5(dd, J = 7.70, 4.94 Hz, 6.2(m, 2H), .9(s, 1H), 3.3(td, J = 7.17, 5.77 Hz, 2H, 1.5(m, 2H), 1.3(m, 10H), 0. (m, 3H) 75 C.sub.16H.sub.23rN.sub.3O 273.18 Yellow 1H NMR(CDCl.sub.3, 400 MHz) d 8.1(dd, solid J = 4.79, 1.72 Hz, 1H), 7.5(dd, J = 7.66, 1.72 Hz, 1H), 6.5(dd, J = 7.67, 4.89 Hz, 1H), 6.3, (s, 2H), 5.8(s, 1H), 5.2(ddd, J = 7.67, 6.47, 1.20 Hz, 1H), 5.0(m, 1H), 3.9(t, J = 6.06 Hz, 2H)2.0(m, 4H), 1.6(m, 9 H). 76 C.sub.18H.sub.29BrN.sub.2O 368.15 Brown 1H NMR(CDCl.sub.3, 400 MHz) d solid 8.4(dd, J = 4.70, 1.95 Hz, 1H), 7.9(dd, J = 7.57, 2.04 Hz, 1H), 7.3(dd, J = 7.60, 4.75 Hz, 1H), 6.1(s, 1H), 3.4(m, 2H), 1.6(dt, J = 14.61, 7.28 Hz, 2H), 1.3(m, 18H) 0.8(d, J = 13.74 Hz, 3H) 77 C.sub.19H.sub.29F.sub.3N.sub.2O 358.22 White 1H NMR(CDCl.sub.3, 400 MHz)d 8.7(dd, solid J = 4.72, 1.29 Hz, 1H), 7.8(m, 1H), 7.5(dd, J = 7.81, 4.76 Hz, 1H), 5.7(t, J = 1.9 Hz, 1H), 3.4(m, 2H), 1.5 J = 7.35 Hz, 2H), 1.2(m, 18H), 0.8(t, J = 6.84 Hz, 3H) 78 C.sub.20H.sub.31F.sub.3N.sub.2O 372.24 White 1H NMR(CDCl.sub.3, 400 MHz) d 7.3(d, solid J = 8.13 Hz, 1H), 6.8(d, J = 13.50 Hz, 1H), 6.8(m, 1H), 6.0(d, J = 0.60 Hz, 1H, 5.6(s, 2H), 3.3(q, J = 6.51 Hz, 2H), 1.5(q, J = 7.28 Hz, 2H), 1.3(m, 18H), 0.8(t, J = 6.83 Hz, 3H) 79 C.sub.17H.sub.29N.sub.3O 291.23 Brown 1H NMR(CDCl.sub.3, 400 MHz) d 8.8(d, solid = 4.89 Hz, 2H), 7.9(s, 1H), 7.4(t, = 4.85 Hz, 1H), 3.4(q, J = 6.65 Hz, 2H), 1.6(m, 2H), 1.3(ddt, J = 27.30, 10.48, 5.24 Hz, 18H), 0.8(t, J = 6.86 Hz, 3H) 80 C.sub.18H.sub.30N.sub.2OS 322.21 Yellow 1H NMR(CDCl.sub.3, 400 MHz) d 11.7(m, 1H), solid 9.4(m, 1H), 8.6(dd, J = 7.17, 2.15 Hz, 1H), 7.4(dt, J = 6.81, 3.64 Hz, 1H), 7.4(t, J = 6.69 Hz, 1H), 3.4(m, 2H), 1.6(m, 2H), 1.3(m, 18H), 0.8(t, J = 9.41 Hz, 3H) indicates data missing or illegible when filed

Example 1: Validation of T Cell Proliferation Inhibition Effect

[0056] To investigate whether the compounds obtained in the Preparation Example have an inhibitory effect on T cell proliferation, the T cell proliferation was determined ex vivo using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE), which binds to intracellular molecules by covalent bonds.

[0057] Spleens were harvested and minced from C57BL/6 mice at 7 weeks of age, and then single cells were isolated using a strainer (40 m pore size, SPL). Red blood cells were removed using ACK (Ammonium-Chloride-Potassium) lysis buffer to isolate only leukocytes. Subsequently, CD90.2 microbeads (130-121-278, Miltenyi Biotech.) were added, and subjected to react at 4 C. for 20 minutes. After that, spleen T cells were isolated using a MACS Magnetic Stand and LS column. The isolated T cells from the spleen were resuspended in 1 mL of Free media (RPMI-1640+200 U/mL penicillin+200 g/mL streptomycin), followed by the addition of 0.3 L of CFSE (10 mM), and reacted at 37 C. for 5 minutes. Subsequently, 10 mL of Free media was added to stop the reaction, and the cells were centrifuged to obtain the cell pellet. RPMI 1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 g/mL streptomycin was added to suspend the cells, and 210.sup.5 cells per well were seeded into a 96-well plate and T cells were activated by treatment with CD3 and CD28 antibodies (each at 0.5 g/mL).

[0058] The compound diluted in DMSO was treated in triplicate at concentrations of 10 M, 30 M, and 50 M, respectively. After incubation at 37 C. with 5% CO.sub.2 for 3 days, cell proliferation levels were determined using a FACS Canto machine.

[0059] In the FACS graph of FIG. 1, the y-axis represents the quantity (number) of cells, while the x-axis represents the fluorescence level of the cells. Cells stained with CFSE exhibit a decrease in CFSE intensity as they undergo cell division. This reduction in CFSE fluorescence results in a leftward shift along the x-axis in the graph. This indicates cell proliferation.

[0060] FIG. 2 depicts the graphs of cell proliferation read by FACS after administration of Compounds 9, 69, and 84, respectively. Each graph shows increasing drug concentrations administered from bottom to top, corresponding to drug concentrations of 10 M, 30 M, and 50 M, respectively. Compounds 69 and 84 demonstrate inhibition of cell proliferation at concentrations ranging from 10 to 30 M. However, Compound 9 shows no inhibition of cell proliferation even at a concentration of 50 M.

[0061] To collectively indicate the proliferation inhibition rate for the experimental results, the relative value of the proliferation amount after compound administration to the proliferation amount after CD3/CD28+DMSO administration was calculated. Subsequently, it was converted into an inhibition amount and expressed as a percentage, thereby determining the proliferation inhibition rate. Specifically, the proliferation inhibition rate was calculated as follows:

[00001]$\mathrm{Proliferation}\mathrm{inhibition}\mathrm{rate}\left(\%\right)=$$\{1-(\mathrm{Proliferation}\mathrm{amount}\mathrm{in}\mathrm{drug}-\mathrm{treated}\mathrm{cells}$$\mathrm{Proliferation}\mathrm{amount}\mathrm{after}\mathrm{CD}3/\mathrm{CD}28+\mathrm{DMSO}\mathrm{treatment})\}100$

TABLE-US-00003 TABLE 2 Proliferation inhibition rate (%) 50 M 30 M 10 M Compound 10 92% 72% 15% Compound 11 99% 62% 10% Compound 12 99% 38% 5% Compound 13 100% 48% 10% Compound 14 100% 100% 100% Compound 15 90% 35% 10% Compound 16 100% 100% 0% Compound 19 100% 99% 19% Compound 25 99% 90% 20% Compound 26 100% 100% 73% Compound 27 100% 96% 62% Compound 28 91% 47% 11% Compound 29 65% 33% 5% Compound 30 55% 41% 16% Compound 31 69% 57% 15% Compound 32 54% 42% 12% Compound 33 100% 100% 33% Compound 34 87% 43% 6% Compound 35 93% 92% 85% Compound 37 65% 55% 23% Compound 38 85% 73% 40% Compound 39 89% 61% 7% Compound 40 97% 97% 86% Compound 41 100% 100% 80% Compound 43 72% 50% 27% Compound 45 97% 59% 30% Compound 46 93% 94% 47% Compound 50 97% 66% 0% Compound 51 100% 100% 100% Compound 52 100% 95% 42% Compound 53 85% 65% 22% Compound 54 77% 60% 55% Compound 55 95% 82% 52% Compound 56 62% 50% 26% Compound 57 100% 100% 93% Compound 58 68% 51% 39% Compound 60 98% 72% 10% Compound 61 98% 86% 16% Compound 63 89% 78% 30% Compound 64 100% 100% 79% Compound 65 77% 43% 39% Compound 67 100% 88% 35% Compound 68 100% 67% 57% Compound 69 100% 100% 99% Compound 70 98% 78% 29% Compound 71 100% 100% 100% Compound 72 86% 80% 68% Compound 73 86% 76% 32% Compound 74 95% 91% 66% Compound 75 98% 98% 95% Compound 76 65% 49% 36% Compound 77 66% 47% 24% Compound 78 66% 45% 8% Compound 79 100% 88% 46% Compound 80 100% 100% 43% Compound 82 85% 80% 60% Compound 83 100% 63% 0% Compound 84 100% 96% 89%

[0062] On the other hand, as shown in Table 3 below, compounds not belonging to Formula 1 according to the present invention were confirmed to have a very low proliferation inhibition rate.

TABLE-US-00004 TABLE 3 Proliferation inhibition rate (%) 50 M 30 M 10 M Compound 1 7% 6% 9% Compound 2 11% 10% 11% Compound 3 18% 15% 9% Compound 4 16% 12% 23% Compound 9 0% 0% 0% Compound 10 3% 9% 5% Compound 81 22% 2% 0%

Example 2: Cytotoxicity Experiment

[0063] To evaluate the cytotoxicity of the compound according to the present invention, the following experiment was conducted.

[0064] The T lymphocyte cell line Jurkat E6-1, purchased from the Korean Cell Line Bank, was cultured in RPMI-1640 medium comprising 10% FBS, 100 U/mL penicillin, and 100 g/mL streptomycin. After culturing, the cells were harvested and centrifuged at 1,300 rpm for 5 minutes. After removal of the supernatant, the cells were resuspended in the same medium at a concentration of approximately 2.210.sup.5 cells/mL, and 90 L of the cell suspension was distributed per well into a 96-well plate (Costar 96 well cell culture plate, Corning). After treating 10 L of each compound at different concentrations onto the respective wells of the plate, it was cultured for 24 hours at 37 C. in a 5% CO.sub.2 incubator. Subsequently, 10 L of CCK-8 was added to each well, and it was cultured again for 2 hours at 37 C. in a 5% CO.sub.2 incubator. Absorbance was then measured at 450 nm to determine the relative cell survival rate compared to untreated cells, as shown in Table 4.

[0065] The values listed in Table 4 represent the relative cell survival rates in the groups treated with each compound at different concentrations, with the cell survival rate of untreated cells set as 100%.

TABLE-US-00005 TABLE 4 Relative cell survival rate (%) 50 M 30 M 20 M 10 M Compound 10 83 85 88 91 Compound 12 79 83 92 100 Compound 13 57 70 71 95 Compound 14 72 70 81 86 Compound 16 85 92 101 121 Compound 17 66 80 80 106 Compound 18 99 99 101 102 Compound 19 83 82 87 94 Compound 20 105 107 108 113 Compound 21 124 109 106 101 Compound 22 36 39 42 42 Compound 23 54 62 62 66 Compound 24 54 61 68 71 Compound 25 84 87 90 95 Compound 26 82 85 97 101 Compound 27 63 71 77 109 Compound 29 60 77 80 107 Compound 30 106 108 109 120 Compound 31 102 102 111 111 Compound 33 70 79 91 100 Compound 34 87 101 109 112 Compound 35 86 87 89 97 Compound 37 92 90 90 90 Compound 38 89 89 91 90 Compound 39 79 78 102 89 Compound 40 86 96 99 105 Compound 41 80 82 83 85 Compound 42 103 104 109 110 Compound 43 108 108 104 101 Compound 44 93 94 98 100 Compound 45 74 76 94 96 Compound 47 96 97 97 98 Compound 48 98 99 99 100 Compound 49 98 98 98 98 Compound 50 68 70 75 74 Compound 51 90 92 94 99 Compound 52 84 84 85 88 Compound 53 95 98 97 96 Compound 54 76 77 83 89 Compound 55 105 108 110 115 Compound 56 86 89 91 92 Compound 57 101 104 108 108 Compound 58 94 97 98 100 Compound 61 74 76 94 96 Compound 63 79 75 78 70 Compound 64 87 87 87 91 Compound 65 77 86 84 87 Compound 67 92 93 93 94 Compound 68 82 88 91 92 Compound 69 84 88 94 95 Compound 70 125 124 122 119 Compound 71 88 92 94 101 Compound 73 104 98 97 94 Compound 74 77 81 84 101 Compound 75 85 86 95 97 Compound 76 70 92 95 115 Compound 77 123 123 124 116 Compound 78 120 117 113 112 Compound 81 108 107 105 103 Compound 82 88 97 90 95 Compound 83 77 87 105 102 Compound 84 94 96 94 96

Example 3: Confirmation of Cytokine Expression Reduction Effect

[0066] To confirm the effect of compounds of the present invention on the secretion of cytokines by T cells, the following experiment was conducted.

[0067] Spleens were harvested and minced from C57BL/6 mice at 7 weeks of age, and single cells were isolated using a strainer (40 m pore size, SPL). Red blood cells were removed using ACK (Ammonium-Chloride-Potassium) lysis buffer to isolate only leukocytes. These were then reacted with 10 v/v % CD90.2 microbeads (130-121-278, Miltenyi Biotech.) at 4 C. for 20 minutes, resulting in the isolation of spleen T cells from magnetic-based purification. The T cells were cultured in a 96-well plate at an amount of 210.sup.5 cells/well. For T cell activation, each well was treated with anti-CD3/CD28 antibodies at a concentration of 1 g/mL. Subsequently, Vehicle (DMSO) and compounds (Compound 14, Compound 19, Compound 26, Compound 31, Compound 35, Compound 40, Compound 41, Compound 56, Compound 69, Compound 75) at a concentration of 30 M were treated in each well, and it was cultured at 37 C. in a 5% CO.sub.2 incubator. After 24 and 72 hours, the T cell culture medium was taken, and centrifugation was performed at 13,000 rpm for 10 minutes to obtain the supernatant.

[0068] To measure the concentration of cytokines present in the T cell culture medium, Mouse Th1/Th2/Th17 Cytokine CBA Kit (Cytometric Bead Array kit) 560485 from BD Science was utilized for flow cytometry analysis. The secretion levels of IL-2 at 24 hours after each drug treatment, and IFN-, TNF-, and IL-17A at 72 hours were measured after each drug treatment.

[0069] As shown in FIGS. 3 to 6 representing the experimental results, T cells stimulated with anti-CD3/CD28 antibodies but not treated with compounds from the present invention exhibited abundant secretion of IL-2, IFN-, TNF-, and IL-17A. In contrast, when treated with compounds (Compound 14, Compound 19, Compound 26, Compound 31, Compound 35, Compound 40, Compound 41, Compound 56, Compound 69, Compound 75), there was a significant decrease in the secretion of these cytokines. Based on this, it is evident that compounds of the present invention have the effect of reducing cytokine secretion in the process of inhibiting T cell proliferation.

Example 4: Confirmation of Treatment Efficacy in Psoriasis Model

[0070] To confirm the therapeutic effect of compounds according to the present invention on psoriasis, a psoriasis animal model was established to evaluate the alleviation of skin lesions and changes in immune cell profiles by administering Compound 69 or Compound 83 via injection.

[0071] To establish a psoriasis mouse animal model, BALB/c mice (7 weeks old, 20 g, female) were purchased from Hana Biotech Co. and allowed to acclimate to the housing environment for one week. Afterward, the fur on the dorsal area of the mice was initially shaved using a shaver, followed by complete removal with depilatory cream (Nicrin Cream, comprising thioglycolic acid 80%, manufactured by ILDONG Pharmaceutical CO., LTD). The mice were then housed for 24 hours to confirm any wounds on their backs.

[0072] Subsequently, in order to verify the preventive and therapeutic effects of compounds according to the present invention on psoriasis, five experimental groups were established as shown in FIG. 7 and Table 5. From the second to the fifth group, Aldara cream was applied once daily for two weeks (14 days, total of 14 applications) at a dose of 80 mg (imiquimod, 4 mg) per mouse to induce psoriasis. Furthermore, to compare the preventive and therapeutic effects of compounds according to the present invention (Compound 69 and Compound 83) on psoriasis, 40 mg/kg of the compound per mouse was dissolved in DMSO corresponding to 10% of the dosing volume, and then diluted in a mixture of Cremophor EL-PEG 400-distilled water to achieve a final ratio of DMSO: Cremophor EL:PEG 400:distilled water to 1:1:4:4 (v/v/v/v). Subsequently, the respective injections were intraperitoneally administered at a dose of 100 L per mouse, twice a day with a 12-hour interval. For the Vehicle control group, injections excluding the drug but comprising the vehicle solution (DMSO: Cremophor EL:PEG 400:distilled water=1:1:4:4 (v/v/v/v)) were administered at a dose of 100 L per mouse, twice a day with a 12-hour interval.

TABLE-US-00006 TABLE 5 Topical application of No. of Group imiquimod 4 mg Intervention Mouse Normal X Depilation only (no administration) 5 Paoriasis Depilation only (no administration) 5 Psoriasis Solvent (DMSO:Cremophor EL:PEG 5 (Vehicle) 400:distilled water = 1:1:4:4 (v/v/v/v)) 100 L, administered intraperitoneally twice daily Psoriasis Solvent (DMSO:Cremophor EL:PEG 5 (Compound 69) 400:distilled water = 1:1:4:4 v/v/v/v) Psoriasis 100 L + Compound 40 mg/kg, 5 (Compound 83) administered intraperitoneally twice daily

[0073] 14 days after the experiment, the erythema, thickness, and exfoliation of the skin on the back of each mouse were observed in the respective groups, and the pathological tissue of the area was analyzed through H&E staining. As shown in FIG. 8, in the groups where only psoriasis was induced (Psoriasis, Non-injection) and in the groups where psoriasis was induced along with intraperitoneal injection of vehicle (Psoriasis, Vehicle), erythema, thickness, and exfoliation of the skin area were severe. However, in the groups treated with Compound 69 or Compound 83, skin lesions were either minimally present or hardly observed.

[0074] As shown in FIG. 9, in the groups where only psoriasis was induced (Psoriasis, Non-injection) and in the groups where psoriasis was induced along with intraperitoneal injection of vehicle (Psoriasis, Vehicle), severe hyperkeratosis, parakeratosis, and irregular acanthosis were observed, along with significant infiltration of inflammatory cells. However, in the groups treated with Compound 69 or Compound 83, such phenomena were either minimally present or hardly observed.

[0075] To assess the impact of each compound on immune cells in vivo, the spleens of mice treated with each compound were harvested, and cells were extracted, and cells were suspended in MACS buffer (2 mM EDTA, 0.5% FBS, 137 mM NaCl, 2.7 mM KCl, 10 mM Na.sub.2HPO.sub.4, 1.8 mM KH.sub.2PO.sub.4, Miltenyi Biotech.). For flow cytometry analysis, each mouse's splenocytes were aliquoted at 510.sup.5 cells per FACS tube (5 mL round tube, Falcon). To prevent non-specific antibody binding, each tube was treated with 1 g/mL of anti-mouse CD16/CD32 (InVivoMAb) for 30 minutes, followed by centrifugation at 13,000 rpm for 5 minutes, and resuspended in 100 L of MACS buffer. Subsequent experiments were conducted depending on the type of immune cells to be examined.

[0076] For B cells, each FACS tube was stained with 1 g/mL of FITC-conjugated anti-B220 antibody (eBioscience) at 4 C. for 30 minutes, followed by washing with 2 mL of MACS buffer. Subsequently, each tube was centrifuged at 15,000 rpm for 5 minutes, the supernatant was removed, and the precipitated cells were fixed using 200 L of 4% paraformaldehyde solution.

[0077] For T cells, each FACS tube was stained with 1 g/mL of PerCP-Cy5.5-conjugated anti-CD3 antibody (Biolegend), FITC-conjugated anti-CD8 antibody (eBioscience) and Cy7-conjugated anti-CD4 antibody (eBioscience) at 4 C. for 30 minutes, followed by washing with 2 mL of MACS buffer. Subsequently, each tube was centrifuged at 15,000 rpm for 5 minutes, the supernatant was removed, and the precipitated cells were fixed using 200 L of 4% paraformaldehyde solution.

[0078] For macrophages, each FACS tube was stained with 1 g/mL of FITC-conjugated anti-CD11b antibody (eBioscience) at 4 C. for 30 minutes, followed by washing with 2 mL of MACS buffer. Subsequently, each tube was centrifuged at 15,000 rpm for 5 minutes, the supernatant was removed, and the precipitated cells were fixed using 200 L of 4% paraformaldehyde solution.

[0079] Through the process of staining immune cells and conducting flow cytometric analysis, as seen in FIGS. 10a to 10c, in the groups where psoriasis was induced by applying imiquimod only (Psoriasis, Non-injection) and in the groups where psoriasis was induced by applying imiquimod along with intraperitoneal injection of Vehicle (Psoriasis, Vehicle), there was a sharp increase in CD11b-positive granulocytes and a relative decrease in the composition ratio of B cells and T cells in the spleen. However, in the groups treated with Compound 69 or Compound 83 via intraperitoneal injection, the proportion of CD11b granulocytes decreased, accompanied by an increase in the proportion of B cells and T cells. Consequently, it was confirmed that when the effective compound is administered, the composition ratio of CD11b-positive granulocytes, B cells, and T cells in the spleen becomes similar to that observed in normal mice, indicating the therapeutic efficacy of the drugs.

[0080] Through the above results, it has been confirmed that Compound 69 or Compound 83, compounds according to the present invention, exhibits therapeutic efficacy in the psoriasis, autoimmune disease model and affects the functioning of immune cells.