Broad spectrum macrocyclic antibiotics

Abstract

Provided herein are antibacterial compounds, wherein the compounds in some configurations have a broad spectrum of biological activity. In various configurations, the compounds act by inhibiting bacterial type 1 signal peptidase (SpsB), which is an essential protein in bacteria. Also provided herein are pharmaceutical compositions and methods of treatment using the compounds.

Description

LCMS (Method 5-95 AB, ESI): tR= 0.814 min, [M + H]+= 784.6; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 3H), 7.33 (d, J =8.0 Hz, 1H), 7.18-7.01 (m, 6H), 6.87 (d, J) =8.0 Hz, 1H), 6.80 (d, J =8.0 Hz, 1H), 6.15 (s, 1H), 5.00-4.75 (m, 3H), 4.18 (s, 2H), 3.80-3.70 (m, 2H), 3.30-3.10 (m, 3H), 3.07-3.01 (m, 3H), 2.63-2.59 (m, 2H), 2.40 (s, 3H), 2.30-2.15 (m, 1H), 2.13-2.02 (m, 1H), 1.70-1.50 (m, 3H), 1.37-1.27 (m, 8H), 0.90 (t, J =6.8 Hz, 3H) Example 276: Synthesis of compound 476

[0001] Compound 476 (formic acid salt) was prepared as a white solid using similar methods described in Example 7. LCMS (Method 5-95 AB, ESI): tR= 0.718 min, [M + H]+= 876.4; 1H NMR (400 MHz, MeOH-d4)  8.72 (s, 1H), 8.46 (br s, 2H), 8.28 (d, J =8.0 Hz, 1H), 7.52 (d, J =8.0 Hz) 1H), 7.35-7.30 (m, 1H), 7.25-7.20 (m, 1H), 7.12 (d, J =8.4 Hz, 1H), 7.06 (d, J =8.4 Hz, 1H), 6.86 (s, 1H), 6.64 (s, 1H), 6.56 (s, 1H), 5.22-5.18 (m, 1H), 4.80-4.70 (m, 2H), 4.67 (d, J =14.4 Hz, 1H), 4.34-4.22 (m, 4H), 4.20 (s, 2H), 3.59-3.52 (m, 1H), 3.31-3.25 (m, 4H), 3.18-3.12 (m, 2H), 3.00-2.95 (m, 1H), 2.92 (s, 3H), 2.66 (s, 3H), 2.28-2.17 (m, 1H), 2.15-2.01 (m, 1H), 1.39 (s, 9H) Example 277: Synthesis of compound 477

[0002] Compound 477 (formic acid salt) was prepared as a white solid using similar methods described in Example 7. LCMS ( روش 5-95 AB, ESI): tR= 0.722 min, [M + H]+= 906.4;1H NMR (400 MHz, MeOH- d4)  8.72 (s, 1H), 8.50 (br s, 3H), 8.30 (d, J =7.6 Hz, 2H), 7.53 (d, J =8.0 Hz, 2H), 7.31 (d, J =7.6 Hz, 1H), 7.22-7.14 (m, 2H), 7.06 (d, J =8.0 Hz, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 6.50 (s, 1H), 5.20-5.15 (m, 1H), 4.81-4.75 (m, 2H), 4.28-4.14 (m, 4H), 4.19 (s, 2H), 3.72 (d, J =7.2 Hz, 2H), 3.43-3.38 (m, 2H), 3.22-3.13 (m, 5H), 3.05-3.01 (m, 1H), 2.95 (s, 3H), 2.67 (s, 3H), 2.27-2.66 (m, 1H), 2.18-2.16 (m, 1H), 1.38 (s, 9H) مثال ۲۷۸: سنتز ترکیب ۴۷۸

[0003] Compound 478 (formic acid salt) was prepared from compound 105 (Example U) using similar methods described in Example G (Compound 101) as a white solid. LCMS (ESI); 6.82 (dd, J = 9.8, 2.4 Hz, 2H), 6.39 (s, 1H), 5.15 (dd, J = 7.9, 5.5 Hz, 1H), 4.98 (dd, J = 11.5, 3.2 Hz, 1H), 4.29 – 4.19 (m, 7H), 3.30 (d, J = 3.3 Hz, 1H), 3.24-3.17 (m, 5H), 3.16-3.09 (m, 2H), 2.93 (s, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H), 2.34-2.25 (m, 1H), 2.19-2.10 (m, 1H), 1.63 (q, J = 7.3 Hz, 2H), 1.39 – 1.28 (m, 9H), 1.26-1.19 (m, 1H), 0.96 – 0.88 (m, 3H), 0.57 – 0.49 (m, 4H) Example 279: Synthesis of compound 479

[0004] Compound 479 (formic acid salt) was prepared by similar methods described in Example G (Compound 101) as a white solid. LCMS (ESI); 6.88 (dd, J = 17.2, 2.4 Hz, 2H), 6.34 (s, 1H), 5.15 (dd, J = 7.8, 5.5 Hz, 1H), 4.94 (dd, J = 11.5, 3.1 Hz, 1H), 4.62 (t, J = 7.4 Hz, 1H), 4.31 – 4.19 (m, 6H), 3.25 (q, J = 4.9 Hz, 4H), 3.16 – 3.09 (m, 2H), 2.94 (s, 3H), 2.64 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.34-2.23 (m, 1H), 2.19 – 2.09 (m, 1H), 1.88-1.78 (m, 1H), 1.73-1.59 (m, 2H), 1.38-1.29 (m, 10H), 0.98 (t, J = 7.4 Hz, 3H), 0.95-0.89 (m, 2H) Example 280: Synthesis of compound 480

[0005] Compound 480 (formic acid salt) was prepared by similar methods described in Example 279 and Example G (Compound 101) to give a white solid. LCMS (ESI); 3H), 6.99 (d, J = 8.3 Hz, 1H), 6.84 – 6.79 (m, 1H), 5.87 (s, 1H), 4.99 – 4.91 (m, 2H), 4.69 – 4.61 (m, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.21 – 3.99 (m, 6H), 3.12 – 2.92 (m, 4H), 2.61 (td, J = 7.6, 3.9 Hz, 3H), 2.40 (d, J = 22.7 Hz, 3H), 1.80 (dt, J = 12.5, 6.5 Hz, 1H), 1.64 (d, J = 21.1 Hz, 3H), 1.30 (d, J = 13.8 Hz, 12H), 0.97 (t, J = 7.4 Hz, 3H), 0.92 – 0.87 (m, 3H) Example 281: Synthesis of compound 481

[0006] Compound 481-1 was prepared as an off-white solid following a procedure similar to that for compound 101-I using (2S,4R)-1-benzyloxycarbonyl-4-(tert-butoxycarbonylamino)pyrrolidine-2-carboxylic acid. LCMS (ESI): [M+H]+= 926

[0007] Compound 481 (formic acid salt) was prepared by similar methods described in Example G (Compound 101) to give an off-white solid. LCMS (ESI): [M+H]+= 852; 1H NMR (400 MHz, Methanol-d4) δ 7.42 – 7.36 (m, 1H), 7.29 – 7.04 (m, 8H), 6.87 (dd, J = 21.4, 2.5 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H). 5.21 (t, J = 7.2 Hz, 1H), 4.80 – 4.72 (m, 1H), 4.24 – 4.15 (m, 5H), 3.84 – 3.78 (m, 1H), 3.75 – 3.68 (m, 1H), 3.25 – 3.19 (m, 1H), 3.19 – 3.11 (m, 4H), 2.95 (d, J = 3.2 Hz, 3H), 2.62 (t, J = 7.6 Hz, 2H), 2.39 (s, 2H), 2.34 (q, J = 5.4, 4.6 Hz, 4H), 1.62 (dt, J = 14.9, 8.1 Hz, 3H), 1.38 – 1.28 (m, 10H), 0.93 – 0.88 (m, 3H) Example 282: Synthesis of compound 482

[0008] Compound 482 (formic acid salt) was prepared as a white solid using similar methods described in Example G (Compound 101). LCMS (Method A, ESI): tR= 3.519 min, [M + H]+= 860; 1H NMR (400 MHz, Methanol-d4) δ 7.40 – 7.34 (m, 1H), 7.23 (dd, J = 8.6, 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.85 (dd, J = 18.5, 2.5 Hz, 2H), 6.30 (s, 1H), 5.02 (dd, J = 7.9, 5.8 Hz, 1H), 4.88 (d, J = 3.1 Hz, 1H), 4.80 – 4.74 (m, 1H), 4.26 – 4.18 (m, 6H), 4.00 – 3.88 (m, 2H), 3.58 (dd, J = 10.1, 4.1 Hz, 1H), 3.22 – 3.16 (m, 4H), 2.88 (s, 3H), 2.44 – 2.37 (m, 2H), 2.31 – 2.26 (m, 1H), 1.65 (q, J = 7.4 Hz, 2H), 1.42 – 1.27 (m, 26H), 0.93 – 0.87 (m, 3H) Example 283: Synthesis of compound 483

[0009] Compound 483 (formic acid salt) was prepared as an off-white solid using similar methods described in Example G (Compound 101). LC-MS: (method A, ESI): tR= 3.522 min, [M + H]+= 860; 1H NMR (400 MHz, Methanol-d4) δ 7.31 (dd, J = 8.6, 2.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 19.8, 2.4 Hz, 2H), 6.22 (s, 1H), 4.99 (dd, J = 8.3, 5.2 Hz, 1H), 4.81 (s, 1H), 4.69 (q, J = 6.7 Hz, 1H), 4.24 – 4.10 (m, 6H), 4.01 – 3.96 (m, 2H), 3.63 (q, J = 7.4 Hz, 1H), 3.22 – 3.15 (m, 4H), 3.11 – 3.01 (m, 1H), 2.81 (s, 3H), 2.38 – 2.26 (m, 4H), 1.58 (q, J = 7.3 Hz, 2H), 1.36 – 1.19 (m, 24H), 0.87 – 0.80 (m, 3H) Example 284: Synthesis of compound 484

[0010] Compound 484 (formic acid salt) was prepared as a white solid using similar methods described in Example G (Compound 101). LC-MS: ( روش A, ESI): tR= 2.073 min, [M + H]+= 796;1H NMR (400 MHz, DMSO- d6) δ 9.04 (d, J = 7.8 Hz, 1H), 8.78 (t, J = 5.7 Hz, 1H), 8.73 (d, J = 7.7 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.22 – 7.13 (m, 2H), 7.06 (dd, J = 27.1, 8.6 Hz, 2H), 6.71 (d, J = 2.5 Hz, 2H), 6.28 (s, 1H), 4.97 – 4.90 (m, 1H), 4.80 – 4.67 (m, 2H), 4.17 (d, J = 5.8 Hz, 2H), 4.03 – 3.93 (m, 3H), 3.18 (d, J = 16.8 Hz, 2H), 3.04 – 2.97 (m, 1H), 2.88 – 2.72 (m, 10H), 2.05 – 1.91 (m, 2H), 1.80 – 1.71 (m, 4H), 1.19 (d, J = 6.7 Hz, 3H) مثال ۲۸۵: سنتز ترکیب ۴۸۵

[0011] Step 1: A solution of ethyl 3-oxopentanoate (1 mL, 7.02 mmol), triethyl orthoacetate (2 mL, 11 mmol), pyridine (57 μL, 0.698 mmol), acetic acid (40 μL, 0.697 mmol) and toluene (6.0 mL, 56 mmol) in a sealed vial was heated at 120 °C for 23 h. The reaction mixture was evaporated under reduced pressure to give the crude product as an orange oil. This crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to give 254.2 mg (17%) of ethyl (Z)-2-(1-ethoxyethylidene)-3-oxopentanoate as an orange oil. LCMS (ESI): [M+H]+= 215.0

[0012] Step 2: To a solution of 4-tert-butylbenzonitrile (9 mL, 53 mmol) in diethyl ether (100 mL, 960 mmol) at 0 °C, lithium bis(trimethylsilyl)amide (1 mol / L) in THF (110 mL, 110.0 mmol) was added dropwise over 30 min. The reaction was stirred at 0 °C for 2 h and then warmed to room temperature. After another 6 h, the reaction was cooled in an ice bath and quenched by carefully adding hydrogen chloride (12 mol / L in water) (20 mL, 240 mmol), diluted with water (50 mL), and then stirred for 10 min. The resulting mixture was extracted with water (4 × 50 mL). The combined aqueous extracts were adjusted to pH ~13 with aqueous sodium hydroxide (10 mol / L) in water (15 mL, 150 mmol), and then extracted with 10% isopropanol in dichloromethane (4 × 50 mL). The combined dichloromethane extracts were dried over magnesium sulfate, and filtered. The filtered solids were stirred with 1:1 DCM:EtOAc and filtered again, the combined filtrates were evaporated in vacuo to give 3.494 g (37%) of 4-(tert-butyl)benzimidamide.LCMS (ESI): [M+H]+= 177.15; 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.98 (br s, 3H), 1.29 (s, 9H).

[0013] Step 3: A mixture of ethyl (2Z)-2-(1-ethoxyethylidene)-3-oxo-pentanoate (254.2 mg, 1.186 mmol), 4-tert-butyl-benzamidine (197.0 mg, 1.118 mmol), sodium ethoxide (21% w / w solution in ethanol) (0.80 mL, 2.1 mmol), and ethanol (1.5 mL, 26 mmol) was heated in a sealed vial at 70°C overnight. The reaction mixture was evaporated onto celite. The crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to give 80.2 mg (22%) of ethyl 2-(4-(tert-butyl)phenyl)-4-ethyl-6-methylpyrimidine-5-carboxylate as a clear colorless oil. LCMS (ESI): [M+H]+= 327

[0014] Step 4: To a solution of ethyl 2-(4-tert-butylphenyl)-4-ethyl-6-methyl-pyrimidine-5-carboxylate (97 mg, 0.2972 mmol) in tetrahydrofuran (2.0 mL, 25 mmol), lithium hydroxide (1.0 M in water) (0.30 mL, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h. After addition of additional lithium hydroxide (1.0 M in water) (0.90 mL, 0.90 mmol) and methanol (1 mL), the reaction mixture was heated to 50 °C overnight. The reaction mixture was diluted with dichloromethane, neutralized with hydrochloric acid (1 mol / L) in water (1.2 mL), and washed with brine. The aqueous phase was extracted with another portion of dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo to yield 88.4 mg (99.7%) of 2-(4-(tert-butyl)phenyl)-4-ethyl-6-methylpyrimidine-5-carboxylic acid, which was used without further purification. LCMS (ESI): [M+H]+= 299.15

[0015] Compound 485 (TFA salt) was prepared from 2-(4-(tert-butyl)phenyl)-4-ethyl-6-methylpyrimidine-5-carboxylic acid and compound 101-K using similar methods described in Example G. LCMS (method A, ESI): tR= 2.971 min, [M+H]+= 918.5; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 7.3 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.37 – 8.29 (m, 3H), 7.99 – 7.72 (m, 6H), 7.56 (d, J = 8.5 Hz, 2H), 7.28 – 7.22 (m, 1H), 7.21 – 7.07 (m, 3H), 6.74 (s, 1H), 6.45 (s, 1H), 5.09 – 4.99 (m, 1H), 4.82 – 4.66 (m, 2H), 4.28 – 4.05 (m, 7H), 3.21 – 2.98 (m, 11H), 2.91 (s, 3H), 2.77 (q, J = 7.4 Hz, 2H), 2.02 (d, J = 39.8 Hz, 2H), 1.34 (s, 9H), 1.29 (t, J = 7.5 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H) Example 286: Synthesis of compound 486

[0016] Compound 486 (TFA salt) was prepared from ethyl 3-oxohexanoate using similar methods described in Example 285. LCMS (method A, ESI): tR= 3.162 min, [M+H]+= 932.5; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 7.9 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.38 – 8.30 (m, 3H), 7.93 – 7.76 (m, 10H), 7.56 (d, J = 8.5 Hz, 2H), 7.26 – 7.08 (m, 3H), 6.74 (d, J = 2.4 Hz, 1H), 6.47 (s, 1H), 5.09 – 4.98 (m, 1H), 4.81 – 4.67 (m, 2H), 4.29 – 4.05 (m, 6H), 3.28 – 2.93 (m, 6H), 2.91 (s, 2H), 2.79 – 2.63 (m, 2H), 2.12 – 1.92 (m, 2H), 1.78 (q, J = 7.5 Hz, 2H), 1.34 (s, 9H), 1.21 (d, J = 6.7 Hz, 2H), 0.95 (t, J = 7.3 Hz, 2H) Example 287: Synthesis of compound 487

[0017] Compound 487 (TFA salt) was prepared from ethyl 4-methyl-3-oxopentanoate using similar methods described in Example 285. LCMS (Method A, ESI): tR= 3.260 min, [M+H]+= 932.5; 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.38 – 8.29 (m, 3H), 7.83 (s, 9H), 7.57 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 1H), 7.20 – 7.06 (m, 3H), 6.73 (s, 2H), 6.46 (s, 1H), 5.08 – 4.97 (m, 1H), 4.80 – 4.65 (m, 2H), 4.28 – 4.06 (m, 6H), 3.25 – 2.97 (m, 8H), 2.91 (s, 3H), 2.13 – 1.92 (m, 2H), 1.34 (s, 9H), 1.29 (d, J = 6.6 Hz, 6H), 1.21 (d, J = 6.7 Hz, 3H) Example 288: Synthesis of compound 488

[0018] Step 1: To a solution of ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate (519.9 mg, 3.091 mmol) in ethanol (8.0 mL, 140 mmol), 4-methylbenzenesulfonohydrazide (596.9 mg, 3.109 mmol) was added. The reaction mixture was stirred at room temperature for 90 min, and then purified in vacuo to ethyl 3-(2-tosylhydrazono)bicyclo[3.1.0]hexane-6-carboxylate, which was not further purified. LCMS (ESI): [M+H]+= 337.05

[0019] Step 2: The product obtained in Step 1 was combined with (4-tert-butylphenyl)boronic acid (840.2 mg, 4.720 mmol), potassium carbonate (669 mg, 4.8405 mmol) and 1,4-dioxane (12 mL, 140 mmol) and the mixture was heated at 100 °C for 2 h. Additional (4-tert-butylphenyl)boronic acid (514.5 mg, 2.890 mmol) and 1,4-dioxane (10 mL) were added and the reaction mixture was heated at 110 °C overnight. The reaction mixture was evaporated in vacuo onto Celite. This crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-20% ethyl acetate in heptane) to give 249.5 mg of ethyl 3-(4-(tert-butyl)phenyl)bicyclo[3.1.0]hexane-6-carboxylate as a yellow oil (28% yield after 2 steps).

[0020] Compound 488 (TFA salt) was prepared from ethyl 3-(4-(tert-butyl)phenyl)bicyclo[3.1.0]hexane-6-carboxylate using similar procedures described in Example 285. LCMS (Method A, ESI): tR= 2.997 min, [M+H]+= 879.5 Example 289: Synthesis of compound 489

[0021] Step 1: To a solution of 4-tert-butylbenzamidine (1.02 g, 5.78 mmol) in ethanol (29 mL), diethyl 2-(ethoxymethylene)propanedioate (1.25 g, 5.78 mmol) was added, followed by the addition of sodium ethoxide (2.6 M in ethanol, 2.4 mL, 5.78 mmol). The reaction was allowed to stir under nitrogen at room temperature. After 1.5 h, the reaction was concentrated to 2.29 g of crude product without further purification.

[0022] Step 2: To a vial containing ethyl 2-(4-tert-butylphenyl)-6-oxo-1H-pyrimidine-5-carboxylate (1.20 g, 4.0 mmol), phosphoryl chloride (1.9 mL, 20 mmol) was added. The reaction was heated to 60 °C. After another 1.5 h, 3 equivalents of phosphoryl chloride (1.2 mL, 12 mmol) were added. After 3 h, the reaction was evaporated in vacuo and used directly in the next step.

[0023] Step 3: To a solution of ethyl 2-(4-tert-butylphenyl)-4-chloro-pyrimidine-5-carboxylate (1.28 g, 4 mmol) in THF (8 mL) was added a solution of methylamine (2 M) in THF (8 mL, 16 mmol). After stirring for 2 h at room temperature, the reaction was concentrated, treated with water, and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (eluent gradient: 0-40% isopropyl acetate / heptane, then 100% isopropyl acetate) gave the desired product (0.754 g, 60%) as a white solid. LCMS (ESI); 7.1 Hz, 2H), 3.11 (d, J = 4.8 Hz, 3H), 1.37 – 1.30 (m, 12H)

[0024] Step 4: To a solution of ethyl 2-(4-tert-butylphenyl)-4-(methylamino)pyrimidine-5-carboxylate (0.15 g, 0.50 mmol) in THF (2.7 mL) and methanol (0.8 mL) was added a solution of lithium hydroxide (1M) in water (1.5 mL, 1.5 mmol). The reaction was heated to 60 °C. After stirring overnight, the reaction was evaporated in vacuo, treated with dilute hydrochloric acid to pH 5-6, and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude solid was dissolved in DCM and filtered through a pad of Celite, eluting with 5% methanol / DCM. The filtrate was evaporated in vacuo to give the title compound (142 mg) as a white solid. LCMS (ESI): [M+1]+= 286;1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.77 (s, 1H), 8.33 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.14 (s, 1H), 3.09 (d, J = 4.7 Hz, 3H), 1.32 (s, 9H)

[0025] Step 5: Compound 489 (TFA salt) was prepared from 2-(4-(tert-butyl)phenyl)-4-(methylamino)pyrimidine-5-carboxylic acid using the method described in Example G. LCMS (Method A, ESI): tR= 2.82 min, [M + H]+= 906.4; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.8 Hz, 1H), 8.95 (d, J = 7.8 Hz, 1H), 8.83 (s, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.36 – 8.24 (m, 2H), 7.94 – 7.68 (m, 10H), 7.59 – 7.48 (m, 2H), 7.30 – 7.20 (m, 2H), 7.15 (d, J = 8.7 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 6.76 – 6.68 (m, 2H), 6.32 (s, 1H), 5.04 – 4.90 (m, 1H), 4.83 – 4.64 (m, 2H), 4.23 – 4.07 (m, 6H), 3.17 – 2.99 (m, 10H), 2.73 (s, 3H), 2.11 (s, 2H), 1.40 – 1.27 (m, 11H), 1.22 (d, J = 6.8 Hz, 3H) Example 290: Synthesis of compound 490

[0026] Compound 490 (TFA salt) was prepared as a white solid using similar methods described in Example 289. LCMS (Roche A, ESI): tR= 2.66 min, [M + H]+= 920.5;1H NMR (400 MHz, DMSO- d6) δ 9.12 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.39 – 8.23 ​​(m, 4H), 7.95 – 7.72 (m, 10H), 7.56 – 7.49 (m, 2H), 7.28 – 7.02 (m, 4H), 6.73 (d, J = 2.4 Hz, 2H), 6.40 (s, 1H), 4.91 (q, J = 7.4 Hz, (1H), 4.81 – 4.65 (m, 2H), 4.26 – 4.06 (m, 6H), 3.22 – 2.91 (m, 15H), 2.85 (s, 2H), 2.08 – 1.95 (m, 2H), 1.33 (s, 9H), 1.21 (d, J = 6.7 Hz, 3H) Example 291: Synthesis 491

[0027] Step 1: To a mixture of 2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carboxylic acid (prepared according to Example 69) (811 mg, 3.0 mmol) and DCM (9 mL), DIPEA (1.57 mL, 9 mmol) was added followed by HATU (1.25 g, 3.3 mmol). The reaction mixture was stirred at 20°C for 5 min, then [(1S)-1-[(tert-butoxycarbonylamino)methyl]-2-methoxy-2-oxo-ethyl]ammonium chloride (917 mg, 3.6 mmol) was added. The mixture was stirred at 20°C for 18 h, then diluted with DCM, washed with saturated aqueous ammonium chloride, brine, and then dried over sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 40% ethyl acetate / cyclohexane) to give methyl (2S)-3-(tert-butoxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoate (1.37 g, 97%) as a white solid foam. LCMS (ESI): [M + H]+= 471

[0028] Step 2: Methyl (2S)-3-(tert-butoxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoate (1.37 g, 2.91 mmol) was dissolved in HCl in dioxane (4.0 M, 5 mL, 20 mmol) and stirred at 20 °C for 5 h. Ammonium chloride - solvent was removed to give 1.3 g (109%) of [(2S)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]-3-methoxy-3-oxo-propyl]ammonium chloride as an off-white solid. LCMS (ESI): [M + H]+= 371

[0029] Step 3: To a solution of [(2S)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]-3-methoxy-3-oxo-propyl]ammonium chloride (407 mg, 1 mmol) in DCM (4 mL) under nitrogen at 0 °C was added DIPEA (0.52 mL, 3 mmol) followed by dropwise addition of benzyl chloroformate (0.17 mL, 1.1 mmol). The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, diluted with DCM and warmed to 20 °C. The phases were separated and the organic layer was washed with brine, dried over sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 50% ethyl acetate / cyclohexane) to give methyl (2S)-3-(benzyloxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoate (426 mg, 84%) as a white foam. LCMS (ESI): [M + H]+= 505

[0030] Step 4: To methyl (2S)-3-(benzyloxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoate (423 mg, 0.84 mmol) in THF (4 mL) was added lithium hydroxide (1.0 M aqueous solution, 1.0 mL, 1.0 mmol). The mixture was stirred at 20°C for 2 h. The solvent was removed. The residue was dissolved in water and acidified to approximately pH 2 with 1M aqueous HCl. The mixture was extracted with ethyl acetate twice and the combined organic layers were washed with brine, dried over sodium sulfate and the solvent was removed to give (2S)-3-(benzyloxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoic acid (416 mg, 101%) as a white foam. LCMS (ESI): [M + H]+= 491

[0031] Step 5: To a mixture of compound 101-G (592 mg, 0.83 mmol) and (2S)-3-(benzyloxycarbonylamino)-2-[[2-(4-tert-butylphenyl)-4-methyl-pyrimidine-5-carbonyl]amino]propanoic acid (407 mg, 0.83 mmol) in THF (5 mL) under nitrogen was added sodium (279 mg, 3.32 mmol) followed by DEPBT (745 mg, 2.49 mmol). The mixture was stirred at 60 °C for 18 h. The mixture was cooled to ambient temperature, diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and brine, then dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel chromatography (solvent gradient: 50%-100% ethyl acetate in cyclohexane) to give compound 491-1 (422 mg, 43%) as a white glassy solid. LCMS (ESI): [M + H]+= 1186

[0032] Starting from compound 494-1 and (N-tert-butoxycarbonyl)glycine, the usual amide coupling (HATU / DIEA), hydrolysis and general B elimination (TFA / HFIP) procedures (described in Examples 5 and 7) were followed to afford compound 491 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): tR= 2.50 min, [M + H]+= 933.7 .1H NMR (400 MHz, DMSO- d6)  9.18 (d, J = 8.2 Hz , 1H), 8.99 (d, J = 8.2 Hz , 1H), 8.85 (s, 1H), 8.76-8.70 (m, 1H), 8.66-8.60 (m, 1H), 8.40-8.31 (m, 3H), 8.10-7.84 (m, 9H), 7.58 (d, J = 8.9 Hz , 2H), 7.28-7.03 (m, 4H), 6.73 (s, 2H), 6.36 (s, 1H), 5.10-5.02 (m, 1H), 4.79-4.67 (m, 2H), 4.27-4.07 (m, 6H), 3.77-2.97 (m, 11H), 2.86 (s, 2H), 2.63 (s, 3H), 1.33 (s, 9H), 1.22 (d, J = 7.4 Hz , 3H) مثال ۲۹۲: سنتز ترکیب ۴۹۲

[0033] Step 1: To a mixture of methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphoryl-acetate (994 mg, 3.0 mmol) and tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (562 mg, 3.0 mmol) in DCM (5 mL), 1,8-diazabicyclo[5.4.0]undecane (0.45 mL, 3 mmol) was added. The mixture was stirred at 20°C for 18 h. The reaction mixture was diluted with DCM, washed successively with 1M aqueous HCl and brine, and then dried over sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 30% ethyl acetate / cyclohexane) to give methyl (E)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate (746mg, 63%) as a colorless oil. LCMS (ESI): [M + Na]+= 415

[0034] Step 2: A solution of methyl (E)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate (740 mg, 1.89 mmol) in methanol (10 mL) was added to ,2-bis[(2S,5S)-2,5-diethylphosphoplano]benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (136 mg, 0.19 mmol) in a glass-lined steel bomb. The bomb was purged with nitrogen four times and then with hydrogen, the pressure was increased to 4.5 atmospheres, and the mixture was stirred for 18 hours. The pressure was released, the mixture was removed from the bomb, and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 20% ethyl acetate / cyclohexane) to give methyl (2S)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pentanoate (425 mg, 57% pure) as a white solid. LCMS (ESI): [M + H]+= 395

[0035] Step 3: To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pentanoate (412 mg, 1.04 mmol) in THF (5 mL), LiOH solution (1.0M, 1.1 mL, 1.1 mmol) was added. The mixture was stirred at 20 °C for 5 h. The solvent was removed and the residue was dissolved in water, acidified with 1M aqueous HCl, and extracted twice with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, and solvent removal gave (2S)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (390 mg, 98%) as a white solid. LCMS (ESI): [M - H]+= 379

[0036] Compound 101-G was coupled with (2S)-2-(benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid and hydrogenated as described in Example E. The resulting compound was coupled with 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid.

[0037] Hydrolysis of the ester, coupling with iminoacetonitrile hydrochloride and overall deprotonation was followed using the method described in Example G to afford compound 492 (formic acid salt) as a white solid. LCMS (ESI): tR= 2.78 min, [M + H]+= 932.5.1H NMR (400 MHz, DMSO-d6)  9.25 (d, J = 7.6 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.74-8.69 (m, 1H), 8.39-8.29 (m, 3H), 7.56 (d, J = 8.3 Hz, 2H), 7.30-7.06 (m, 5H), 6.78-6.71 (m, 2H), 6.46 (s, 1H), 5.11-5.03 (m, 1H), 4.79-4.64 (m, 2H), 4.22-4.05 (m, 7H), 3.25-3.01 (m, 6H), 2.95 (s, 3H), 2.25-2.17 (m, 1H), 2.00-1.91 (m, 1H), 1.33 (s, 15H), 1.19 (d, J = 6.9 Hz, 3H) Example 293: Synthesis of compound 493

[0038] Compound 493-1 was prepared as a white solid (373 mg) by similar methods to those described in Example 291, using [(1S)-3-(tert-butoxycarbonylamino)-1-methoxycarbonyl-propyl]ammonium chloride instead of [(1S)-1-[(tert-butoxycarbonylamino)methyl]-2-methoxy-2-oxo-ethyl]ammonium chloride. LCMS (ESI): [M + H]+= 1066

[0039] To compound 493-1 (373 mg, 0.35 mmol) in acetonitrile (3.0 mL) was added potassium carbonate (58 mg, 0.42 mmol) and 2-bromoacetamide (46 mg, 0.33 mmol). DMF (0.5 mL) was added to aid solubility. The mixture was stirred at 20°C for 18 h, after which potassium carbonate (58 mg, 0.42 mmol) and di-tert-butyl dicarbonate (92 mg, 0.42 mmol) were added. The reaction was stirred at 20°C for 3 h, and then the resulting mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with brine, dried over Na2SO4, and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 7% methanol / DCM) to give compound 493-2 (295 mg, 69%) as a glass. LCMS (ESI): [M + H]+= 1247

[0040] Starting from compound 493-2, the usual hydrolysis, amide coupling (HATU / DIEA) and elimination B (TFA / HFIP) procedures (described as in Example G) afforded compound 493 (formic acid salt) as a white solid. LCMS (ESI): tR= 2.51 min, [M + H]+= 947.5.1H NMR (400 MHz, DMSO-d6)  9.15 (d, J = 7.2 Hz, 1H), 8.97 (d, J = 7.8 Hz, 2H), 8.82 (s, 2H), 8.73-8.67 (m, 2H), 8.44-8.32 (m, 3H), 8.02-7.66 (m, 4H), 7.63-7.55 (m, 3H), 7.30-7.00 (m, 5H), 6.73 (s, 2H), 6.38 (s, 1H), 5.05-4.93 (m, 1H), 4.80-4.67 (m, 2H), 4.30-4.02 (m, 6H), 3.21-2.94 (m, 8H), 2.84 (s, 3H), 2.65 (s, 3H), 2.54 (s, 2H), 1.34 (s, 9H), 1.22 (d, J = 7.0 Hz, 3H) Example 294: Synthesis of compound 494

[0041] Step 1: A mixture of compound 493-1 (340 mg, 0.32 mmol) and sodium formate (26 mg, 0.38 mmol) in ethyl formate (5 mL) was stirred at 50 °C for 5 h. The mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with brine, dried over Na2SO4, and the solvent was removed. The residue was purified by silica gel chromatography (solvent gradient: 0-10% methanol / DCM) to give compound 494-1 (273 mg, 78%) as a white solid. LCMS (ESI): [M + H]+= 1095

[0042] Starting from compound 494-1, conventional hydrolysis conditions, amide coupling (HATU / DIEA) and general B elimination processes (TFA / HFIP) (described in Examples E and G) led to compound 494 (formic acid salt) as a white solid. LCMS (ESI): tR= 2.94 min, [M + H]+= 918.7 .1H NMR (400 MHz, DMSO- d6)  9.11-9.00 (m, 2H), 8.84-8.77 (m, 2H), 8.39-7.98 (m, 8H), 7.60-7.55 (m, 2H), 7.23-7.02 (m, 4H), 6.76-6.66 (m, 2H), 6.37 (s, 1H), 4.89-4.67 (m, 4H), 4.17 (d, J = 6.9 Hz, 2H), 4.10-4.01 (m, 4H), 3.30-3.19 (m, 2H), 3.17 (s, 1H), 3.05-2.87 (m, 6H), 2.83 (s, 2H), 2.65 (s, 3H), 2.03-1.74 (m, 2H), 1.37 (s, 9H), 1.19 (d, J = 8.4 Hz, 3H) Example 295: compound centz 495

[0043] Step 1: To a solution of methyl (S)-NZ-aziridine-2-carboxylate (1.26 mL, 6.38 mmol) and tert-butyl N-(2-hydroxyoxyethyl)carbamate (3.45 mL, 22.32 mmol) in chloroform (45 mL) at 0 °C under argon, boron trifluoride diethyl etherate (0.81 mL, 6.38 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 30 min. The reaction was quenched with saturated aqueous NaHCO3 (70 mL) and extracted with DCM. The organic extracts were dried over magnesium sulfate and the solvent was removed. The crude residue was purified by silica gel chromatography (eluting with 50% ethyl acetate / cyclohexane) to give methyl (2S)-2-(benzyloxycarbonylamino)-3-[2-(tert-butoxycarbonylamino)ethoxy]propanoate (1.3 g, 3.28 mmol) as a colorless oil. LCMS (ESI): [M + Na]+= 419

[0044] Step 2: To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-3-[2-(tert-butoxycarbonylamino)ethoxy]propanoate (1.3 g, 3.28 mmol) in THF (30 mL), lithium hydroxide (1.0 M, 6.56 mL, 6.56 mmol) was added and the reaction mixture was stirred at 50 °C for 30 min. The reaction was quenched with 1N aqueous HCl (8.0 mL) followed by water (50 mL) and the resulting mixture was extracted with DCM. The combined organic extracts were dried over magnesium sulfate and the solvent was removed to give (2S)-2-(benzyloxycarbonylamino)-3-[2-(tert-butoxycarbonylamino)ethoxy]propanoic acid (1.20 g, 3.14 mmol) as a colorless oil. LCMS (ESI): [M + Na]+= 405

[0045] Compound 101-G was coupled with (2S)-2-(benzyloxycarbonylamino)-3-[2-(tert-butoxycarbonylamino)ethoxy]propanoic acid and protonated as described in E. The resulting compound was coupled with -(4-tert-butylphenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid, followed by ester hydrolysis, coupling with aminoacetonitrile hydrochloride and overall deprotonation using the methods described in Example G to afford compound 495 (formic acid salt) as a white solid. LCMS (ESI): tR= 2.48 min, [M + H]+= 934.4.1H NMR (400 MHz, DMSO-d6)  9.21-9.11 (m, 1H), 8.96 (d, J = 8.0 Hz, 1H), 8.72 (t, J = 5.4 Hz, 1H), 8.41-8.29 (m, 3H), 7.90-7.74 (m, 6H), 7.55 (d, J = 8.4 Hz, 2H), 7.28-7.06 (m, 4H), 6.73-6.69 (m, 1H), 6.43 (s, 1H), 5.20-5.12 (m, 1H), 4.78-4.56 (m, 1H), 4.28-4.07 (m, 6H), 3.86-3.78 (m, 2H), 3.74-3.61 (m, 6H), 3.25-2.96 (m, 9H), 2.91 (s, 3H), 2.65 (m, 2H), 2.46 (d, J = 5.2 Hz, 1H), 1.34 (s, 9H), 1.24-1.18 (m, 3H) Example 296: Synthesis of compound 496

[0046] Step 1: To a solution of 4-bromophenol (1 g, 5.78 mmol) in DMF (10 mL), bromocyclohexane (1.8 g, 11.0 mmol) and K2CO3 (2.4 g, 17.4 mmol) were added and the reaction was stirred at 80 °C for 16 h. The reaction mixture was extracted with ethyl acetate, poured into water (20 mL) (50 mL× 3). The combined organic layers were washed with brine (100 mL× 2), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether, to give compound 496-1 (170.0 mg, 11%) as a colorless oil.

[0047] Step 2: To a solution of compound 496-1 (170.0 mg, 0.67 mmol) in DMF (5 mL), bis(pinacolato)diboron (254 mg, 1.00 mmol), Pd(dppf)Cl2 (24.4 mg, 0.03 mmol) and potassium acetate (196 mg, 2.00 mmol) were added and the resulting mixture was stirred at 80 °C under nitrogen for 3 h. The reaction was extracted with ethyl acetate, poured into water (20 mL) (20 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (eluent: 8% ethyl acetate in petroleum ether) to give compound 496-2 (140 mg, 70% yield) as a yellow oil.

[0048] Step 3: To a mixture of compound 496-2 (200 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL), methyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate under nitrogen (described in Example 53) (199 mg, 0.99 mmol) and K2CO3 (274 mg, 2.0 mmol) and Pd(dppf)Cl2 (48.4 mg, 0.07 mmol) were added and the resulting mixture was stirred at 110 °C for 16 h. After filtration, the filtrate was extracted with ethyl acetate (20 mL×2), diluted with H2O (20 mL). The combined organic layer was washed with water and brine (30 mL each), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (eluent: 10% ethyl acetate in petroleum ether) to give methyl 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylate (110 mg, 59% yield) as a white solid. LCMS (ESI): [M+H]+= 341.0

[0049] Step 4: To a solution of methyl 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylate (110 mg, 0.32 mmol) in methanol (10 mL), 1.0 M aqueous NaOH (1.62 mL, 1.62 mmol) was added and the mixture was stirred at 80 °C for 4 h. The reaction mixture was added with ethyl acetate (40 mL), adjusted to pH = 4 using saturated aqueous KHSO4. The organic layer was washed with brine (30 mL×2), dried over Na2SO4, and concentrated to give compound 496-3 (100 mg, 95% yield) as a white solid, which was used directly in the next step.

[0050] Compound 496-4 was prepared from compound 101-G and (S)-2-(((benzyloxy)carbonyl)amino)-4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoic acid using similar conditions described in Example E. LCMS (ESI): [M + H]+= 958

[0051] Step 5: Example E was applied to compound 496-4 (3.37 g, 3.52 mmol) and compound 496-3 (1.26 g, 3.87 mmol) to give compound 496-5 (3.78 g, 85%) as a white solid. LCMS (ESI): [M + H]+= 1266

[0052] Step 6: To a solution of compound 496-5 (3.05 g, 2.41 mmol) in THF (15 mL), a solution of tetramethylammonium fluoride (1.0 M in THF, 3.6 mL, 3.6 mmol) was added. The mixture was stirred at 50 °C for 18 h. The mixture was cooled to room temperature and the solvent was removed. The residue was dissolved in ethyl acetate, washed with brine, dried over Na2SO4, and the solvent was removed to give compound 496-6 (3.20 g, 118%) as an off-white solid. The residue was used directly without further purification. LCMS (ESI): [M + H]+= 1122

[0053] Step 7: To compound 496-6 (280 mg, 0.25 mmol) in DCM (3 mL) at 0 °C, DIPEA (0.07 mL, 0.38 mmol) was added, followed by acetic anhydride (28 mg, 0.28 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was partitioned between DCM and water, and the phases were separated. The organic layer was washed with brine, dried over Na2SO4, and the solvent was removed. The residue was purified by silica gel column (8% methanol / DCM) to give compound 496-7 (195 mg, 67%) as a white solid. LCMS (ESI): [M + H]+= 1164

[0054] Steps 8-9: Starting from compound 496-7, the usual hydrolysis, amide coupling (HATU / DIEA) and general B elimination processes (TFA / HFIP) (Example G) were followed to afford compound 496 (trifluoroacetic acid salt) as a white solid. LCMS (ESI); 1H), 7.28-6.93 (m, 7H), 6.76-6.68 (m, 2H), 6.39 (s, 1H), 4.88-4.81 (m, 1H), 4.78-4.67 (m, 2H), 4.49-4.42 (m, 1H), 4.19-4.15 (m, 2H), 4.07-3.94 (m, 4H), 3.23-3.14 (m, 3H), 3.03-2.82 (m, 4H), 2.84 (s, 3H), 2.44 (s, 1H), 1.99-1.92 (m, 2H), 1.79 (s, 3H), 1.77-1.69 (m, 3H), 1.58-1.37 (m, 4H), 1.33-1.23 (m, 1H), 1.19 (d, J = 7.2 Hz, 3H) Example 297: Synthesis of compound 497

[0055] Compound 497 (trifluoroacetic acid salt) was prepared as a white solid using similar methods described in Example 296 using methanesulfonyl chloride instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.30 min, [M + H]+= 1024.4.1H NMR (400 MHz, DMSO-d6)  9.01-8.86 (m, 2H), 8.67 (t, J = 7.4 Hz, 1H), 8.33-8.28 (m, 3H), 7.30-7.02 (m, 9H), 6.78-6.72 (m, 2H), 6.42 (s, 1H), 4.97-4.91 (m, 1H), 4.77-4.69 (m, 2H), 4.48-4.40 (m, 1H), 4.28-4.03 (m, 7H), 3.26-2.98 (m, 8H), 2.90 (s, 3H), 2.88 (s, 3H), 2.00-1.91 (m, 3H), 1.86-1.70 (m, 3H), 1.59-1.51 (m, 1H), 1.50-1.35 (m, 4H), 1.33-1.24 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H) Example 298: Synthesis of compound 498

[0056] Compound 498 (formic acid salt) was prepared as a white solid using the methods of Example 296 using trimethyl isocyanate instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.06 min, [M + H]+= 989.4.1H NMR (400 MHz, DMSO-d6)  9.06-8.96 (m, 2H), 8.78 (t, J = 5.5 Hz, 1H), 8.33-8.29 (m, 5H), 7.21-7.18 (m, 1H), 7.16-7.10 (m, 2H), 7.07-7.02 (m, 4H), 6.76-6.68 (m, 2H), 6.39 (s, 1H), 6.16-6.09 (m, 1H), 5.51-5.39 (m, 2H), 4.89-4.81 (m, 1H), 4.78-4.67 (m, 2H), 4.48-4.41 (m, 1H), 4.22-4.14 (m, 2H), 4.08-3.95 (m, 4H), 3.21-2.85 (m, 7H), 2.84 (s, 3H), 2.45 (s, 1H), 2.00-1.92 (m, 2H), 1.92-1.84 (m, 1H), 1.76-1.69 (m, 2H), 1.58-1.51 (m, 1H), 1.48-1.37 (m, 3H), 1.33-1.24 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H) Example 299: Synthesis of compound 499

[0057] Compound 499 (trifluoroacetic acid salt) was prepared as a white solid using the method described in Example 296 using trimethylsilyl isocyanate instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.05 min, [M + H]+= 975.3.1H NMR (400 MHz, DMSO-d6)  9.01-8.95 (m, 2H), 8.70 (t, J = 5.3 Hz, 1H), 8.34-8.26 (m, 3H), 7.88 (br s, 6H), 7.28-7.03 (m, 6H), 6.77-6.70 (m, 2H), 6.41 (s, 1H), 6.14-6.07 (m, 1H), 5.78-5.64 (m, 2H), 5.01-4.94 (m, 1H), 4.79-4.66 (m, 2H), 4.49-4.41 (m, 1H), 4.28-4.08 (m, 7H), 3.51-3.43 (m, 2H), 3.24-3.00 (m, 8H), 2.94 (s, 2H), 2.47-2.44 (m, 1H), 2.00-1.92 (m, 2H), 1.77-1.69 (m, 2H), 1.59-1.24 (m, 7H), 1.21 (d, J = 7.0 Hz, 3H) Example 300: Synthesis of Compound 500

[0058] Compound 500 (trifluoroacetic acid salt) was prepared as a white solid using the method described in Example 296 using tert-butyl (chlorosulfonyl)carbamate (formed by mixing equivalent amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.22 min, [M + H]+= 1025.4. ¹H NMR (400 MHz, DMSO-d6)  9.01-8.95 (m, 2H), 8.72-8.67 (m, 1H), 8.34-8.25 (m, 3H), 7.92-7.81 (br s, 6H), 7.26-7.03 (m, 7H), 6.75-6.68 (m, 3H), 6.53 (s, 2H), 6.45 (s, 1H), 4.97-4.90 (m, 1H), 4.79-4.69 (m, 2H), 4.48-4.42 (m, 1H), 4.25-4.10 (m, 6H), 3.25-2.97 (m, 9H), 2.89 (s, 3H), 2.01-1.95 (m, 3H), 1.83-1.69 (m, 3H), 1.57-1.25 (m, 6H), 1.21 (d, J = 6.8 Hz, 3H) Example 301: Synthesis of compound 501

[0059] Compound 501 (formic acid salt) was prepared as a white solid using the method described in Example 296 using trimethylsilyl isocyanate instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.06 min, [M + H]+= 1003.5. ¹H NMR (400 MHz, DMSO-d6)  9.11-8.99 (m, 2H), 8.80 (t, J = 5.6 Hz, 1H), 8.35-8.28 (m, 4H), 7.19-7.02 (m, 7H), 6.76-6.70 (m, 2H), 6.41 (s, 1H), 6.05-5.96 (m, 1H), 5.38 (s, 2H), 4.86-4.68 (m, 4H), 4.48-4.42 (m, 2H), 4.21-4.13 (m, 2H), 4.08-4.00 (m, 6H), 3.22-3.07 (m, 2H), 3.05-2.95 (m, 3H), 2.86 (s, 6H), 2.68-2.63 (m, 1H), 2.48 (s, 4H), 2.01-1.93 (m, 3H), 1.80-1.70 (m, 3H), 1.63-1.24 (m, 9H), 1.20 (d, J = 6.8 Hz, 3H) Example 302: Synthesis of compound 502

[0060] Compound 502 (trifluoroacetic acid salt) was prepared as a white solid using similar methods described in Example 296 using tert-butyl (chlorosulfonyl)carbamate (formed by mixing equivalent amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) instead of acetic anhydride in Step 7. LCMS (ESI): tR= 3.09 min, [M + H]+= 1001.5 . ¹H NMR (400 MHz, DMSO-d6)  9.10-8.99 (m, 2H), 8.80-8.74 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.35-8.29 (m, 4H), 7.24-7.03 (m, 7H), 6.74 (dd, J = 1.6, 13.2 Hz, 2H), 6.65 (s, 3H), 6.38 (s, 1H), 5.13 (dd, J = 7.6, 13.6 Hz, 1H), 4.77-4.70 (m, 2H), 4.48-4.42 (m, 1H), 4.21-4.15 (m, 2H), 4.14-4.01 (m, 6H), 3.18 (d, J = 16.0 Hz, 2H), 3.06-2.97 (m, 2H), 2.95-2.91 (m, 6H), 2.48 (s, 4H), 2.46-2.43 (m, 1H), 1.97 (d, J = 6.4 Hz, 3H), 1.78-1.73 (m, 3H), 1.57-1.23 (m, 7H), 1.20 (d, J = 6.8 Hz, 3H) Example 303: Synthesis 503 Compound 503 (trifluoroacetic acid salt) was prepared as a white solid using similar methods described in Example 296 using tert-butyl (chlorosulfonyl)carbamate (formed by mixing equivalent amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) instead of acetic anhydride in step 7. LCMS (ESI): tR= 3.15 min, [M + H]+= 1039.6 . ¹H NMR (400 MHz, DMSO-d6)  8.97 (d, J = 6.8 Hz, 2H), 8.70 (t, J = 5.6 Hz, 1H), 8.34-8.25 (m, 3H), 7.94-7.88 (m, 6H), 7.25-7.03 (m, 7H), 6.73 (t, J) = 2.4 Hz, 2H), 6.53-6.44 (m, 3H), 4.82-4.69 (m, 3H), 4.48-4.42 (m, 1H), 4.25-4.11 (m, 6H), 3.25-2.88 (m, 12H), 2.49-2.43 (m, 4H), 1.97-1.26 (m, 15H), 1.22 (d, J = 6.8 Hz, 3H) Example 304: Synthesis of compound 504

[0061] Step 1: A mixture of compound 496-6 (described in Example 296) (280 mg, 0.25 mmol) and sodium formate (20.4 mg, 0.38 mmol) in ethyl formate (4 mL) was stirred at 50 °C for 18 h. The mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with brine, dried over Na2SO4, and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 7% methanol / DCM) to give compound 504-1 (168 mg, 58%) as a white solid. LCMS (ESI): [M + H]+= 1150

[0062] Starting from compound 504-1, the usual hydrolysis, amide coupling (HATU / DIEA) and general B elimination (TFA / HFIP) procedures (as described in Examples 5 and 7) were followed to provide compound 504 (formic acid salt) as a white solid. LCMS (ESI): tR = 3.70 min, [M + H]+ = 974.3. ¹ H NMR (400 MHz, DMSO-d6)  9.05-8.97 (m, 2H), 8.72-8.67 (m, 1H), 8.38-8.00 (m, 6H), 7.25-6.99 (m, 6H), 6.80-6.67 (m, 2H), 6.42 (s, 1H), 4.89-4.82 (m, 1H), 4.80-4.66 (m, 3H), 4.49-4.40 (m, 2H), 4.17 (d, J = 5.7 Hz, 3H), 4.13-4.00 (m, 6H), 3.30-3.19 (m, 4H), 3.05-2.90 (m, 6H), 2.85 (s, 3H), 2.68-2.63 (m, 1H), 2.00-1.87 (m, 3H), 1.82-1.68 (m, 3H), 1.59-1.20 (m, 7H), 1.19 (d, J = 5.7 Hz, 3H) Example 305: Synthesis of compound 505

[0063] Compound 505 (formic acid salt) was prepared as a white solid from compound 101-G and compound 496-3 (described in Example 296) using similar methods described in Example 7. LCMS (ESI): tR = 3.15 min, [M + H]+ = 974.4. ¹H NMR (400 MHz, DMSO-d6)  9.06-8.87 (m, 2H), 8.74-8.63 (m, 1H), 8.37-8.28 (m, 2H), 8.25 (s, 1H), 7.45-6.91 (m, 6H), 6.88-6.66 (m, 2H), 6.42 (s, 1H), 4.96-4.58 (m, 3H), 4.51-4.40 (m, 1H), 4.17 (d, J = 5.8 Hz, 2H), 4.12-3.99 (m, 4H), 3.25-3.09 (m, 1H), 3.05-2.85 (m, 6H), 2.34-2.22 (m, 2H), 2.09-1.89 (m, 2H), 1.84-1.67 (m, 2H), 1.60-1.36 (m, 4H), 1.35-1.17 (m, 4H) Example 306: Synthesis of compound 506

[0064] Step 1: Following coupling with compound 101-G (357 mg, 0.50 mmol) and Fmoc-L-Asn(Trt)-OH (448 mg, 0.75 mmol), compound 506-1 (561 mg, 87%) was obtained. LCMS (ESI): [M + H]+= 1292

[0065] Step 2: To a solution of compound 506-1 (503 mg, 0.389 mmol) in DMF (3 mL) was added piperidine (0.385 mL, 3.89 mmol). The mixture was stirred at ambient temperature for 18 h. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over Na2SO4, and the solvent was removed. The remaining crude material was purified by silica gel chromatography (solvent gradient: 0-10% methanol / DCM) to give compound 506-2 (300 mg, 72%) as an off-white solid. LCMS (ESI): [M + H]+= 1070

[0066] Compound 506 (trifluoroacetic acid salt) was obtained as a white solid from compound 506-2, followed by the usual amide coupling (HATU / DIEA), hydrolysis, amide coupling (HATU / DIEA) and total Boc / Trityl removal (TFA / HFIP) procedures (described as in Example G). LCMS (ESI): tR = 3.10 min, [M + H]+ = 933.5. ¹H NMR (400 MHz, DMSO-d6)  9.03 (d, J = 7.7 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.34-8.27 (m, 2H), 7.84-7.76 (m, 1H), 7.40 (s, 1H), 7.10 (s, 1H), 7.08-7.01 (m, 3H), 6.99-6.90 (m, 2H), 6.80-6.73 (m, 2H), 6.31 (s, 1H), 5.31-5.23 (m, 1H), 4.68-4.58 (m, 2H), 4.50-4.41 (m, 1H), 4.08-3.96 (m, 4H), 3.10-3.00 (m, 1H), 2.95-2.83 (m, 5H), 2.68-2.59 (m, 2H), 2.42-2.38 (m, 1H), 2.45 (s, 1H), 2.01-1.90 (m, 2H), 1.78-1.69 (m, 2H), 1.59-1.22 (m, 6H), 1.17 (d, J = 6.5 Hz, 3H) Example 307: Synthesis of compound 507 Compound 507 was obtained as a white solid using similar methods described in Example R using S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoic acid, 2-[4-(cyclohexoxy)phenyl]-4,6-dimethyl-pyrimidine-5-carboxylic acid And compound 101-G was prepared and purified by chiral SFC. LCMS (ESI): tR= 3.06 min, [M + H]+= 960.3 . ¹H NMR (400 MHz, DMSO-d6)  9.08-8.93 (m, 2H), 8.76-8.66 (d, J = 7.1 Hz, 1H), 8.36-8.25 (m, 2H), 7.89 (br s, 6H), 7.39-7.01 (m, 7H), 6.78-6.68 (m, 2H), 6.45 (s, 1H), 5.03-4.93 (m, 1H), 4.80-4.67 (m, 2H), 4.50-4.40 (m, 1H), 4.33-4.07 (m, 6H), 3.82-3.74 (m, 1H), 3.64-3.54 (m, 1H), 3.24-2.97 (m, 6H), 2.92 (s, 3H), 2.69-2.62 (m, 1H), 2.47 (s, 1H), 2.43 (s, 1H), 2.02-1.91 (m, 2H), 1.79-1.68 (m, 2H), 1.61-1.15 (m, 9H) Example 308: Synthesis of compound 508

[0067] Compound 508 was isolated as a minor epimer from the synthesis of compound 507 via chiral SFC. LCMS (ESI): tR = 3.13 min, [M + H]+ = 933.5. ¹H NMR (400 MHz, DMSO-d6)  9.06 (d, J = 7.1 Hz, 1H), 8.66 (t, J = 5.4 Hz, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.74-8.49 (m, 2H), 8.36-8.18 (m, 2H), 7.86 (br s, 6H), 7.32-7.22 (m, 1H), 7.20-7.01 (m, 5H), 6.94 (s, 1H), 6.42 (s, 1H), 5.04-4.93 (m, 1H), 4.65-4.54 (m, 1H), 4.50-4.40 (m, 1H), 4.28-4.11 (m, 6H), 3.97-3.86 (m, 1H), 3.84-3.75 (m, 1H), 3.65-3.56 (m, 1H), 3.23-3.05 (m, 6H), 3.01 (s, 3H), 2.74-2.64 (m, 1H), 2.41 (s, 1H), 2.02-1.90 (m, 2H), 1.80-1.68 (m, 2H), 1.61-1.14 (m, 9H) Example 309: Synthesis of compound 509

[0068] Compound 509 (trifluoroacetic acid salt) was prepared as a white solid using the same methods as Example R from (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)butanoic acid, 2-[4-(cyclohexoxy)phenyl]-4,6-dimethyl-pyrimidine-5-carboxylic acid and compound 101-G. LCMS (ESI): tR= 3.14 min, [M + H]+= 947.5 .1H NMR (400 MHz, DMSO- d6) 1H NMR (400 MHz, DMSO- d6)  8.98-8.95 (m, 2H), 8.69 (t, J = 4.5 Hz, 1H), 8.33-8.23 (m, 3H), 7.94-7.84 (br s, 6H), 7.26-7.04 (m, 7H), 6.76-6.70 (m, 2H), 6.45 (s, 1H), 5.18-4.97 (m, 2H), 4.79-4.67 (m, 2H), 4.49-4.42(m, (2H), 4.29-4.07 (m, 6H), 3.56-3.50 (m, 2H), 3.22-2.97 (m, 7H), 2.89 (s, 3H), 2.00-1.83 (m, 3H), 1.79-1.69 (m, 3H), 1.99-1.51 (m, 1H), 1.50-1.35 (m, 4H), 1.33-1.25 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H) Example 310: Synthesis of 510

[0069] Step 1: To a mixture of compound 496-4 (described in Example 296) (479 mg, 0.50 mmol) and (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid (195 mg, 0.60 mmol) in DCM (7 mL), DIPEA (0.17 mL, 1 mmol) was added, followed by a reasonable portion of HATU (247 mg, 0.65 mmol). The mixture was stirred at 20°C for 16 h. The mixture was diluted with DCM, washed with water, brine, and then dried over Na2SO4 and the solvent was removed. The crude product was purified by silica gel chromatography (solvent gradient: 70-80% ethyl acetate / cyclohexane) to give compound 510-1 (435 mg, 69%) as a colorless oil. LCMS (ESI): [M + H]+= 1265

[0070] Step 2: To compound 510-1 (432 mg, 0.34 mmol) in DMF (4 mL), piperidine (0.34 mL, 3.41 mmol) was added and the mixture was stirred at 20°C for 16 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel chromatography (solvent gradient: 7-10% methanol / DCM) to afford compound 510-2 (313 mg, 88%) as a white solid. LCMS (ESI): [M + H]+=1044

[0071] Step 3: The methods of Example G were applied to compound 510-2 to afford compound 510-3 (133 mg, 33% after 3 steps) as a colorless glass. LCMS (ESI): [M + H]+= 1376

[0072] Step 4: To a solution of compound 510-3 (130 mg, 0.09 mmol) in THF (2 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.14 mL, 0.14 mmol) and the mixture was stirred at 60 °C for 24 h. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and brine, the phases were separated. The organic layer was dried over sodium sulfate and the solvent was removed. The general elimination procedure B (TFA / HFIP) from Example G was followed to give compound 510 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): tR= 2.86 min, [M + H]+= 1032.2.1H NMR (400 MHz, DMSO-d6)  8.97 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 6.4 Hz, 1H), 8.73 (t, J = 5.6 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 7.99-7.89 (m, 6H), 7.79 (s, 3H), 7.33-7.02 (m, 7H), 6.71 (s, 2H), 6.30 (s, 1H), 4.96-4.89 (m, 1H), 4.78-4.67 (m, 2H), 4.47-4.33 (m, 2H), 4.24-4.10 (m, 5H), 3.27-2.81 (m, 9H), 2.74 (s, 3H), 2.47 (s, 4H), 2.06-1.84 (m, 4H), 1.78-1.23 (m, 11H), 1.21 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H) Example 311: Synthesis of compound 511

[0073] Steps 1 and 2: The procedures of Example G were applied to compound 496-4 (described in Example 296) (1.20 g, 0.95 mmol) to afford compound 511-1 (898 mg, 73% over 2 steps) as a white foam. LCMS (ESI): [M + H]+= 1266

[0074] Step 3: To a solution of compound 511-1 (895 mg, 0.69 mmol) in THF (5 mL) was added a solution of tetramethylammonium fluoride (1.0 M in THF, 1 mL, 1 mmol). The mixture was stirred at 20 °C for 16 h, then the temperature was increased to 50 °C and stirred for a further 6 h. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and brine and the phases were separated. The organic layer was collected and dried over Na2SO4 and removal of the solvent gave compound 511-2 (888 mg, 112%) as a white solid. This material was used directly in the next steps without further purification. LCMS (ESI): [M + H]+= 1146

[0075] Steps 4 and 5: Starting from compound 511-2 and 2-[tert-butyl(dimethyl)silyl]oxyacetic acid, amide coupling (HATU / DIEA) and total B elimination (TFA / HFIP) procedures were followed for Example G to afford compound 511 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): tR= 3.05 min, [M + H]+= 1004.8 .1H NMR (400 MHz, DMSO- d6)  9.01 (d, J =7 Hz, 1H), 8.96 (d, J = 7.0 Hz, 1H), 8.69 (t, J = 5.5 Hz, 1H), 8.32 (d, J = 8.7 Hz, 2H), 8.27 (d, J = 8.7 Hz, 1H), 7.94-7.80 (br s, 6H), 7.28-7.02 (m, 7H), 6.73 (dd, J = 2.0, 10.7 Hz, 2H), 6.43 (s, 1H), 4.89-4.66 (m, 4H), 4.49-4.41 (m, 2H), 4.28-4.08 (m, 6H), 3.78 (s, 2H), 3.32-2.97 (m, 9H), 2.85 (s, 3H), 2.03-1.92 (m, 3H), 1.82-1.69 (m, 3H), 1.60-1.35 (m, 5H), 1.35-1.24 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H) Example 312: Syntz compound 512

[0076] Step 1: To a solution of 1,1'-carbonylimidazole (55 mg, 0.34 mmol) in THF (2 mL) under nitrogen at 20°C, a solution of compound 511-2 (195 mg, 17 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at 20°C for 1 h, then O-(tert-butyldimethylsilyl)hydroxylamine (75 mg, 0.51 mmol) was added. The mixture was stirred at 20°C for 18 h. The temperature was increased to 50°C and stirring was continued for 4 h. The mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, and the phases were separated. The organic layer was washed with 0.1M aqueous HCl, brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was used directly in the next step without further purification. LCMS (ESI): [M + H]+= 1206

[0077] Step 2: The general B elimination process (TFA / HFIP) from Example G was followed to provide compound 512 (trifluoroacetic acid salt) as a white solid. . LCMS (ESI): tR= 3.20 min, [M + H]+= 1005.7.1H NMR (400 MHz, DMSO-d6)  9.01-8.95 (m, 2H), 8.70 (t, J = 5.5 Hz, 1H), 8.60-8.51 (br s, 2H), 8.35-8.25 (m, 4H), 7.97-7.83 (br s, 6H), 7.28-7.01 (m, 7H), 6.87 (t, J = 5.5 Hz, 1H), 6.75-6.71 (br s, 2H), 6.44 (s, 1H), 4.87-4.79 (m, 2H), 4.79-4.67 (m, 2H), 4.50-4.41 (m, 2H), 4.29-4.08 (m, 6H), 3.26-2.96 (m, 9H), 2.86 (s, 3H), 2.01-1.93 (m, 3H), 1.80-1.69 (m, 3H), 1.60-1.50 (m, 1H), 1.50-1.35 (m, 4H), 1.35-1.25 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H) Example 313: Synthesis of compound 513

[0078] Compound 513 (formic acid salt) was prepared as a white solid from compound 101-K using similar methods described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 0.754 min, [M + H]+= 918.8; 1H NMR (400 MHz, MeOH-d4) δ 8.46 (br s, 3H), 8.28 (d, J =8.4 Hz, 2H), 7.32-7.26 (m, 3H), 7.20 (d, J =8.4) Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.75 (brs, 1H), 6.45 (s, 1H), 5.25-5.21 (m, 1H), 4.85-4.78 (m, 2H), 4.29-4.19 (m, 6H), 3.23-3.05 (m, 8H), 3.00 (s, 3H), 2.69 (t, J =7.6 Hz, 2H), 2.53 (s, 6H), 2.33-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.70-1.64 (m, 2H), 1.38-1.33 (m, 7H), 0.92 (t, J = 6.8 Hz, 3H) Examples 314-358: Synthesis of compounds 514-558

[0079] The following compounds in Table 3 were prepared using similar methods as previously described. Table 3 Structure Composition Number 514 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 Example 359: Synthesis of compound 559 Step 1. Methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-25-nitro-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0080] To a mixture of compound 559-1 (77.4 mg, 0.0746 mmol) and acetic acid (1.0 mL, 17 mmol) was added nitric acid (11 μL, 0.22 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, and the resulting residue was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-5% methanol in dichloromethane) to afford 63.1 mg (78%) of the title compound. LCMS (ESI): [M+H]+= 1082.45 Step 2. methyl (4 S ,7 S ,10 S )-25-amino-10-(( S )-4-(( tert -butoxycarbonyl)amino)-2-(2-(4-( tert -butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0081] به یک محلول از methyl (4 S ,7 S ,10 S )-10-(( S )-4-(( tert -butoxycarbonyl)amino)-2-(2-(4-( tert -butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-25-nitro-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (63.1 mg, 0.0583 mmol) in ethanol (2.0 mL), palladium (10 wt% on carbon) (6.5 mg, 0.0061 mmol) was added. The reaction mixture was purged with nitrogen and then hydrogen and stirred at room temperature under a hydrogen balloon for 24 h. The reaction mixture was filtered through celite, washed with methanol and water, filtered and evaporated in vacuo to give the title compound (57.7 mg, 94%). LCMS (ESI): [M+H]+= 1052.4 Step 3. methyl (4S,7S,10S)-25-acetamido-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0082] To a solution of methyl (4S,7S,10S)-25-amino-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (57.7 mg, 0.0548 mmol) in dichloromethane (1.5 mL), acetic anhydride (16 μL, 0.169 mmol) and pyridine (27 μL, 0.330 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated onto Celite, and the crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-5% methanol in DCM) to afford 60.0 mg (69%) of the title compound. LCMS (ESI): [M+H]+= 1094.5 Step 4. (4S,7S,10S)-25-acetamido-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylic acid

[0083] To a solution of methyl (4S,7S,10S)-25-acetamido-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (41.3 mg, 0.0377 mmol) in tetrahydrofuran (1.0 mL), water (0.20 mL) and lithium hydroxide (1.0 M in water) (10 mL, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo, and then taken up in quantitative yield without purification. LCMS (ESI): [M+H]+= 1081.25 Step 5. tert -butyl (( S )-4-(((3 S ,6 S ,9 S )-15-acetamido-26-(2-(( tert -butoxycarbonyl)amino)ethoxy)-9-((cyanomethyl)carbamoyl)-16-hydroxy-6-methyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-3-yl)(methyl)amino)-3-(2-(4-( tert -butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-4-oxobutyl)carbamate

[0084] به مخلوطی از (4 S ,7 S ,10 S )-25-acetamido-10-(( S )-4-(( tert -butoxycarbonyl)amino)-2-(2-(4-( tert -butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylic acid (0.0377 mmol, 0.0377 mmol), aminoacetonitrile hydrochloride (7.5 mg, 0.081 mmol), HATU (32 mg, 0.0825 mmol) and DMF (1 mL), N,N-diisopropylethylamine (33 μL, 0.189 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. To the reaction mixture was added 8.6 mg of aminoacetonitrile hydrochloride, 50 μL of N,N-diisopropylethylamine and 31.6 mg of HATU. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 2:1:1 water:brine:sodium bicarbonate, 10% aqueous citric acid, and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-10% methanol in dichloromethane) to give 33.1 mg (42%) of the title compound. LCMS (ESI): [M+H]+= 1118 Step 6. (4S,7S,10S)-25-acetamido-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-aminoethoxy)-N -(cyanomethyl)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxamide

[0085] To a solution of tert-butyl ((S)-4-((((3S,6S,9S)-15-acetamido-26-(2-((tert-butoxycarbonyl)amino)ethoxy)-9-((cyanomethyl)carbamoyl)-16-hydroxy-6-methyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-3-yl)(methyl)amino)-3-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-4-oxobutyl)carbamate (33.1 mg, 0.0296 mmol) in 1,1,3,3,3-hexafluoro-2-propanol (1.0 mL), trifluoroacetic acid (0.1 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, azeotroped with diethyl ether (2 × 2 mL). The resulting residue was purified by preparative reverse phase HPLC and lyophilized (freeze dried) to give 3.4 mg (12%) of the title compound. LCMS ( روش A, ESI): tR= 4.443 min, [M+H]+= 918.4;1H NMR (400 MHz, DMSO- d6) δ 9.92 (s, 1H), 9.20 – 9.07 (m, 2H), 9.00 (d, J = 7.9 Hz, 1H), 8.73 – 8.65 (m, 1H), 8.58 – 8.41 (m, 1H), 8.36 – 8.28 (m, 3H), 7.56 (d, J = 8.5 Hz, 3H), 7.22 – 7.12 (m, 3H), 6.86 – 6.47 (m, 3H), 6.43 (s, 1H), 5.04 (s, 1H), 4.84 – 4.63 (m, 2H), 4.37 – 4.12 (m, 5H), 3.20 (d, J = 4.9 Hz, 3H), 3.12 (d, J = 3.5 Hz, 3H), 2.95 (d, J = 15.8 Hz, 6H), 2.18 – 2.01 (m, 5H), 1.33 (d, J = 2.2 Hz, 12H), 1.21 (d, J = 6.9 Hz, 3H) مثال ۳۶۰: سنتز ترکیب ۵۶۰ گام ۱. methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-hydroxy-5-iodophenyl)propanoate

[0086] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-4-hydroxy-phenyl)propanoate (1.4814 g, 4.256 mmol) in methanol (10.0 mL) were added silver sulfate (1.418 g, 4.548 mmol) and iodine (1.123 g, 4.40 mmol), respectively. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate. The organic phase was dried over brine and magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to afford 1.5246 g (81%) of the title compound. LCMS (ESI): [M+Na]+= 461.95 Step 2. methyl (S)-3-(4-(benzyloxy)-3-fluoro-5-iodophenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0087] To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-hydroxy-5-iodophenyl)propanoate (1.5246 g, 3.471 mmol), potassium carbonate (962 mg, 6.9604 mmol), and N,N-dimethylformamide (12 mL), benzyl bromide (0.50 mL, 4.2 mmol) was added. The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to afford 1.6527 g (95%) of the title compound as a clear colorless gum. LCMS (ESI): [M+Na]+= 552.0 Step 3. methyl ( S )-3-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(( tert -butoxycarbonyl)amino)propanoate

[0088] A mixture of methyl (S)-3-(4-(benzyloxy)-3-fluoro-5-iodophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.6527 g, 3.122 mmol), bis(pinacolato)diboron (1.3990 g, 5.455 mmol), potassium acetate (0.985 g, 9.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed with dichloromethane (1:1) (0.289 g, 0.354 mmol) and dimethyl sulfoxide (10.0 mL) was heated at 70 °C under nitrogen for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water (2X) and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. This crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to afford 0.9468 g (57%) of the title compound. LCMS (ESI); 9.4, 4.7 Hz, 1H), 3.62 (s, 3H), 2.99 (dd, J = 13.7, 4.7 Hz, 1H), 2.82 (dd, J = 13.8, 10.4 Hz, 1H), 1.32 (s, 9H), 1.29 (s, 12H) Step 4. methyl ( S )-2-amino-3-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0089] To a solution of methyl (S)-3-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (945 mg, 1.785 mmol) in dichloromethane (8 mL), trifluoroacetic acid (1.0 mL, 13 mmol) was added. The reaction mixture was stirred at room temperature. After 7 h, the reaction mixture was evaporated in vacuo to afford the title compound as a TFA salt, which was used without further purification. LCMS (ESI): [M+H]+= 430 Step 5. methyl (5S,8S,11S)-11-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-(4-(2-(( tert -butoxycarbonyl)amino)ethoxy)-3-iodophenyl)-4,8-dimethyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecane-12-oate

[0090] To a solution of (2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]-2-[4-[2-(tert-butoxycarbonylamino)ethoxy]-3-iodo-phenyl]acetyl]amino]propanoic acid (1.011 g, 1.542 mmol) in THF (5 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (365.9 mg, 2.084 mmol) and 4-methylmorpholine (0.90 mL, 8.2 mmol) were added. After 20 min, a solution of methyl (S)-2-amino-3-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.785 mmol, 1.785 mmol) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water (2X) and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-5% methanol in dichloromethane) to afford 1.412 g (86%) of the title compound. LCMS (ESI): [M+H-tBu]+= 1011.20, [M+NH4]+= 1084.30 Step 6. methyl (4 S ,7 S ,10 S )-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0091] To a mixture of methyl (5S,8S,11S)-11-(4-(benzyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-(4-(2-((tert-butoxycarbonyl)amino)ethoxy)-3-iodophenyl)-4,8-dimethyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oate (1.412 g, 1.324 mmol) and potassium phosphate tribasic (883 mg, 4.0766 mmol) in acetonitrile solvent (60 mL), water (6.0 mL) was added and the complex was obtained by adding [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed with dichloromethane (1:1) (169.0 mg, 0.2070 mmol) was followed. The reaction mixture was heated under a nitrogen balloon at 70 °C for 90 min. The reaction mixture was evaporated under reduced pressure to remove most of the acetonitrile. The residue was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-5% methanol in dichloromethane) to afford 335.0 mg (31%) of the title compound. LCMS (ESI): [M+H]+= 813.3 Step 7. methyl (4 S ,7 S ,10 S )-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0092] یک سوسپانسیون از methyl (4 S ,7 S ,10 S )-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (335 mg, 335 mg, 0.4121 mmol) in ethanol (3 mL) was purged with nitrogen. Ammonium formate (411.1 mg, 6.520 mmol) and palladium hydroxide (20% on carbon) (139.7 mg, 0.1990 mmol) were added and the reaction mixture was heated under microwave irradiation at 100 °C for 20 min. 72.7 mg of palladium hydroxide (20% on carbon) and 220.3 mg of ammonium formate were added and the mixture was heated under microwave irradiation at 100 °C for 45 min. The reaction mixture was filtered through celite, washed with dichloromethane. The filtrate was then diluted with dichloromethane and washed with aqueous sodium bicarbonate to remove the formate salt. The aqueous phase was extracted with an additional portion of DCM, and the combined DCM fractions were dried over brine and magnesium sulfate, filtered, and evaporated in vacuo to give 261.8 mg (quantitative) of the title compound, which was used without further purification. LCMS (ESI): [M+H]+= 589.25 Step 8. methyl (4 S ,7 S ,10 S )-10-(( S )-2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-4-(( tert -butoxycarbonyl)amino)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0093] To a solution of (2S)-4-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid (196.0 mg, 0.4449 mmol) in THF (1 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (117.1 mg, 0.6670 mmol) and 4-methylmorpholine (0.20 mL, 1.8 mmol) were added and after 20 min a solution of (4S,7S,10S)-16-(2-((tert-butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (261.8 mg, 0.4003 mmol) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to afford 273.4 mg (68%) of the title compound. LCMS (ESI): [M+H]+= 1011.40 Step 9. methyl (4 S ,7 S ,10 S )-10-(( S )-2-amino-4-(( tert -butoxycarbonyl)amino)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0094] به یک محلول از methyl (4 S ,7 S ,10 S )-10-(( S )-2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-4-(( tert -butoxycarbonyl)amino)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (273.4 mg, 0.2704 mmol) in THF (3 mL), tetrabutylammonium fluoride (1 mol / L in THF, 0.55 mL, 0.55 mmol) was added. The reaction mixture was stirred at room temperature. After 4 h, the reaction mixture was partitioned between heptane (50 mL) and water (50 mL) and 5 mL of 10% aqueous citric acid was added. The organic layer was extracted again with 10% aqueous citric acid. The combined aqueous portion was adjusted to pH ~ 8 with solid sodium bicarbonate and extracted with DCM (3 × 50 mL). The combined dichloromethane portion was dried over magnesium sulfate, filtered, and evaporated in vacuo to afford the title compound in low yield, which did not require purification. LCMS (ESI): [M+H]+= 789.40 Step 10. methyl (4 S ,7 S ,10 S )-10-(( S )-4-(( tert -butoxycarbonyl)amino)-2-(2-(4-( tert -butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)- N -methylbutanamido)-16-(2-(( tert -butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0095] To a solution of 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (91.5 mg, 0.322 mmol) in tetrahydrofuran (2 mL), triethylamine (0.20 mL, 1.4 mmol) was added followed by thionyl chloride (42 μL, 0.577 mmol). The reaction mixture was stirred at room temperature for 10 min, and then evaporated in vacuo. The resulting residue was suspended in 2 mL of THF. Half of this THF solution (ca. 0.161 mmol) was added to a 0° cold solution of methyl (4S,7S,10S)-10-((S)-2-amino-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16-(2-((tert-butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.135 mmol, 0.135 mmol) and trimethylamine (60 μL, 0.426 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at 0° C., allowing the ice bath to slowly warm to room temperature.After 3 h, the reaction mixture was evaporated onto Celite, and the crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) to afford 99.6 mg (70%) of the title compound. LCMS (ESI): [M+H]+= 1055.50. Step 11. (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-aminoethoxy)-N -(cyanomethyl)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxamide

[0096] The title compound was prepared as a TFA salt of methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16-(2-((tert-butoxycarbonyl)amino)ethoxy)-25-fluoro-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate following similar procedures to Example 559, steps 4 to 6. LCMS (Method A, ESI): tR= 4.499 min, [M+H]+= 879.4; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 7.3 Hz, 1H), 8.99 (d, J = 7.9 Hz, 1H), 8.70 (t, J = 5.6 Hz, 1H), 8.45 (d, J = 9.0 Hz, 1H), 8.37 – 8.30 (m, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.22 – 7.07 (m, 3H), 6.81 (s, 1H), 6.52 (s, 1H), 6.43 (s, 1H), 5.04 (q, J = 7.7) Hz, 1H), 4.80-4.64 (m, 2H), 4.33-4.21 (m, 2H), 4.19-4.15 (m, 2H), 3.46-3.38 (m, 2H), 3.24-3.18 (m, 3H), 3.17-3.07 (m, 1H), 3.03-2.93 (m, 3H), 2.91 (s, 3H), 2.54 (s, 1H), 2.47-2.44 (m, 1H), 2.14 – 1.89 (m, 2H), 1.34 (s, 11H), 1.21 (d, J = 6.7 Hz, 3H) Example 361: Synthesis of compound 561 Step 1: methyl ((S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-(4-methoxyphenyl)acetyl)-L-alaninate

[0097] To a solution of methyl ((S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-(4-hydroxyphenyl)acetyl)-L-alaninate (13.8 mmol, 5.54 g) in acetone (10 mL), potassium carbonate (14.25 mmol, 1.97 g) and iodomethane (14.25 mmol, 2.02 g) were added and the reaction was stirred at room temperature overnight. The solvent was evaporated. Ethyl acetate was added and the mixture was filtered. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated to give compound 561-1 (1.355 g, 100%) as an oil, which was used as is. (MS+1) m / z 381.1 Step 2: methyl ((S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-(3-iodo-4-methoxyphenyl)acetyl)-L-alaninate

[0098] To a solution of compound 561-1 (3.562 mmol, 1.355 g) in methanol (50 mL) at 0 °C was added successively silver sulfate (3.740 mmol, 1.166 g) and iodine (3.740 mmol, 949 mg). The reaction mixture was stirred at room temperature for 1 h. A solution of 10% (w / w) sodium thiosulfate was added to quench the yellow reaction. Most of the methanol was rotary evaporated, after which saturated sodium bicarbonate and ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified on silica, eluting with 0 to 3% methanol in DCM to afford compound 561-2 (1.393 g, 77.2%). Step 3: ((S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-(3-iodo-4-methoxyphenyl)acetyl)-L-alanine

[0099] To a solution of compound 561-2 (2.751 mmol, 1.393 g) in THF (16 mL) at 0 °C was added lithium hydroxide, 0.5M in water (2.751 mmol, 5.50 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and adjusted to pH 2-3 by addition of 0.5M hydrochloric acid. Extraction with ethyl acetate, washing with brine, drying over magnesium sulfate, concentration in vacuo gave crude compound 561-3 (1.353 g, 99.9%) as a pale yellow-brown solid, which was used without further purification. (MS+1) m / z 493.0 Step 4: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-diiodo-4-methoxyphenyl)propanoate

[0100] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3,5-diiodophenyl)propanoate (1.1 mmol, 5.471 g) in acetone (50 mL), potassium carbonate (4.40 mmol, 5.528 g) and iodomethane (4.40 mmol, 5.677 g, 2.49 mL) were added and the reaction was stirred at room temperature overnight. The solvent was evaporated. Ethyl acetate was added and the mixture was filtered. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified on silica, eluting with 0 to 40% ethyl acetate in heptane to afford compound 561-4 (95.321 g, 94.82%) as a white foam. (MS+1) m / z 561.8 Step 5: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-hydroxy-5-iodo-4-methoxyphenyl)propanoate

[0101] A mixture of compound 561-4 (16.7 mmol, 9.40 g) and trimethyl borate (83.7 mmol, 8.7 g, 9.53 mL) in diethyl ether (100 mL) was cooled to −70 °C. n-Butyllithium (2.5 mol / L) in hexane (41.9 mmol, 11.00 g, 17 mL) was added dropwise while maintaining the internal temperature below −65 °C. The reaction mixture was warmed to room temperature and stirred overnight.

[0102] The reaction mixture was cooled to 0°C, and treated with acetic acid (167 mmol, 10.0 g, 9.6 mL) and hydrogen peroxide (30% w / w) in water (17.1 mL). The reaction mixture was stirred overnight and warmed to room temperature. The reaction was quenched with saturated aqueous NH4Cl and extracted with isopropyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified on silica, eluted with 0 to 50% ethyl acetate in heptane to provide compound 561-5 (2.45 g, 32.5%) as a white foam. (MS+1) m / z 452.3 Step 6: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0103] Compound 561-5 (4.63 mmol, 2.09 g), bis(pinacolato)diboron (10.2 mmol, 2.59 g), potassium acetate (18.5 mmol, 1.82 g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.463 mmol, 386 mg) were suspended in dry dimethyl sulfoxide (50 mL) (degassed by sparging with nitrogen) and heated to 85 °C under nitrogen overnight. The reaction mixture was cooled to room temperature, and then filtered through celite. The filtrate was diluted with 1:1 isopropyl acetate and water, and filtered through celite. The layers were separated and the aqueous layer was extracted with isopropyl acetate 3X. The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The dark brown residue was purified by flash chromatography (silica, 20 to 60% ethyl acetate in heptane) to give compound 561-6 (1.743 g, 83.4%) as a white solid. (MS+1) m / z 452.1 Step 7: methyl (S)-2-amino-3-(3-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

[0104] Compound 561-6 (1.405 mmol, 634 mg) in dichloromethane (4 mL) was cooled to 0 °C and treated with trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. Et2O was added to the residue, followed by concentration. The procedure was repeated 2 more times. The residue was dried under high vacuum to give compound 561-7 (493.4 mg, 100.0%), which was used as is. (MS+1) m / z 352.1 Step 8: methyl (6S,9S,12S)-12-(3-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-(3-iodo-4-methoxyphenyl)-2,2,5,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-oate

[0105] To a solution of compound 561-7 (1.405 mmol, 493.4 mg) in acetonitrile (5 mL) and N,N-dimethylformamide (3 mL), 1-hydroxybenzotriazole hydrate (1.532 mmol, 234.6 mg), compound 561-3 (1.277 mmol, 672 mg), TEA (0.38 mL, 0.38 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.192 mmol, 611.9 mg) were added at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, NaHCO3, and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude compound 561-8 as an off-white solid, which was used without further purification. (MS+1) m / z 826.1 Step 9: methyl (4S,7S,10S)-10-((tert-butoxycarbonyl)(methyl)amino)-25-hydroxy-16,26-dimethoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0106] A mixture of compound 561-8 (2.000 mmol, 1.651 g), potassium tribasic phosphate (7.000 mmol, 1.53 g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.2000 mmol, 165 mg) in degassed acetonitrile solvent under nitrogen was heated at 65 °C for 2 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and dilute aqueous NH4Cl solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 0-100% ethyl acetate in DCM) provided compound 561-9 (276 mg, 17.14%) as a white solid. (MS+1) m / z 572.1 Step 10: methyl (4S,7S,10S)-25-(2-(((benzyloxy)carbonyl)amino)ethoxy)-10-((tert-butoxycarbonyl)(methyl)amino)-16,26-dimethoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0107] To a solution of compound 561-9 (0.249 mmol, 142 mg) and benzyl (2-bromoethyl)carbamate (0.746 mmol, 203 mg) in N,N-dimethylformamide (5 mL), cesium carbonate (1.243 mmol, 405 mg) was added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and concentrated. The residue was purified on silica eluted with 0 to 2% methanol in DCM to give compound 561-10 (124 mg, 47.96%). (MS+1) m / z 749.3 Step 11: methyl (4S,7S,10S)-25-(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0108] 10 (0.1416 mmol, 106 mg) in dichloromethane (8 mL) was cooled to 0 °C and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. Et2O was added to the residue, and then concentrated again. The procedure was repeated 2 more times. The residue was dried under high vacuum to give crude compound 561-11 (91.8 mg, 100%), which was used further without purification. (MS+1) m / z 649.1 Step 12: methyl (4S,7S,10S)-10-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-25-(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0109] To a mixture of (2S)-4-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)butanoic acid (0.2127 mmol, 74.97 mg) and compound 561-11 (0.1418 mmol, 92 mg) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (1.418 mmol, 183 mg, 0.247 mL) and HATU (0.284 mmol, 110 mg) were added. After stirring at room temperature for 15 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified on silica eluted with 0-5% methanol in DCM to afford compound 561-12 (128 mg, 85.4%). (MS+1) m / z 983.4 Step 13: methyl (4S,7S,10S)-10-((S)-2-amino-4-(((benzyloxy)carbonyl)amino)-N-methylbutanamido)-25-(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0110] Compound 561-12 (0.2360 mmol, 232 mg) in dichloromethane (10 mL) was cooled to 0 °C and treated with trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 0.5 h, and then concentrated. Et2O was added to the residue and concentrated again. The procedure was repeated 2 more times. The residue was dried under high vacuum to give compound 561-13, which was not further purified. (MS+1) m / z 883.3 Step 14: methyl (4S,7S,10S)-10-((S)-4-(((benzyloxy)carbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido )-25-(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0111] To a mixture of 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (0.355 mmol, 101 mg) and compound 561-13 (0.237 mmol, 209 mg) in N,N-dimethylformamide (8 mL), N,N-diisopropylethylamine (2.367 mmol, 306 mg, 0.413 mL) and HATU (0.473 mmol, 1834 mg) were added. After stirring at room temperature for 15 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified on silica eluting with 0-10% methanol in DCM to give compound 561-14 (138 mg, 51%). (MS+1) m / z 1149.5 Step 15: (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-25-(2-aminoethoxy)-16,26-dihydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylic acid acid

[0112] Aluminum chloride (7.233 mmol, 965 mg) and 1-dodecanethiol (7.233 mmol, 1.464 mg, 1.73 mL) in dichloromethane (15 mL) were stirred at room temperature for 0.5 h. 14 (0.120 mmol, 156 mg) in dichloromethane (15 mL) was added gradually. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dried under high vacuum to give crude compound 561-15, which was not further purified. (MS+1) m / z 839.4 Step 16: methyl (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-25-(2-aminoethoxy)-16,26-dihydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0113] To compound 561-15 (0.1204 mmol, 101 mg) in anhydrous methanol (15 mL), was added thionyl chloride (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give crude compound 561-16, which was not further purified. Step 17: methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido )-25-(2-((tert-butoxycarbonyl)amino)ethoxy)-16,26-dihydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0114] 16 (0.1184 mmol, 101 mg) in acetone (15 mL) and water (5 mL) was treated with saturated aqueous K2CO3 to pH 9-10. Di-tert-butyl dicarbonate (1.184 mmol, 266.4 mg) was then added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was purified on silica eluting with 0-10% methanol in DCM to provide compound 561-17 (124.7 mg, 100.0%). (MS+1) m / z 1053.6 Step 18: methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-25-(2-((te rt-butoxycarbonyl)amino)ethoxy)-16-((tert-butoxycarbonyl)oxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0115] A mixture of compound 561-17 (0.1184 mmol, 124.7 mg), N,N-diisopropylethylamine (0.5920 mmol, 76 mg, 0.103 mL), di-tert-butyl dicarbonate (0.5920 mmol, 133 mg) in dichloromethane (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified on silica with 0 to 10% methanol in DCM to give compound 561-18 (117 mg, 86%). (MS+1) m / z 1154.2 Step 19: (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-25-(2-((te rt-butoxycarbonyl)amino)ethoxy)-16-((tert-butoxycarbonyl)oxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylic acid

[0116] Compound 561-18 (0.101 mmol, 116 mg) was dissolved in 1,4-dioxane (6 mL) and water (3 mL). Lithium hydroxide (0.5 M, 0.304 mmol, 0.61 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Water (6 mL) was added to the reaction mixture, and the mixture was acidified to pH ~3 with 0.5 M hydrochloric acid. The resulting white precipitate was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to give crude compound 561-19 (106.8 mg, 92.64%) as a white solid, which was used without purification. (MS+1) m / z 1140.4 Step 20: tert-butyl (2-(((3S,6S,9S)-3-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-26-((te rt-butoxycarbonyl)oxy)-9-((cyanomethyl)carbamoyl)-16-hydroxy-6-methyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-15-yl)oxy)ethyl)carbamate

[0117] To a mixture of compound 561-19 (0.035 mmol, 40 mg), aminoacetonitrile hydrochloride (0.35 mmol, 33 mg) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (0.526 mmol, 68 mg, 0.092 mL) and HATU (0.0526 mmol, 21 mg) were added. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica eluted with 0 to 10% pure methanol in DCM to provide compound 561-20 (17.1 mg, 41.4%). (MS+1) m / z 1177.8 Step 21: (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-25-(2- aminoethoxy)-N-(cyanomethyl)-16,26-dihydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxamide

[0118] Compound 561-20 (0.0145 mmol, 17.1 mg) was stirred in trifluoroacetic acid (0.25 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (4.75 mL) at room temperature for 1 h. The reaction mixture was concentrated. Et2O was added to the residue and concentrated again; this process was repeated 2 more times. The residue was dried under high vacuum and then purified by reverse phase HPLC to provide compound 561 (6 mg, 47.1%) as a white powder. 1H NMR (400 MHz, Methanol-d4) δ 8.34 (dd, J = 8.7, 2.2 Hz, 2H), 7.59 – 7.52 (m, 2H), 7.18 (dd, J = 8.2, 2.3 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.43 (s, 1H), 5.26 – 5.19 (m, 2H), 4.28 (td, J = 8.7, 7.5, 4.2 Hz, 2H), 4.20 (d, J = 7.3 Hz, 1H), 3.46 (s, 1H), 3.41 (t, J = 5.1 Hz, 3H), 3.15 (d, J = 7.5 Hz, 3H), 3.04 (s, 1H), 2.99 (s, 3H), 2.30 (dq, J = 14.2, 7.2 Hz, 1H), 2.16 (dq, J = 14.3, 7.5 Hz, 1H), 1.38 – 1.33 (m, 9H) مثال ۳۶۲: سنتز ترکیب ۵۶۲ گام ۱: methyl (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoate hydrochloride

[0119] To a solution of (2S)-2-amino-3-(3-bromo-4-hydroxy-phenyl)propanoic acid (39.32 mmol, 10.3 g) in methanol (100 mL) was slowly added thionyl chloride (86.5 mmol, 10.29 g, 6.30 mL) at 0 °C. The resulting mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dried under high vacuum to give the title compound (12.21 g, 100%), which was used without further purification. (MS+1) m / z 272.0 Step 2: methyl (S)-3-(3-bromo-4-hydroxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0120] To a mixture of methyl (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoate hydrochloride (39.32 mmol, 12.21 g) in 1:1 acetone / water (100 mL) was added sodium bicarbonate (118 mmol, 9.91 g) and di-tert-butyl dicarbonate (58.98 mmol, 13.27 g). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched to pH 3 to 4 by addition of 1N HCl. The aqueous phase was extracted twice with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford methyl (S)-3-(3-bromo-4-hydroxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate, which was used without further purification. (MS+1) m / z 372.0 Step 3: methyl (S)-3-(3-bromo-4-hydroxy-5-iodophenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0121] To a solution of (S)-3-(3-bromo-4-hydroxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (18.95 mmol, 7.09 g) in N,N-dimethylformamide (50 mL) was added N-iodosuccinimide (22.74 mmol, 5.22 g). The reaction was stirred at room temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 and brine, dried over sodium sulfate, and concentrated. The residue was purified on silica eluted with 15 to 30% ethyl acetate in heptane to provide the title compound (6.86 g, 72.4%) as a white solid. (MS+1) m / z 499.9 Step 4: methyl (S)-3-(3-bromo-5-iodo-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0122] Methyl (S)-3-(3-bromo-4-hydroxy-5-iodophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (6.24 mmol, 3.12 g) was dissolved in acetone (50 mL) and treated successively with potassium carbonate (31.2 mmol, 4.31 g) and iodomethane (7.49 mmol, 1.06 g, 0.466 mL). The solution was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue, which had been washed with water and brine, was dissolved in ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (0 to 40% ethyl acetate in heptane) to give the title compound (2.28 g, 71.1%) as a white foam. (MS+1) m / z 513.9 Step 5: methyl (S)-3-(3-bromo-5-hydroxy-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0123] Bis(pinacolato)diboron (8.046 mmol, 2.04 g), methyl (S)-3-(3-bromo-5-iodo-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (5.364 mmol, 2.76 g), potassium acetate (13.41 mmol, 1.32 g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.2682 mmol, 223 mg) were suspended in dry dimethyl sulfoxide (50 mL) (degassed by sparging with nitrogen) and heated to 65 °C under nitrogen overnight. The mixture was cooled to room temperature, and filtered through celite. The filtrate was diluted with 1:1 ethyl acetate:water and filtered through celite. The layers were separated and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo to give the crude product methyl (S)-3-(3-bromo-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate as a dark brown gum, which could not be further purified. (MS+1) m / z 514.1

[0124] Methyl (S)-3-(3-bromo-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate from above (5.364 mmol, 2.76 g) was dissolved in methanol (24 mL) and hydrogen peroxide (30% in water) (8 mL) and stirred at room temperature for 1 h. The methanol was removed under reduced pressure. To the residue was added ethyl acetate and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica eluting with 0 to 50% ethyl acetate in heptane to give the title compound (1.15 g, 53% after 2 steps). (MS+1) m / z 404.0 Step 6: tert-butyl ((S)-2-(((benzyloxy)carbonyl)(methyl)amino)-2-(4-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetyl)-L-alaninate

[0125] Bis(pinacolato)diboron (19.22 mmol, 4.88 g), tert-butyl (2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]-2-(4-hydroxy-3-iodo-phenyl)acetyl]amino]propanoate (12.01 mmol, 6.827 g), potassium acetate (36.03 mmol, 3.536 g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.6005 mmol, 500 mg) were suspended in dry dimethyl sulfoxide (120 mL) (degassed by nitrogen sparging), and heated to 85 °C overnight under nitrogen. The mixture was cooled to room temperature, and then filtered through celite. The filtrate was diluted with 1:1 ethyl acetate and water, and filtered through celite. The layers were separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and the residue was passed through a flash silica column eluted with 20 to 80% ethyl acetate in heptane to provide the title compound (3.85 g, 56.4%). (MS+1) m / z 569.2 Step 7: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2',5-dihydroxy-6-methoxy-5'-((5S,8S)-4,8,11,11-tetramethyl-3,6,9-trioxo-1-phenyl-2,10-dioxa-4,7-diazadodecane-5-yl)-[1,1'-biphenyl]-3-yl)propanoate

[0126] A mixture of tert-butyl ((S)-2-(((benzyloxy)carbonyl)(methyl)amino)-2-(4-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetyl)-L-alaninate (3.42 mmol, 1.94 g), methyl (S)-3-(3-bromo-5-hydroxy-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (2.85 mmol, 1.92 g), potassium tribasic phosphate (11.4 mmol, 2.49 g) in acetonitrile (60 mL) and degassed water (4 mL) was heated under nitrogen at 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-50% ethyl acetate in DCM) to provide the title compound (2.64 g, 60.5%). (MS+1) m / z 766.3 Step 8: ((S)-2-(5'-((S)-2-amino-3-methoxy-3-oxopropyl)-3',6-dihydroxy-2'-methoxy-[1,1'-biphenyl]-3-yl)-2-(((benzyloxy)carbonyl)(methyl)amino)acetyl)-L-alanine

[0127] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2',5-dihydroxy-6-methoxy-5'-((5S,8S)-4,8,11,11-tetramethyl-3,6,9-trioxo-1-phenyl-2,10-dioxa-4,7-diazadodecan-5-yl)-[1,1'-biphenyl]-3-yl)propanoate (1.72 mmol, 2.64 g) in TFA (8 mL) and DCM (32 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. Et2O was added to the residue and reconcentrated, and the process was repeated two more times. The residue was dried under high vacuum to give the crude title compound (1.05 g, 100%), which was carried forward without further purification. (MS+1) m / z 610.2 Step 9: methyl (4S,7S,10S)-10-(((benzyloxy)carbonyl)(methyl)amino)-16,25-dihydroxy-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0128] [001860] To a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, 50% in DMF (3.79 mmol, 2.41 g, 2.21 mL) and N,N-diisopropylethylamine (8.61 mmol, 1.11 g, 1.50 mL) in N,N-dimethylformamide (42 mL) at room temperature was added a solution of ((S)-2-(5'-((S)-2-amino-3-methoxy-3-oxopropyl)-3',6-dihydroxy-2'-methoxy-[1,1'-biphenyl]-3-yl)-2-((((benzyloxy)carbonyl)(methyl)amino)acetyl)-L-alanine (1.72 mmol, 1.05 g) in N,N-dimethylformamide (43 mL) The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified on silica eluted with 0 to 5% methanol in DCM to give the title compound (747 mg, 49.1%). (MS+1) m / z 592.2 Step 10: methyl (4S,7S,10S)-10-(((benzyloxy)carbonyl)(methyl)amino)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0129] To a solution of methyl (4S,7S,10S)-10-(((benzyloxy)carbonyl)(methyl)amino)-16,25-dihydroxy-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.3222 mmol, 373.7 mg) and tert-butyl n-(2-bromoethyl)carbamate (1.611 mmol, 380 mg) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.611 mmol, 524.8 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and concentrated. The residue was purified on silica washed with 0 to 5% methanol in DCM to give the title compound (266 mg, 48%). (MS+1) m / z 878.0 Step 11: methyl (4S,7S,10S)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0130] To a solution of methyl (4S,7S,10S)-10-(((benzyloxy)carbonyl)(methyl)amino)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.1545 mmol, 266 mg) in isopropyl alcohol (50 ml), 20% Pd(OH)2 (50 mg) was added and the reaction was placed under a hydrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give methyl (4S,7S,10S)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (114.9 mg, 100%) which was obtained without further purification. (MS+1) m / z 744.0 Step 12: methyl (4S,7S,10S)-10-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bi s(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0131] To a mixture of (2S)-4-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid (0.232 mmol, 102 mg) and methyl (4S,7S,10S)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-10-(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.154 mmol, 114 mg) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (0.7724 mmol, 99.8 mg, 0.135 mL) and HATU (0.3862 mmol, 149.8 mg) were added. After stirring at room temperature for 0.5 h, the reaction mixture was partitioned between ethyl acetate and water, washed with brine, and the organic layer was concentrated. The residue was purified on silica eluting with 0 to 10% methanol in DCM to provide the title compound (286 mg, 95%). (MS+1) m / z 1167.4 Step 13: methyl (4S,7S,10S)-10-((S)-2-amino-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate

[0132] A mixture of methyl (4S,7S,10S)-10-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.1471 mmol, 286 mg) in 10% piperidine in DMF (10 mL) was stirred at room temperature for 10 min, then concentrated and dried under high vacuum to give the crude title compound (138.9 mg, 100%), which was taken up without further purification. (MS+1) m / z 944.6 Step 14: methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido )-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0133] To a solution of methyl (4S,7S,10S)-10-((S)-2-amino-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.1471 mmol, 138.9 mg) in N,N-dimethylformamide (5 mL), 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (0.1765 mmol, 50.2 mg), N,N-diisopropylethylamine (0.7356 mmol, 95 mg, 0.128 mL), and HATU (0.2207 mmol, 85.6 mg) was added. After stirring at room temperature for 0.5 h, the reaction mixture was diluted with ethyl acetate, washed 3 times with water. The combined organic layer was concentrated and the residue was purified using silica gel chromatography, eluting with 0 to 10% methanol in DCM to give the title compound (93 mg, 52%). (MS+1) m / z 1211.5 Step 15: (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido )-16,25-bis(2-aminoethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylic acid

[0134] Aluminum chloride (12.0 mmol, 1.60 g) and 1-dodecanethiol (12 mmol, 2.43 g, 2.88 mL) were stirred in dichloromethane (10 mL) at room temperature for 0.5 h, and then added to a solution of methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-methoxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.077032 mmol, 148 mg) in dichloromethane. Chloromethane (10 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue dried under high vacuum to give the crude title compound, which was carried out without further purification. (MS+1) m / z 883.4 Step 16: methyl (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido )-16,25-bis(2-aminoethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0135] To a solution of (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylic acid (0.07596 mmol, 67 mg) in anhydrous methanol (10 mL), was added thionyl chloride (15 mmol, 1.80 g, 1.1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the crude title compound, which was used immediately in the next step without further purification. (MS+1) m / z 896.8 Step 17: methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate

[0136] A mixture of methyl (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.07589 mmol, 68 mg) suspended in acetone (10 mL) and water (5 mL), was treated with saturated aqueous NaHCO3 to pH 9 to 10. An additional amount of di-tert-butyl dicarbonate (1.518 mmol, 341.5 mg) was then added and the reaction mixture was stirred at room temperature for 0.5 h until complete conversion was observed. The reaction mixture was diluted with ethyl acetate and filtered through celite. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 10% methanol in DCM to give the title compound (51.3 mg, 56.5%). (MS+1) m / z 1196.8 Step 18: (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylic acid

[0137] Methyl (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylate (0.0524 mmol, 114 mg) was dissolved in 1,4-dioxane (3 mL) and water (1 mL), and lithium hydroxide (0.5 M, 0.26204 mmol, 0.524 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 0.5 h. Water (3 mL) was added and the reaction mixture was acidified with 0.5 M hydrochloric acid to pH 3–4. The resulting white precipitate was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give the crude title compound (105 mg, 93%) as a white solid, which was used in the next step without further purification. (MS+1) m / z 1183.5 Step 19: tert-butyl ((S)-4-(((3S,6S,9S)-15,26-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-9-((cyanomethyl)carbamoyl)-16-hydroxy-6-methyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-3-yl)(methyl)amino)-3-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-4-oxobutyl)carbamate

[0138] To a mixture of (4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylic acid (0.03721 mmol, 80 mg) and aminoacetonitrile hydrochloride (0.1861 mmol, 17.2 mg) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (0.3721 mmol, 48.1 mg, 0.0649 mL) and HATU (0.05582 mmol, 21.7 mg) was added. The reaction was stirred at room temperature for 0.5 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 0 to 10% methanol in DCM, to give the title compound (36 mg, 63.4%). (MS+1) m / z 1221.8 Step 20: (4S,7S,10S)-10-((S)-4-amino-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25- bis(2-aminoethoxy)-N-(cyanomethyl)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxamide

[0139] tert-butyl ((S)-4-((((3S,6S,9S)-15,26-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-9-((cyanomethyl)carbamoyl)-16-hydroxy-6-methyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-3-yl)(methyl)amino)-3-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-4-oxobutyl)carbamate (0.0236 mmol, 36 mg) was dissolved in TFA (0.1 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (4.9 mL) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated. Et2O was added to the residue and concentrated again. This process was repeated two more times, and the residue was purified by reverse-phase HPLC to give the title compound (23.4 mg, 92.1%) as a white powder. (MS+1) m / z 921.41H NMR (400 MHz, Methanol-d4) δ 8.39 – 8.30 (m, 2H), 7.59 – 7.49 (m, 2H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.47 (s, 1H), 6.42 (s, 1H), 5.22 (dd, J = 7.5, 6.0 Hz, 1H), 4.83 (d, J = 19.6 Hz, 3H), 4.45 – 4.32 (m, 2H), 4.36 – 4.22 (m, 2H), 4.26 – 4.09 (m, 2H), 3.47 – 3.22 (m, 6H), 3.19 – 3.04 (m, 2H), 2.99 (s, 3H), 2.65 (s, 1H), 2.57(s, 6H), 2.30 (dq, J = 14.1, 7.3 Hz, 1H), 2.16 (dq, J = 14.7, 7.6 Hz, 1H), 1.38 (s, 12H). مثال ۳۶۳: سنتز ترکیب ۵۶۳

[0140] 4S,7S,10S)-10-((S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenecyclodecaphane-4-carboxylic acid (0.01269 mmol, 25 mg) was dissolved in TFA (0.1 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (4.9 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC to give the title compound (12.4 mg, 98.1%) as a white powder. m / z 883.4 1H NMR (400 MHz, Methanol-d4) δ 8.39 – 8.30 (m, 2H), 7.59 – 7.49 (m, 2H), 7.29 (dd, J = 8.9, 2.5 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 5.22 (t, J = 6.8 Hz, 1H), 4.86 (s, 2H), 4.43 – 4.21 (m, 3H), 3.48 – 3.29 (m, 5H), 3.28 (dd, J = 3.4, 1.7 Hz, 2H), 3.20 – 3.03 (m, 2H), 3.00 (s, 3H), 2.65 (s, 1H), 2.57 (s, 5H), 2.30 (dq, J = 14.1, 7.5, 7.1 Hz, 1H), 2.16 (dq, J = 14.6, 7.6 Hz, 1H), 1.38 (s, 9H), 1.43 – 1.26 (m, 4H). مثال ۳۶۴: سنتز ترکیب ۵۶۴

[0141] Step 1: Starting from 4-bromophenol and bromocycloheptane, SN2 reaction conditions (described in Example 10) and Suzuki boronation conditions (described in Example 10) were used to give 2-(4-(cycloheptyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.73(d, J=8.8 Hz, 2H), 6.86(d, J=8.8 Hz, 2H), 4.51-4.45 (m, 1H), 2.05-1.98 (m, 2H), 1.82-1.72 (m, 4H), 1.60-1.57 (m, 4H), 1.51-1.44 (m, 2H), 1.34 (s, 12H). tert-Butyl (3-bromopropyl)carbamate and 4-amino-6-(4-(cycloheptyloxy)phenyl)-2-methyl nicotinic acid were prepared as a white solid using similar methods described in Example 213. LCMS (Method 5-95 AB, ESI): tR= 0.791 min, [M + H]+= 341.0

[0142] Compound 564 (FA salt) was prepared as a white solid from 101E, tert-butyl (3-bromo propyl)carbamate and 4-amino-6-(4-(cycloheptyloxy)phenyl)-2-methylnicotinic acid using similar procedures described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 0.703 min, [M / 2 + H]+= 495.1; 1H NMR (400 MHz, MeOH-d4)  8.45 (br s, 1H), 7.68-7.65 (m, 2H), 7.28-7.16 (m, 2H), 7.10-7.07 (m, 1H), 7.03-6.95 (m, 4H), 6.89-6.87 (m, 1H), 6.81-6.72 (m, 1H), 6.43-6.37 (m, 1H), 5.07-5.02 (m, 1H), 4.74-4.71 (m, 1H), 4.59-4.53 (m, 1H), 4.20-4.15 (m, 4H), 4.08-4.02 (m, 2H), 3.20-3.01 (m, 4H), 2.98-2.93 (m, 7H), 2.51 (d, J = 3.2 Hz, 3H), 2.21-2.09 (m, 2H), 2.04-1.99 (m, 6H), 1.82-1.70 (m, 4H), 1.62-1.60 (m, 4H), 1.52-1.51 (m, 2H), 1.39-1.31 (m, 3H) Example 365: Synthesis of compound 565

[0143] Compound 565 (FA salt) was prepared as a white solid from 101E and bromocyclohexane using similar methods described in Example 364. LCMS ( روش 5-95 AB, ESI): tR= 0. 692 min, [M + H]+= 974.5 ;1H NMR (400 MHz, MeOH- d4)  8.40 (br s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.26-7.14 (m, 2H), 7.07-6.93 (m, 5H), 6.89 (br s, 1H), 6.78-6.70 (m, 1H), 6.41-6.33 (m, 1H), 5.02-4.99 (m, 1H), 4.72-4.69 (m, 2H), 4.41-4.36 (m, 1H), 4.19-4.13 (m, 4H), 4.04-4.00 (m, 2H), 3.17-3.05 (m, 3H), 2.99-2.90 (m, 7H), 2.51 (br s, 3H), 2.20 (br s, 1H), 2.14-2.11 (m, 1H), 1.98 (br s, 6H), 1.75 (br s, 2H), 1.54-1.20 (m, 9H) مثال ۳۶۶: سنتز ترکیب ۵۶۶

[0144] Step 1: To a solution of 4-hydroxybenzonitrile (5 g, 43.8 mmol), cycloheptanol (11.7 g, 98.5 mmol) and triphenylphosphine (27.6 g, 105 mmol) in toluene (50 mL), DIAD (21.3 g, 105 mmol) was added at 25 °C under nitrogen. The reaction was stirred at 80 °C for 2 h. The volatiles were removed and the residue was purified by silica chromatography, eluting with 0-5% ethyl acetate in petroleum ether, to give 4-(cycloheptyloxy)benzonitrile (6.1 g, 65% yield) as a white solid.

[0145] Step 2: To a solution of 4-(cycloheptyloxy)benzonitrile (3.8 g, 17.6 mmol) in THF (40 mL), LiHMDS (1 M in THF, 70.6 mL) was added at 0 °C. The reaction was stirred at 25 °C for 40 h. After that, hydrochloride (4 M in H2O, 60 mL) was added and the mixture was stirred for 10 min, after which it was adjusted to pH = 12 using NaOH and extracted with DCM (100 mL). The organic layer was dried over sodium sulfate and concentrated to give 4-(cycloheptyloxy)benzimidamide (2.6 g, 63% yield) as a brown oil. 4-Amino-2-(4-(cycloheptyloxy)phenyl)-6-methylpyrimidine-5-carboxylic acid was prepared as a white solid using similar methods described in Example 221 and Example 213. LCMS (Method 5-95 AB, ESI): tR= 0.671 min, [M + H]+= 342.5

[0146] Compound 566 (FA salt) was prepared as a white solid from 101E and 4-Amino-2-(4-(cyclo heptyloxy)phenyl)-6-methylpyrimidine-5-carboxylic acid using a similar procedure to Example 364. LCMS (Method 5-95 AB, ESI): tR= 0.589 min, [M + H]+= 989.6; 1H NMR (400 MHz, MeOH-d4)  8.53 (br s, 1H), 8.11 (d, J =8.0 Hz, 2H), 7.28-7.06 (m, 4H), 6.89 (d, J =8.0 Hz, 2H), 6.83 (s, 1H), 6.6 4-6.61 (m, 2H), 4.79-4.67 (m, 3H), 4.61-4.60 (m, 1H), 4.39-4.09 (m, 6H), 3.28-3.01 (m, 10H), 2.31 (s, 3H), 2.23-2.08 (m, 7H), 1.88-1.80 (m, 5H), 1.75-1.60 (m, 4H), 1.58 (s, 2H), 1.43-1.32 (m, 4H) Example 367: Synthesis of compound 567

[0147] Step 1: A solution of 101E (1 g, 1.78 mmol), K2CO3 (4.4 g, 32 mmol) and [(2R)-oxiran-2-yl] methyl 3-nitrobenzenesulfonate (6.9 g, 26.7 mmol) in DMF (10 mL) was stirred at 50 °C for 24 h. The reaction mixture was washed with brine (150 mL×3) and ethyl acetate (150 mL) was added, dried over Na2SO4, concentrated and the residue was column purified (2% methanol in DCM) to give compound 567-1 (1.0 g, 83% yield) as a white solid. LCMS (10-80AB_7min, ESI): tR= 3.611 min, [M + Na]+= 696.1

[0148] Step 2: A solution of compound 567-1 (1.0 g, 1.48 mmol) in acetonitrile (20 mL) and water (5 mL), CeCl3 (183 mg, 0.74 mmol) and NaN3 (1.45 g, 22 mmol) was added and the mixture was stirred at 75 °C for 24 h. Water (100 mL) was added to the above solution and the mixture was stirred for 5 min. The resulting precipitate was collected for the next step. The filtrate was treated with hydrochloric acid (1 mol / L) to pH 6, extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue, together with the precipitate, was treated with PPh3 (2 g, 7.9 mmol), H2O (0.3 mL) in THF (20 mL) at 50 °C for 15 h. The volatiles were removed and the residue was treated with SOCl2 (230 mg, 2 mmol) in methanol (6 mL) at 75 °C for 1 h. After concentration under vacuum, the residue was dissolved in THF / H2O (20 mL, v / v=7:1) to which NaHCO3 (415 mg, 4.9 mmol) and Boc2O (925 mg, 4.2 mmol) were added. The mixture was stirred at 30 °C for 2 h.The reaction mixture was extracted with ethyl acetate (100 mL×2), added to water (50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the residue was column purified, eluting with 30% acetone in petroleum ether until PPh3O was removed, and then 70% ethyl acetate in petroleum ether, to give compound 567-2 (860 mg, 67% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.878 min, [M + Na]+= 930.2.

[0149] Compound 567 (FA salt) was prepared as a white solid from compound 567-2 by similar methods described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 0.708 min, [M + H]+= 964.8; 1H NMR (400 MHz, MeOH-d4)  8.51 (br s, 1H), 8.20 (d, J =8.0 Hz, 2H), 7.47 (d, J =8.0 Hz, 2H). 7.29-7.15 (m, 2H), 7.02 (s, 1H), 6.80 (s, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 5.36-5.23 (m, 1H), 4.81-4.70 (m, 2H), 4.32-4.04 (m, 7H), 4.02-3.90 (m, 1H), 3.20-3.04 (m, 4H), 3.03-2.87 (m, 6H), 2.46 (s, 6H), 2.31-2.10 (m, 2H), 1.38 (s, 9H), 1.33 (d, J =6.4 Hz, 3H) Example 368: Synthesis of compound 568

[0150] Compound 568 (FA salt) was prepared as a white solid from 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using a similar procedure to Example 367. LCMS (Method 5-95 AB, ESI): tR= 0.742 min, [M / 2 + H]+= 504.0; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 1H), 8.19-8.01 (m, 2H), 7.22 (br s, 2H), 7.08-6.85 (m, 4H), 6.77 (s, 1H), 6.71 (s, 1H), 6.36 (br s, 1H), 5.40-5.30 (m, 1H), 4.82-4.68 (m, 2H), 4.51-3.86 (m, 10H), 3.28-2.64 (m, 10H), 2.58-2.22 (m, 7H), 2.21-2.08 (m, 1H), 2.07-1.98 (m, 2H), 1.90-1.79 (m, 2H), 1.68-1.26 (m, 9H) Example 369: Synthesis of compound 569

[0151] Compound 569 (FA salt) was prepared as a white solid from -(4-isopropoxyphenyl)-4,6-dimethylpyrimidine-5-carboxylic acid by similar methods described in Example 367. LCMS (method 5-95 AB, ESI): tR= 0.679 min, [M + H]+= 966.5; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 1H), 8.10-8.04 (m , 2H), 7.24 (br s, 2H), 7.02 (d, J = 8.8 Hz) 1H), 6.94-6.87 (m, 3H), 6.76 (s, 2H), 6.30 (s, 1H), 5.38-5.36 (m, 1H), 4.77-4.69 (m, 2H), 4.34-4.16 (m, 7H), 3.98-3.95 (m, 1H), 3.31-3.26 (m, 1H), 3.16-3.06 (m, 4H), 3.01 (s, 3H), 2.95-2.92 (m, 2H), 2.76-2.48 (m, 2H), 2.35 (s, 6H), 2.30-2.12 (m, 2H), 1.38 (d, J = 6.0 Hz, 6H) 1.33 (d, J = 6.8 Hz, 3H) Example 370: Synthesis of compound 570

[0152] Compound 570 (FA salt) was prepared as a white solid from 101E and [(2S)-oxiran-2-yl] methyl 3-nitrobenzenesulfonate by similar methods described in Example 367. LCMS (Roche 5-95 AB, ESI): tR= 0. 720 min, [M + H]+= 964.6 ;1H NMR (400 MHz, MeOH- d4)  8.53 (br s, 1H), 8.14 (d, J =8.0 Hz, 2H), 7.45 (d, J =8.0 Hz, 2H), 7.27-7.16 (m, 2H), 7.06-6.92 (m, 2H), 6.78 (s, 1H), 6.67 (s, 1H), 6.41 (s, 1H), 5.41-5.18 (m, 1H), 4.83-4.70 (m, 2H), 4.41-3.90 (m, 9H), 3.23-2.82 (m, 10H), 2.43 (s, 6H), 2.33-2.08 (m, 2H), 1.39 (s, 9H), 1.33 (d, J = 6.4 Hz, 3H) Example 371: Syntz, compound 571

[0153] Step 1: A solution of compound 571-1 (from Example V (Compound 106-B1) 300 mg, 0.37 mmol) in 10% TFA in DCM (30 mL) was stirred at 25 °C for 5 h. The volatiles were removed and the residue, to which Boc2O (93 mg, 0.43 mmol) was added, was redissolved in THF (12 mL). The resulting mixture was added to saturated NaHCO3 solution to pH 8 and the reaction was stirred at 25 °C for 2 h. The reaction was extracted with ethyl acetate (30 mL×3) and added to water (30 mL). The combined organic layers were washed with brine (50 mL×2), dried over sodium sulfate, concentrated, and the residue was purified by preparative TLC (10% methanol in DCM, Rf = 0.4) to give compound 571-2 (251 mg, 96% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.907 min, [M + Na]+= 727.5

[0154] Compound 571 (FA salt) was prepared as a white solid from compound 571-2 by similar methods described in Example 367. LCMS (Roche 10-80 AB, ESI, 7 min): tR= 1.756 min, [M + H]+= 935.6 ;1H NMR (400 MHz, MeOH- d4)  8.52 (br s, 2H), 8.28-8.14 (m, 2H), 7. 50 -7. 45 (m, 2H), 7.32-7.18 (m, 2H), 7.10-6.96 (m, 2H), 6.83 (s, 1H), 6.65-6.40 (m, 2H), 5.30 (m, 1H), 4.85-4.77 (m, 2H), 4.46-4.29 (m, 3H), 4.25-4.00 (m, 4H), 3.30-3.26 (m, 2H), 3.14 (br s, 3H), 3.07-3.01 (m, 3H), 3.00-2.86 (m, 3H), 2.45 (s, 6H), 2.35-2.23 (m, 1H), 2.22-2.09(m, 1H), 1.39 (s, 9H), 1.34 (d, J =6.0 Hz, 3H) Example 372: Syntz, compound 572

[0155] Step 1: To a solution of 2-(trimethylsilyl)ethanol (7.0 g, 60 mmol) and Et3N (10 g, 100 mmol) in DCM (15 mL), 4-nitro-phenylchloroformate (10 g, 50 mmol) was added and the mixture was stirred at 30 °C for 1 h. The reaction was quenched with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic layers were dried over sodium sulfate, concentrated, and the residue was purified by column, eluting with 2% ethyl acetate in petroleum ether, to give (4-nitrophenyl) 2-trimethylsilylethyl carbonate (10 g, 71% yield) as a colorless oil.

[0156] Step 2: To a solution of (4-nitrophenyl) 2-trimethylsilylethyl carbonate (5 g, 17.6 mmol) in DMF (45 mL), (2S)-3-amino-2-(benzyloxycarbonylamino)propanoic acid (3.5 g, 14.7 mmol) and Et3N (3 g, 29.4 mmol) were added at 25 °C and the mixture was stirred at the same temperature for 3 h. The volatiles were removed and the residue was partitioned between DCM and H2O (200 mL each). The organic layer was washed with brine (100 mL×2), dried over Na2SO4, concentrated, and the residue was purified on a silica gel column, eluting with 10%-30% methanol in DCM to give (2S)-2-(benzyloxycarbonylamino)-3-(2-trimethylsilyl ethoxycarbonylamino)propanoic acid (3.4 g, 61% yield) as a white solid.

[0157] Compound 572-1 was prepared as a white solid using similar methods described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 1.146 min, [M + H]+= 1235.4

[0158] Step 3: To a solution of compound 572-1 (120 mg, 0.097 mmol) in DMF (2 mL), TBAF (1 M in THF, 40 μL) was added at 20°C and the reaction was stirred at 50°C for 2 h. The mixture was extracted with ethyl acetate, diluted with water (20 mL) (20 mL×2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated to give INT-A.

[0159] To another solution of chlorosulfonyl isocyanate (17 mg, 0.11 mmol) in DCM (2 mL) at 0 °C, t-BuOH (13 μL, 0.11 mmol) was added and the mixture was stirred for 30 min, followed by the addition of pyridine (26 μL, 0.22 mmol). The resulting mixture was added via pipette to a mixture of INT-A and DIEA (40 mg, 0.30 mmol) in DCM (2 mL) at 0 °C, stirred for 40 min during the formation of a precipitate. The reaction was stirred at 0 °C for 0.5 h. After that, the mixture was washed with brine (10 mL) and diluted with DCM (10 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified by preparative TLC (10% methanol in DCM) to afford compound 572-2 (40 mg, 33% yield).

[0160] Compound 572 (FA salt) was prepared as a white solid from compound 572-2 by similar methods described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 0.756 min, [M + H]+= 969.7; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 2H), 8.01 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H). 7.28-7.21 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.90-9.84 (m, 2H), 6.76 (s, 1H), 6.27 (s, 1H), 5.51-5.47 (m, 1H), 4.76-4.71 (m, 1H), 4.43 (s, 1H), 4.29-4.20 (m, 5H), 4.09 (s, 1H), 3.56-3.51 (m, 1H), 3.40-3.34 (m, 2H), 3.21 (s, 2H), 3.09 (s, 3H), 2.87-2.77 (m, 1H), 2.61-2.53 (m, 1H), 2.35 (s, 6H), 1.39 (s, 9H), 1.33 (d, J = 6.4 Hz, 3H) Example 273: Synthesis of compound 573

[0161] Compound 573 (FA salt) was prepared as a white solid from 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using a similar procedure to Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.801 min, [M + H]+= 997.4; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br s, 3H), 8.12 (d, J = 8.0 Hz, 1H), 7.28-7.15 (m, 2H), 7.06-7.04 (m, 3H), 7.00-6.94 (m, 2H), 6.74-6.64 (m, 3H), 5.76-5.72 (m, 1H), 4.93-4.60 (m, 2H), 4.45-4.35 (m, 2H), 4.20-4.16 (m, 2H), 4.05 (s, 5H), 3.77 (s, 12H), 2.97 (m, 4H), 2.42 (s, 2H), 1.94 (s, 2H), 1.74-1.72 (m, 2H), 1.56-1.36 (m, 6H), 1.25-1.21 (m, 3H) Example 374: Synthesis of compound 574

[0162] Compound 574 (FA salt) was prepared as a white solid from (S)-4-amino-2-(((benzyloxy)carbonyl)amino)butanoic acid using similar methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.782 min, [M + H]+= 983.7; 1H NMR (400 MHz, MeOH-d4)  8.51 (br s, 1H), 8.12-8.06 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H). 7.27-7.23 (m, 2H), 7.07 (d, J =8.4 Hz, 1H), 7.00-6.96 (m, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.40 (s, 1H), 5.33-5.32 (m, 1H), 4.90-4.85 (m, 1H), 4.78-4.73 (m, 1H), 4.45-4.41 (m, 2H), 4.32-4.22 (m, 4H), 3.35 (m, 3H), 3.27-3.17 (m, 4H), 3.07 (m, 3H), 2.91 (m, 1H), 2.43 (s, 6H), 2.04-1.98 (m, 1H), 2.07-1.95 (m, 1H), 1.39 (s, 9H), 1.34 (d, J =6.8 Hz, 3H) Example 375: Synthesis of compound 575

[0163] Compound 575 (FA salt) was prepared as a white solid from 101E and tert-butyl (3-bromo propyl)carbamate by similar methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.772 min, [M + H]+= 997.6; 1H NMR (400 MHz, MeOH-d4)  8.42 (br s, 1H), 7. 99 (d, J =8.0Hz, 2H), 7.35 (d, J =8.4Hz, 2H), 7.27-7.12 (m, 2H), 7.07-6.93 (m, 2H), 6.87-6.75 (m, 1H), 6.69 (s, 1H), 6.19 (br s, 1H), 5.58-5.48 (m, 1H), 4.78-4.62 (m, 1H), 4.50-4.15(m, 5H), 4.13-3.77 (m, 2H), 3.60-3.47 (m, 1H), 3.41-3.32 (m, 1H), 3.28-3.16 (m, 2H), 3.15-2.93 (m, 5H), 2.83-2.68 (m, 1H), 2.60-2.46 (m, 1H), 2.31 (s, 6H), 2.20-1.90 (m, 4H), 1.39 (s, 9H), 1.34 (d, J =6.8 Hz, 3H) Example 376: Synthesis of compound 576

[0164] Compound 576 (FA salt) was prepared as a white solid from 101E, tert-butyl (3-bromo propyl)carbamate, and -(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using similar methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.771 min, [M + H]+= 1039.9; 1H NMR (400 MHz, MeOH-d4)  8.41 (br s, 3H), 8.11 (d, J =6.4 Hz, 2H), 7.22 (br s, 2H), 7.11-6.95 (m, 3H), 6.90 (d, J =8.4 Hz, 2H), 6.77 (s, 1H), 6.40 (br s, 1H), 5.52-5.45 (m, 1H), 4.84-4.74 (m, 2H), 4.48-4.24 (m, 6H), 4.13-4.05 (m, 1H), 3.61-3.49 (m, 1H), 3.42-3.35 (m, 1H), 3.22-2.97 (m, 8H), 2.96-2.85 (m, 1H), 2.39 (s, 6H), 2.22 (br s, 2H), 2.09-2.02 (m, 4H), 1.89-1.80 (m, 2H), 1.69-1.44 (m, 6H), 1.38 (d, J =6.8 Hz, 3H) Example 377: Synthesis of compound 577

[0165] Compound 577 (FA salt) was prepared as a white solid from compound 577-1 (described in Example 367) using similar methods described in Example 372. LCMS (method 10-80 AB, ESI, 7 min): tR= 2.329 min, [M + H]+= 1029.4; 1H NMR (400 M Hz, MeOH-d4)  8.54 (br s, 1H), 7.98 (d, J =8.4 Hz, 2H), 7.34 (d, J =8.4 Hz, 2H). 7.27-7.09 (m, 2H), 6.99 (d, J =8.8 Hz, 2H), 6.87-6.75 (m, 1H), 6.69 (s, 1H), 6.16 (br s, 1H), 5.52-5.95 (m, 1H), 4.55-4.52 (m, 1H), 4.45-4.10 (m, 8 H), 4.00-3.70 (m, 2H), 3.60-3.45 (m, 1H), 3.40-3.25 (m, 5H), 3.17-3.08 (m, 2H), 3.00-2.90 (m, 1H), 2.81-2.65 (m, 1H), 2.30 (s, 6H), 1.40 (s, 9H), 1.34 (d, J=6.4 Hz, 3H) Example 378: Synthesis of compound 578

[0166] Compound 578 (FA salt) was prepared as a white solid from compound 578-1 (synthesis described in Example 367) and 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using similar methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.776 min, [M + H]+= 1072.0; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 1H), 8.08-7.88 (m, 2H), 7.29-7.11 (m, 2H), 7.08-6.80 (m, 5H), 6.72 (s, 1H), 6.24 (br s, 1H), 5.55-5.46 (m, 1H), 4.83-4.62 (m, 2H), 4.49-3.83 (m, 10H), 3.59-3.48 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.18 (m, 1H), 3.16-2.71 (m, 7H), 2.54-2.15 (m, 6H), 2.09-1.98 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.31 (m, 9H) Example 379: Synthesis of compound 579

[0167] Compound 579 (FA salt) was prepared as a white solid from compound 579-1 (synthesis described in Example 367) and -(4-isopropoxyphenyl)-4,6-dimethylpyrimidine-5-carboxylic acid by the methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.582 min, [M + H]+= 1031.4; 1H NMR (400 MHz, MeOH-d4)  8.54 (br s, 1H), 8.14-7.94 (m, 2H), 7.26-7.16 (m, 2H), 7.06-7.01 (m, 1H), 7.01-6.90 (m, 2H), 6.86 (d, J =8.4 Hz, 2H), 6.75 (br s, 1H), 6.34 (s, 1H), 5.54-5.45 (m, 1H), 4.78-4.67 (m, 2H), 4.38-4.08 (m, 8H), 4.00-3.92 (m, 1H), 3.58-3.50 (m, 1H), 3.41-3.33 (m, 2H), 3.30-3.22 (m, 1H), 3.14-2.99 (m, 5H), 2.95-2.81 (m, 2H), 2.34 (s, 6H), 1.39 (d, J =5.6) Hz, 6H), 1.37 (d, J = 6.4 Hz, 3H) Example 380: Synthesis of compound 580

[0168] Compound 580 (FA salt) was prepared as a white solid from (S)-4-amino-2-(((benzyloxy)carbonyl)amino)butanoic acid using similar methods described in Example 377. LCMS (Method 5-95 AB, ESI): tR= 0.776 min, [M + H]+= 1043.8; 1H NMR (400 MHz, MeOH-d4)  8.55 (s, 1H), 8.08 (d, J =6.8 Hz, 2H), 7.40 (d, J =8.0 Hz, 2H). 7.26-7.14 (m, 2H), 7.05-6.82 (m, 3H), 6.75 (s, 1H), 6.28 (br s, 1H), 5.41-5.32 (m, 1H), 4.77-4.67 (m, 1H), 4.42-3.88 (m, 10H), 3.28-3.15 (m, 3H), 3.12-2.98 (m, 5H), 2.95-2.74 (m, 2H), 2.38 (s, 6H), 2.26-2.15 (m, 1H), 2.08-1.95 (m, 1H), 1.39 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H) Example 381: Synthesis of Compound 581

[0169] Compound 581 (TFA salt) was prepared as a white solid from [(2S)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate by similar methods described in Example 377. LCMS ( روش 5-95 AB, ESI): tR= 0. 772 min, [M + H]+= 1029.3 ;1H NMR (400 MHz, MeOH- d4)  7.98 (d , J =8.0 Hz, 2H), 7.36 (d, J =8.0 Hz, 2H), 7.25 (d, J =8.8 Hz, 1H), 7.16 (d, J =8.8 Hz, 1H), 7.05-6.95 (m, 2H), 6.89-6.79 (m, 1H), 6.70 (br s, 1H), 6.19 (br s, 1H), 5.58-5.48 (m, 1H), 4.83-4.61 (m, 2H), 4.44-3.99 (m, 8H), 3.59-3.48 (m, 1H), 3.41-3.31 (m, 2H), 3.29-3.14 (m, 2H), 3.10 (s, 3H), 3.08-3.02 (m, 1H), 3.00-2.92 (m, 1H), 2.82-2.69 (m, 1H), 2.32 (s, 6H), 1.40 (s, 9H), 1.36(d, J =7.2 Hz, 3H) مثال ۳۸۲: سنتز ترکیب ۵۸۲

[0170] Step 1: To a solution of compound 582-1 (from Example V (compound 106-A2 (13 g, 20 mmol) in methanol (100 mL), AgSO4 (4.35 g, 14.0 mmol) and I2 (5.57 g, 22 mmol) were added at 20°C and the reaction mixture was stirred at 20°C for 2 h. After filtration, the filtrate was concentrated and the residue was purified by silica gel column, eluting with 5% methanol in DCM. The resulting material was dissolved in DCM (130 mL), to which was added DIEA (6.5 g, 50 mmol) and SEM-Cl (4.45 mL, 25 mmol). The reaction was stirred at 25°C for 4 h. The mixture was washed with saturated NH4Cl solution and brine (250 mL each), and then washed with DCM (300 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified on a silica gel column to give compound 582-2 (15 g, 83% yield) as an off-white solid. LCMS (Method 5-95 AB, ESI): tR= 1.088 min, [M + Na]+= 930.0

[0171] Step 2: A mixture of KOAc (7.57 g, 77 mmol), compound 582-2 (10.0 g, 11 mmol), Pin2B2 (14 g, 55 mmol), Pd2(dba)3 (504 mg, 0.55 mmol) and PCy3 (309 mg, 1.1 mmol) in DMSO (150 mL) was stirred at 80 °C overnight under N2. The mixture was washed with saturated NaHCO3 solution and brine (500 mL each), diluted with ethyl acetate (500 mL). The organic layer was dried over sodium sulfate, concentrated and the residue was purified on a silica gel column, eluting with 5% methanol in DCM. The resulting material was redissolved in methanol (100 mL) after addition of H2O2 (30%w / w, 20 mL). The reaction was stirred for 6 h at 30 °C. The mixture was washed with water and brine (100 mL each), diluted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified on a silica gel column, eluting with 5% methanol in DCM, to afford compound 582-3 (7.2 g, 9.0 mmol, 82% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.996 min, [M + Na]+= 820.0

[0172] Step 3: A solution of compound 582-3 (2.4 g, 3.0 mmol) and 10% Pd / C (1.6 g, 1.5 mmol) in DMA (20 mL) was stirred under hydrogen (50 psi) at 50°C for 20 h. After filtration, the filtrate was added with CbzOSu (749 mg, 3.0 mmol) and the resulting mixture was stirred at 25°C for 1 h. After that, the mixture, which was washed with brine (100 mL×3), was added with ethyl acetate (120 mL). The organic layer was dried over sodium sulfate, concentrated and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in petroleum ether, to give compound 582-4 (1.9 g, 90% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.904 min, [M + Na]+= 730.2

[0173] Compound 582-4 was prepared as a white solid using similar procedures described in Example 367 (SEM was removed under methyl ester formation conditions). LCMS (Method 5-95 AB, ESI): tR= 0.863 min, [M + Na]+= 946.3

[0174] Compound 582 (TFA salt) was prepared using similar methods described in Example 377 (hypo-acylation on the unprotected phenol during each amide coupling step, which could be converted to the desired product by treatment with 3% ammonia in methanol for 1 h. LCMS (method 10-80 AB, ESI, 7 min): tR= 2.331 min, [M + H ]+= 1045.6; 1H NMR (400MHz, DMSO-d6, T=80°C) δ 8.58-8.84 (m, 2H), 8.52 (br s, 1H), 8.32 (d, J =7.6 Hz, 2H), 8.07 (d, J =8.4 Hz, 1H), 7.54 (d, J =7.6 Hz, 2H), 7.18 (d, J =8.4 Hz, 1H), 7.02 (d, J =8.4 Hz, 1H), 6.83 (br s, 1H), 6.77 (br s, 1H), 6.46 (br s, 1H), 6.34 (s, 1H), 5.20-5.09 (m, 1H), 4.81-4.68 (m, 2H), 4.22-4.06 (m, 8H), 3.45-3.35 (m, 1H), 3.26-3.15 (m, 2H), 3.10-2.92 (m, 6H), 2.88-2.72 (m, 2H), 2.53 (s, 6H), 1.35 (s, 9H), 1.24 (d, J = 6.0 Hz) 3H) Example 383: Synthesis of compound 583

[0175] Compound 583 (TFA salt) was prepared from compound 582-4 (described in Example 382) using similar methods described in Example 53. LCMS (Method 5-95 AB, ESI): tR= 0.706 min, [M + H ]+= 920.4; 1H NMR (400 MHz, MeOH-d4)  8.35 (d, J =8.4 Hz, 2H), 7.55 (d, J =8.4 Hz, 2H), 7.23 (d, J =7.6 Hz, 1H), 7.08 (d, J =8.0 Hz, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 6.42 (s, 1H), 5.25-5.15 (m, 1H), 4.85-4.80 (m, 2H), 4.48-4.15 (m, 6H), 3.45-3.35 (m, 4H), 3.27-3.07 (m, 4H), 3.07-3.00 (m, 3H), 2.59 (s, 6H), 2.35-2.25 (m, 1H), 2.25-2.15 (m, 1H), 1.40 (s, 9H), 1.38 (d, J = 7.2 Hz) 3H) Example 384: Synthesis of compound 584

[0176] Compound 584 (TFA salt) was prepared from compound 582-4 (described in Example 382) using similar methods described in Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.767 min, [M + H ]+= 985.6; 1H NMR (400 MHz, MeOH-d4)  8.16-8.34 (m, 2H), 7.54-7.26 (m, 2H), 7.12-7.05 (m, 2H), 6.85 (s, 1H), 6.71-6.37 (m, 3H), 5.33 (m, 1H), 4.80-4. 78 (m, 2H), 4.38 - 4.20 (m, 6H), 3.61-3.38 (m, 6H), 3.20 -2.90 (m, 2H), 3.02 (s, 3H), 2.53 (s, 6H), 1.36 (s, 9H), 1.27 (d, J = 6.8 Hz) 3H) Example 385: Synthesis of compound 585

[0177] Compound 585 (FA salt) was prepared from compound 585-1 (from Example V (Compound 106-A2) iodomethane, tert-butyl (2-bromoethyl)carbamate using similar methods described in Example 382. LCMS (method 5-95 AB, ESI): tR= 0.758 min, [M + Na ]+= 1021.1; 1H NMR (400 MHz, DMSO-d4)  8.5 1 (s, 2H), 8.32 (d, J =8.4 Hz, 2H), 7.54 (d, J =8.4 Hz, 2H), 7 .09-7.00 (m, 3H), 6.54 (br s, 1H), 6.52 (br s, 1H), 6.39 (s, 1H), 5.24-5.08 (m, 1H), 4.88-4.67 (m, 2H), 4.39-4.20 (m, 7H), 3.91 (s, 3H), 3.68-3.31 (m, 6H), 3.19 (s, 3H), 2.94-2.79 (m, 2H), 2.45 (s, 6H), 1.36 (s, 9H), 1.23 (d, J =6.8 Hz, 3H) Example 386: Synthesis of compound 586

[0178] Compound 586 (FA salt) was prepared from compound 585-1 (from Example V (Compound 106-A2) iodomethane, and (S)-3-(((benzyloxy)carbonyl)amino)-5-((tert-butoxycarbonyl)amino)-2-oxopentanoic acid using similar procedures described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.749 min, [M + Na ]+= 1016.3; 1H NMR (400 MHz, MeOH-d4)  8.50 (br s, 2H), 8.29 (d, J =8.8 Hz, 2H), 7.51 (d, J =8.8 Hz, 2H), 7.06 (d, J =8.4 Hz, 2H), 6.75 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 5.23-5.21(m, 1H), 4.82-4.77 (m, 1H), 4.26-4.04 (m, 8H), 3.80 (s, 3H), 3.29-3.00 (m, 8H), 3.07 (s, 3H), 2.55 (s, 6H), 2.33-2.17 (m, 2H), 1.40 (s, 9H), 1.38 (d, J = 7.2 Hz, 3H) Example 387: Synthesis of compound 587

[0179] Compound 587-2 was prepared from compound 587-1 (from Example V (Compound 106-A2) iodomethane, and tert-butyl (2-bromoethyl)carbamate using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.854 min, [M + Na ]+= 847.2 Compound 587 (FA salt) was prepared from compound 587-2 and (S)-3-(((benzyloxy) carbonyl)amino)-5-((tert-butoxycarbonyl)amino)-2-oxopentanoic acid using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.706 min, [M + H]+= 964.3; 1H NMR (400 MHz, MeOH-d4)  8.49 (br s, 2H), 8.35 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.28-7.21 (m, 1H), 7.08-6.96 (m, 2H), 6.86 (s, 1H), 6.62-6.55 (m, 1H), 6.43 (s, 1H), 5.20-5.09 (m, 1H), 4.84-4.72 (m, 2H), 4.38-4.02 (m, 7H), 3.66 (s, 3H), 3.37-3.31 (m, 3H), 3.21-2.95 (m, 8H), 2.59 (s, 6H), 2.33-2.07 (m, 2H), 1.38 (s, 9H), 1.36 (d, J=6.8 Hz, 3H) Example 388: Synthesis of compound 588

[0180] Compound 588-2 was prepared from compound 588-1 (from Example V (Compound 106-B1) using similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 1.042 min, [M + Na]+= 1059.1

[0181] Compound 588-3 was prepared from compound 588-2 and benzyl bromide (synthesis described in Example 391) using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 1.083 min, [M + Na]+= 1338.6 Compound 588-4 was prepared from hydrogenation of compound 588-3 (described in Example 414). LCMS (Method 5-95 AB, ESI): tR= 1.017 min, [M + Na]+= 1249.6

[0182] Compound 588 (FA salt) was prepared using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.704 min, [M + H ]+= 950.6; 1H NMR (400 MHz, MeOH-d4)  8.50 (br s, 2H), 8.31 (d, J =7.6 Hz, 2H), 7.53 (d, J =8.0 Hz, 2H), 7.16 (s, 1H), 7.07 (d, J =8.8 Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.54 (s, 2H), 5.2 2-5.2 1 (t, J =6.4 Hz, 1H), 4.81 (q, J =6.4 Hz, 1H), 4.41-4.34 (m, 2H), 4.25 (s, 3H), 4.07-4.05 (m, 2H), 3.43-3.34 (m, 2H), 3.22-3.05 (m, 9H), 2.56 (s, 6H), 2.32-2.17 (m, 2H), 1.40 (s, 9H), 1.38 (d, J = 6.8 Hz) 3H) Example 389: Synthesis of compound 589

[0183] Step 1: To a solution of 2-aminoethanol (2 g, 32.7 mmol) and Na2CO3 (10.4 g, 98.2 mmol) in H2O (35 mL), FmocCl (9.3 g, 36.0 mmol) was added at 20°C and the mixture was stirred at the same temperature for 2 h. The mixture was extracted with DCM (100 mL×3). The combined organic layers were dried over sodium sulfate, concentrated and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in petroleum ether, to give (9H-fluoren-9-yl) methyl (2-hydroxyethyl)carbamate (5.6 g, 60.4% yield) as a white solid.

[0184] Step 2: A solution of (9H-fluoren-9-yl) methyl (2-hydroxyethyl)carbamate (1.0 g, 3.5 mmol) and 2-iodoxybenzoic acid (3.0 g, 10.5 mmol) in ethyl acetate (100 mL) was stirred at 80 °C under N2 for 16 h. After filtration, the filtrate was concentrated to afford (9H-fluoren-9-yl)methyl (2-oxoethyl)carbamate (1.0 g, low yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.78 (d, J =8.0 Hz, 2H), 7.60 (d, J =8.0 Hz, 2H), 7.43-7.39 (m, 2H), 7.34-7.31 (m, 2H), 5.50-5.44 (m, 1H), 4.43 (d, J =6.8 Hz, 2H), 4.24 (t, J =6.8 Hz, 1H), 4.20-4.00 (m, 2H)

[0185] Step 3: To a solution of compound 589-1 (synthesis described in Example 388, 200 mg, 0.19 mmol) in HOAc (2 mL), fuming nitric acid (30 μL) was added at 0 °C. The mixture was gradually warmed to 25 °C with stirring and stirred at the same temperature for 3.5 h. The above mixture was added with saturated NaHCO3 solution (40 mL), Boc2O (84 mg, 0.39 mmol) and THF (12 mL) and the resulting mixture was stirred at 25 °C for 1.5 h. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, concentrated and the residue was purified on a silica gel column, eluting with 5% methanol in DCM, to give compound 589-2 (140 mg, 67% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): tR= 1.131 min, [M + H]+= 1082.7

[0186] Step 4: A solution of compound 589-2 (140 mg, 0.13 mmol) and 10% Pd / C (134 mg, 0.13 mmol) in ethanol (10 m) was stirred at 30°C under hydrogen (15 psi) for 1 h. After filtration, the filtrate was concentrated and the residue, to which (9H-fluoren-9-yl)methyl (2-oxoethyl)carbamate (43 mg, 0.15 mmol) and HOAc (50 μL) were added, was redissolved in methanol (4 mL). The resulting mixture was stirred at 25°C for 6 h. After that, the mixture was added with ethyl acetate (40 mL), washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC, eluting with 7% methanol in DCM, to afford compound 589-3 (140 mg, 83% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.136 min, [M + H ]+= 1318.2

[0187] Step 5: A solution of compound 589-3 (140 mg, 0.11 mmol) and TEAF·4H2O (47 mg, 0.21 mmol) in DMF (2 mL) was stirred at 30 °C for 30 min. The mixture was washed with brine (30 mL), added with ethyl acetate (30 mL), dried over Na2SO4, and concentrated. The resulting residue, to which Boc2O (24 mg, 0.12 mmol) and saturated NaHCO3 (2 mL) were added, was redissolved in THF (3 mL). The resulting mixture was stirred at 25 °C for 1 h. The reaction was partitioned between ethyl acetate and water (50 mL each), and the organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated. The residue was purified on preparative TLC, eluting with 5% methanol in DCM, to give compound 589-4 (50 mg, 38% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.052 min, [M + H ]+= 1195.4

[0188] Compound 589 (TFA salt) was prepared using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.733 min, [M + H ]+= 919.6; 1H NMR (400 MHz, MeOH-d4)  8.29 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.91 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 6.21 (s, 1H), 5.15-5.12 (m, 1H), 4.80-4.76 (m, 2H), 4.31-4.26 (m, 2H), 4.19 (s, 2H), 3.45-3.43 (m, 2H), 3.30-3.28 (m, 3H), 3.15-3.09 (m, 5H), 3.02 (s, 3H), 2.55 (s, 6H), 2.26-2.12 (m, 2H), 1.36 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H) Example 390: Synthesis of compound 590

[0189] -(trimethylsilyl)ethyl (2-bromoethyl)carbamate was prepared from 2-bromoethanamine and 4-nitrophenyl (2-(trimethylsilyl)ethyl) carbonate (synthesis described in Example 372) as a pale yellow oil using a similar procedure to Example 372. LCMS (Method 5-95 AB, ESI): tR= 0.973 min, [M + H]+= 1124.1 Compound 590-2 was prepared from compound 590-1 (from Example V (Compound 106-B1) as a white solid using similar methods described in Example 372.

[0190] Compound 590-3 was prepared from compound 590-2 and benzyl bromide (synthesis described in Example 391) as a white solid using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 1.224 min, [M + H]+= 1388.8

[0191] Compound 590-4 was prepared from compound 590-3 and 2-(trimethylsilyl)ethyl (2-bromoethyl)carbamate as a white solid using similar methods described in Example 395. LCMS (Method 5-95 AB, ESI): tR= 1.252 min, [M / 2 + H]+= 837.9

[0192] Compound 590 (TFA salt) was prepared using similar methods described in Example 388. LCMS (Method 5-95 AB, ESI): tR= 0.769 min, [M + H ]+= 1027.7; 1H NMR (400 MHz, MeOH-d4)  8.38-8.18 (m, 2H), 7.57-7.43 (m, 2H), 7.28-6.99 (m, 3H), 6.86 (br) s, 1H), 6.71 (br s, 1H), 6.52 (s, 1H), 5.37-5.26 (m, 1H), 4.83-4.56 (m, 2H), 4.37 (s, 2H), 4.30-4.02 (m, 3H), 3.70-3.45 (m, 3H), 3.43-3.32 (m, 2H), 3.18-2.96 (m, 1H), 3.08 (s, 3H), 2.52 (s, 6H), 1.40 (s, 9H), 1.38 (d, J =6.8 Hz, 3H) Example 391: Synthesis of compound 591

[0193] Step 1: A solution of NBS (634 mg, 3.56 mmol) and E 101 (1 g, 1.78 mmol) in DCM (5 mL) was stirred at 30 °C for 3 h. The volatiles were removed and the residue was purified by silica gel column, eluting with 5% methanol in DCM. The resulting residue, to which K2CO3 (1.15 g, 8.34 mmol) and iodomethane (0.7 mL, 11.3 mmol) were added, was redissolved in DMF (6 mL). The reaction was stirred at 25 °C for 16 h. The mixture was added with ethyl acetate (60 mL), and then filtered. The filtrate was washed with brine (50 mL×3), dried over Na2SO4, concentrated, and the residue was purified on a silica gel column, eluting with 40% ethyl acetate in petroleum ether, to afford compound 591-1 (1.2 g, 96% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.023 min, [M + H]+= 746.0

[0194] Compound 591 (TFA salt) was prepared from compound 591-1 and (S)-3-(((benzyloxy) carbonyl)amino)-5-((tert-butoxycarbonyl)amino)-2-oxopentanoic acid using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.696 min, [M + H ]+= 1024.8; 1H NMR (400 MHz, MeOH-d4)  8.31 (d, J =8.4 Hz, 2H), 7.51 (d, J =8.4 Hz, 2H), 6.92 (d, J =7.6 Hz, 2H), 6.52 (s, 1H), 6.42 (s, 2H), 5.20-5.10 (m, 1H), 4.78-4.72 (m, 2H), 4.28-4.16 (m, 8H), 3.78-3.66 (m, 3H), 3.30-3.20 (m, 3H), 3.19-3.00 (m, 11H), 2.56 (s, 6H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.36 (s, 9H), 1.3 3 (d, J =6.8 Hz, 3H) Example 392: Synthesis of compound 592

[0195] Compound 592 (FA salt) was prepared from compound 591-1 (synthesis described in Example 391) and tert-butyl (2-bromoethyl)carbamate, using similar methods described in Example 391. LCMS (Method 5-95 AB, ESI): tR= 0.703 min, [M + Na ]+= 986.6; 1H NMR (400 MHz, MeOH-d4)  8.50 (br s, 3H), 8.33 (d, J =8.8 Hz, 2H), 7.52 (d, J =8.8 Hz, 2H), 7.00 (s, 1H), 6.96 (s, 1H), 6.57 (br s, 1H), 6.49 (br s, 1H), 6.41 (s, 1H), 5.14-5.11 (m, 1H), 4.77-4.75 (m, 2H), 4.32-4.19 (m, 6H), 3.73 (s, 3H), 3.69 (s, 3H), 3.39-3.34 (m, 6H), 3.14-3.05 (m, 2H), 3.01 (s, 3H), 2.57 (s, 6H), 2.26-2.12 (m, 2H), 1.36 (s, 9H), 1.3 3 (d, J =6.8 Hz, 3H) Example 393: Synthesis of compound 593

[0196] Compound 593 (FA salt) was prepared from compound 591-1 (synthesis described in Example 391) using similar methods described in Example 391. LCMS (Method 5-95 AB, ESI): tR= 0.736 min, [M + H ]+= 1089.6; 1H NMR (400 MHz, MeOH-d4)  8.51 (br s, 1H), 8.18-8.12 (m, 2H), 7.44-7.38 (m, 2H), 6.86 (br s, 1H), 6.71 (br s, 2H), 6.44 ( s , 1H), 6.14 ( s , 1H), 5.39-5.30 (m, 1H), 4.79-4.67 (m, 2H), 4.25-4.03 (m, 8H), 4.02-3.88 (m, 4H), 3.76 (s, 3H), 3.59-3.50 (m, 1H), 3.39-3.30 (m, 2H), 3.29-3.20 (m, 2H), 3.11-3.00 (m, 2H), 3.05 (s, 3H), 2.41 (s, 6H), 1.36 (s, 9H), 1.35 (d, J = 6.4 Hz, 3H) Example 394: Synthesis of compound 594 Compound 594-2 was prepared from compound 594-1 (from Example V (Compound 106-A2)) using similar methods described in Example 395. LCMS (Method 5-95 AB, ESI): tR= 0.950 min, [M + H]+= 1067.5

[0197] Compound 594 (FA salt) was prepared from compound 594-2 and tert-butyl (2-bromoethyl) carbamate by similar methods described in Example 382. LCMS ( روش 5-95 AB, ESI): tR= 0. 729 min, [M + H ]+= 950.4 ;1H NMR (400 MHz, MeOH- d4)  8.56 (br s, 2H), 8.3 5 (d, J =8.0 Hz, 2H), 7.56 (d, J =8.0 Hz, 2H), 7.29 (d, J =8.4 Hz, 1H), 7.16 (d, J =8.4 Hz, 1H), 6.95 (d, J =1.2 Hz, 1H), 6.85 (s, 1H), 6.46 (s, 1H), 6.41 (s, 2H), 5.26-5.22 (m, 1H), 4.84-4.77 (m, 2H), 4.30-4.10 (m, 7H), 3.50 -3.40 (m, 2H), 3.25-3.05 (m, 6H), 3.01 (s, 3H), 2.58 (s, 6H), 2.30-2.27 (m, 1H), 2.18-2.14 (m, 1H), 1. 36 (s, 9H), 1. 34 (d, J =6.8 Hz, 3H) مثال ۳۹۵: سنتز ترکیب ۵۹۵

[0198] Step 1: A solution of compound 595-1 (from Example V (Compound 106-B2 (300 mg, 0.37 mmol) in 5% TFA in HFIP (15 mL) was stirred at room temperature for 1 h. The mixture was concentrated and the residue to which was added tert-butyl (((tert-butoxycarbonyl)amino) (1H-pyrazol-1-yl)methylene)carbamate (158 mg, 0.51 mmol), redissolved in THF (8 mL). The resulting mixture was stirred at room temperature for another 3 h. The reaction was extracted with ethyl acetate (15 mL×3), added to water (15 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, concentrated and purified by column (5% methanol / DCM) to give compound 595-2 (280 mg, 97.5% yield after two steps) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.825 min, [M + H]+= 847.1

[0199] Step 2: To a solution of compound 595-2 (280 mg, 0.33 mmol) in DCM (15 mL), Et3N (100 mg, 0.99 mmol) and Boc2O (2.16 g, 9.92 mmol) were added at room temperature and the reaction was stirred at the same temperature for 72 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, concentrated and column purified (5% methanol / DCM) to give compound 595-3 (300 mg, 96% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.875 min, [M + H]+= 947.4

[0200] Compound 595 (TFA salt) was prepared as a white solid from compound 595-3 by similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 0.749 min, [M + H]+= 90 3.6; 1H NMR (400 MHz, MeOH- d4 )  8.30 (d, J =8.4 Hz, 2H), 7.51 (d, J =8.0 Hz, 2H), 7.27 (d, J =8.4 Hz, 1H), 7.17 (d, J =8.4 Hz, 1H), 6.92-6.86 (m, 2H), 6.85 (d, J =8.4 Hz, 1H), 6.62 (br s, 1H), 6.41 (s, 1H), 5.35-5.26 (m, 1H), 4.83-4.78 (m, 1H), 4.62 (br s, 1 H), 4.42-4.32 (m, 2H), 4.30-4.23 (m, 2H), 3.74-3.61 (m, 2H), 3.14 (t, J =8.0 Hz, 2H), 3.05-2.72 (m, 5H), 2.44 (s, 6H), 2.29-2.10 (m, 2H), 1.38 (s, 9H), 1.34 (d, J=6.4Hz, 3H) Example 396: Synthesis of compound 596

[0201] Compound 596-1 was prepared as a white solid from 101E and tert-butyl (3-bromopropyl) carbamateby similar methods described in Example 54.

[0202] Compound 596 (FA salt) was prepared as a white solid from compound 596-1 by similar methods described in Example 395. LCMS (Method 5-95 AB, ESI): tR= 0.634 min, [M + H]+= 917.5; 1H NMR (400MHz, MeOH-d4) δ 8.52 (br s, 1H), 8.37-8.23 (m, 2H), 7.5-7.46 (m, 2H), 8.33-8.22 (m, 1H), 7.20-6.89 (m, 3H), 6.87-6.75 (m, 1H), 6.62 (br s, 1H), 6.50 (s, 1H), 5.30-5.18 (m, 1H), 4.83-4.79 (m, 2H), 4.33-4.01 (m, 4H), 3.54-3.35 (m, 2H), 3.26-2.91 (m, 7H), 2.56-2.49 (s, 6H), 2.35-1.95 (m, 4H), 1.42 (s, 9H), 1.38 (d, J =6.8 Hz, 3H) Example 397: Synthesis of compound 597

[0203] Compound 597 (FA salt) was prepared as a white solid from compound 597-1 (a by-product during the synthesis of compound 596-1 in Synthesis Example 396) using similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 0.758 min, [M + H]+= 875.4; 1H NMR (400 MHz, MeOH- d4 ) δ 8.50 (br s, 2H), 8.19 (d, J =8.0 Hz, 2H), 7.47 (d, J =8.0 Hz, 2H). 7.06-11 (m, 1H), 6.95-7.05 (m, 3H), 6.79 (br s, 1H), 6.64 (br s, 1H), 6.54 (s, 1H), 5.35-5.29 (m, 1H), 4.82-4.75 (m, 2H), 4.35-4.25 (m, 3H), 4.20-4.10 (m, 1H), 3.27-3.10 (m, 5H), 3.11(s, 3H), 3.05-2.90 (m, 1H), 2.45 (s, 6H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 3H), 1.39 (s, 9H), 1.35 (d, J=7.2Hz, 3H) Example 398: Synthesis of compound 598

[0204] Compound 598 (FA salt) was prepared as a white solid from 6-dimethyl-2-(4-(pentyloxy)phenyl)pyrimidine-5-carboxylic acid (described in Example 128) using similar methods described in Example 396 and Example 54. LCMS ( روش 5-95 AB, ESI): tR= 0 .777 min, [M + H]+= 905.8 ;1H NMR (400 MHz, MeOH- d4 ) δ 8.52 (br s, 2H), 8.28 (d, J =8.4 Hz, 2H), 7. 60-7.25 ( m , 2 H), 7.05- 7.00 (m, 1 H), 6.98 (d, J =8.4Hz, 2H), 6.91 ( d , J =2.4 Hz, 1H), 6.8 3 (br s, 1H), 6.62 (br s, 1H), 6.51 (s, 1H), 5.30-5.20 (m, 1H), 4.82-4.75 (m, 2H), 4.4 1 -4. 29 (m, 2 H), 4.22 ( s , 2 H), 4.06 (t, J = 6.4 Hz, 2H), 3.27-2.95 (m, 9H), 2.49 (s, 6H), 2.35-2.24 (m, 1H), 2.20-2.10 (m, 3H), 1.90-1.80 (m, 2H), 1.55-1.40 (m, 4H), 1.35 (d, J =6.4 Hz, 3H), 0.98 (t, J =6.8 Hz, 3H) مثال ۳۹۹: سنتز ترکیب ۵۹۹

[0205] Step 1: A solution of compound 599-1 (from Example V (compound 106-A2 (300 mg, 0.45 mmol), 1,2-dibromomethane (852 mg, 4.5 mmol) and K2CO3 (627 mg, 4.5 mmol) in DMF (10 mL) was stirred at 25 °C for 12 h. The reaction was washed with brine (50 mL×3), taken up in ethyl acetate (100 mL), dried over Na2SO4, concentrated and the residue purified by preparative TLC (10% methanol in DCM) to afford compound 599-2 (275 mg, 79% yield) as a white solid.

[0206] Step 2: A solution of compound 599-2 (275 mg, 0.36 mmol), methylamine (2M in THF, 1.8 mL), K2CO3 (494 mg, 3.6 mmol) in DMF (10 mL) was stirred at 25 °C for 12 h. The reaction mixture was washed with brine (50 mL×2), taken up in ethyl acetate (100 mL), dried over Na2SO4, concentrated. The residue was treated with 10% TFA / DCM (10 mL) for 1 h. The volatiles were removed and the residue was purified by preparative TLC to give compound 599-3 (160 mg, 72% yield) as an off-white solid. LCMS (Method 5-95 AB, ESI): tR= 0.745 min, [M + H]+= 619.6

[0207] The title compound (FA salt) was prepared as a white solid from compound 599-3 by similar methods described in Example 395. LCMS (Method 5-95 AB, ESI): tR= 0.75 8 min, [M + H]+= 917.4; 1H NMR (400 MHz, MeOH-d 4 ) δ 8.54 (br s, 1H), 8.22 (d, J =8.0Hz, 2H), 7.50 (d, J =8.0Hz, 2H). 7.29-7.15 (m, 2H), 6.96-6.80 (m, 3H), 6.57 (s, 1H), 6.53 (s, 1H), 5.30-5.26 (m, 1H), 4.81-4.60 (m, 2H), 4.46-4.24 (m, 2H), 4.24 (s, 2H), 3.87-3.74(m, 2H), 3.15-2.89 (m, 10H), 2.49 (s, 6H), 2.30-2.12 (m, 2H), 1.39 (s, 9H), 1.36-1.20 (m, 3H) Example 400: Synthesis of compound 600

[0208] Step 1: A solution of compound 599-3 (synthesized in Example 399, 210 mg, 0.3 mmol), Boc2O (273 mg, 1.25 mmol) and Et3N (127 mg, 1.25 mmol) in DCM (20 mL) was stirred at 25°C for 12 h. The volatiles were removed and the residue, which was washed with brine (30 mL×2), was taken up in ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, concentrated and the residue was purified by preparative TLC (10% methanol in DCM) to give compound 600-2 (143 mg, 70% yield) as a white solid.

[0209] Compound 600 (FA salt) was prepared as a white solid from compound 600-2 by similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 0.740 min, [M + H]+= 875.4; 1H NMR (400 MHz, MeOH - d 4) δ 8.52 (br s, 1H), 8.10 (d, J =7.6Hz, 2H), 7.43 (d, J =7.6Hz, 2H). 7.30-7.19 (m, 2H), 7.06-6.74 (m, 3H), 6.73 (br s, 1H), 6.32 (s, 1H), 5.40-5.31 (m, 1H), 4.82-4.65 (m, 2H), 4.53 (s , 2H), 4.35-4.18 (m, 2H), 3.52-3.44 (m, 2H), 3.14 (t, J =7.6 Hz, 2H), 3.01 (s, 3H), 2.95-2.84 (m, 1H), 2.80 (s, 3H), 2.66-2.52 (m, 1H), 2.41 (s, 6H), 2.31-2.13 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.4Hz, 3H) Example 401: Synthesis of compound 601

[0210] Compound 601 (FA salt) was prepared as a white solid from compound 601-1 (described in Example 399) and tert-butyl (2-aminoethyl)carbamate by similar methods described in Example 399 and Example 600. LCMS (method 5-95 AB, ESI): tR= 0.716 min, [M + H]+= 904.5; 1H NMR (400 MHz, MeOH-d4) δ 8.49 (br s, 1H), 8.24 (d, J =8.0 Hz, 1H), 8.10 (d, J =8.0 Hz, 1H), 7.53-7.41 (m, 2H), 7.26-7.15 (m, 2H), 7.10-6.99 (m, 1H), 6.85-6.74 (m, 2H), 6.67 (br s, 1H), 6.34 (s, 1H), 5.33-5.23 (m, 1H), 4.79-4.76 (m, 2H), 4.38-4.30 (m, 2H), 4.26-4.18 (m, 2H), 3.17-3.03 (m, 5H), 2.99-2.88 (m, 6H), 2.51 (s, 3H), 2.39 (s, 3H), 2.30-2.13 (m, 2H), 1.40 (s, 9H), 1.37 (d, J=6.4 Hz, 3H) Example 402: Synthesis of compound 602

[0211] Compound 602 (FA salt) was prepared as a white solid from compound 602-1 (described in Example 399) and tert-butyl (3-aminopropyl)carbamate by methods similar to those described in Example 399 and Example 600. LCMS (Roche 10-80 AB _7min, ESI): tR= 2.087 min, [M + H]+= 918.6 ;1H NMR (400 MHz, MeOH - d4 ) 8.5 7 (br s, 2 H), 8.1 3 (d, J =8.0 Hz, 2H), 7.4 4 (d, J =8.0 Hz, 2H), 7.28-7.19 (m, 2H), 6.91-6.78 (m, 3H), 6.64 (br s, 1H), 6.38 (s, 1H), 5.33-5.18 (m, 1H), 4.82-4.50 (m, 2H), 4.46 (s, 2H), 4.31-4.17(m, 2H), 3.61-3.55 (m, 4H), 3.2 6-3.08 (m, 4H), 3.02 (s, 3H), 2.92-2.51 (m, 2H), 2.41 (s, 6H), 2. 33-2.05 (m, 2H), 2.02-1.87 (m, 2H), 1.39 (s, 9H), 1.35 (d, J =6.8Hz, 3H) Example 403: compound centz 603

[0212] Step 1: To a solution of 4-nitro-phenyl-chloroformate (3.0 g, 14.9 mmol) and 2-(trimethylsilyl)ethanol (2.1 g, 17.9 mmol) in DCM (15 mL), Et3N (3.0 g, 29.8 mmol) was added and the mixture was stirred at 30 °C for 1 h. The reaction was extracted with DCM (30 mL×3), quenched with water (15 mL). The combined organic layers were washed with brine (50 mL×2), dried over sodium sulfate, concentrated, and the residue was purified on a silica gel column, eluting with 5% ethyl acetate in petroleum ether, to give (4-nitrophenyl)2-trimethylsilylethyl carbonate (2.8 g, 68% yield) as a colorless oil.

[0213] Step 2: A solution of compound 603-1 (from Example V (compound 106-B2 (400 mg, 0.50 mmol) in 5% TFA in HFIP (15 mL) was stirred at 30 °C for 1 h. The reaction was concentrated and the residue was redissolved in DMF (15 mL) to which DIEA (577 mg, 4.5 mmol) and (4-nitrophenyl) 2-trimethyl silylethyl carbonate (253 mg, 0.89 mmol) were added at 0 °C, respectively. The resulting mixture was stirred at 30 °C for 16 h. The reaction was extracted with ethyl acetate (30 mL×3), quenched with water (30 mL). The combined organic layers were washed with brine (50 mL×2), concentrated and the residue was applied to a silica gel column to obtain compound 603-2. (310 mg, eluting with 0-5% methanol in DCM, 93% yield) was purified as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.964 min, [M + Na]+= 771.3

[0214] Step 3: Compound 603-3 (130 mg) was prepared as a white solid from compound 603-2 by similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 1.054 min, [M + Na]+= 1227.6

[0215] Step 4: To a solution of compound 603-3 (110 mg, 0.09 mmol) in DMF (3 mL), TBAF (95 mg, 0.36 mmol) was added and the mixture was stirred at 50°C for 3 h. The reaction was extracted with ethyl acetate (15 mL×3), water (15 mL) was added. The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, and concentrated. The residue was redissolved with acetonitrile (5 mL) to which ethyl ethanimide (24 mg, 0.27 mmol) and DIEA (58 mg, 0.45 mmol) were added. The mixture was stirred at 25°C for 2 h. The reaction was concentrated to dryness and the residue, washed with brine (30 mL), was taken up in ethyl acetate (30 mL). The organic layer was dried over sodium sulfate and concentrated and the resulting residue was treated with 5% TFA / HFIP (5 mL) at 25 °C for 3 h. The reaction was concentrated and the residue was purified by preparative HPLC (10-35 acetonitrile / 0.225% FA in water) to give the title compound (TFA salt, 13.6 mg, 16% yield after three steps) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.764 min, [M + H]+= 902.4; 1HNMR (400 MHz, MeOH- d4 ) δ 8.24 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.33-7.15 (m, 2H), 7.03-6.81 (m, 3H), 6.60-6.50 (m, 2H), 5.29-5.21 (m, 1H), 4.82-4.75 (m, 2H), 4.44-4.30 (m, 2H), 4.23 (s, 2H), 3.75-3.63 (m, 2H), 3.21-2.82 (m, 7H), 2.50 (s, 6H), 2.31-2.05 (m, 2H), 2.21 (s, 3H), 1.38 (s, 9H), 1.35 (d, J =6.8Hz, 3H) Examples 404 and 405: Synthesis of compounds 604 and 605

[0216] Step 1: A mixture of 101E (320 mg, 0.58 mmol), K2CO3 (394 mg, 2.85 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (672 mg, 2.85 mmol) in DMF (5 mL) was stirred at 50 °C for 5 days. The reaction mixture was washed with saturated brine solution (30 mL×2), taken up in ethyl acetate (50 mL), dried over sodium sulfate, concentrated and the residue was purified by HPLC (water (0.225% FA)-ACN) to give compound 604-1 (120 mg, 29% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.895 min, [M + Na]+= 739.5

[0217] Both of these title compounds (TFA salt) were prepared as white solids from compound 604-1 by similar methods described in Example 395 and they were separated by HPLC in the final step. Composition 604: LCMS (Method 5-95 AB, ESI): tR= 0.753 min, [M + H]+= 873.9; 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J =8.4 Hz, 2H), 7.49 (d, J =8.4 Hz, 2H), 7.13-6.96 (m, 3H), 6.80 (br s, 1H), 6.74 (d, J =8.4 Hz, 2H), 6.54 (br s, 1H), 5.31-5.10 (m, 2H), 4.80-4.78 (m, 2H), 4.50-4.35 (m, 2H), 4.26-4.18 (m, 3H), 4.08-4.00 (m, 1H), 3.35-3.33 (m, 1H), 3.11 (t, J =7.2Hz, 2H), 3.05-2.98 (m, 4H), 2.49 (s, 6H), 2.30-2.11 (m, 2H), 1.39 (s, 9H), 1.35 (d, J =6.8Hz, 3H). Composition 605: LCMS (Method 5-95 AB, ESI): tR= 0.740 min, [M + H]+= 873.4; 1H NMR (400 MHz, MeOH-d 4) δ 8.55 (br s, 1H), 8.26 (d, J =8.0 Hz, 2H), 7.49 (d, J =8.0 Hz, 2H). 7.25-7.22 (m, 1H), 6.93-6.81 (m, 4H), 6.54 (br s, 2H), 5.32-5.24 (m, 2H), 4.82-4.78 (m, 2H), 4.47-4.44 (m, 2H), 4.30-4.10 (m, 2H), 4.24 (s, 2H), 3.22-3.09 (m, 4H), 3.00 (s, 3H), 2.49 (s, 6H), 2.34-2.10 (m, 2H), 1.39 (s, 9H), 1.35 (d, J =7.2Hz, 3H). Examples 406 and 407: Synthesis of compounds 606 and 607

[0218] Both of these title compounds (FA salt) were prepared as white solids from 101E and tert-butyl (2-bromopropyl)carbamate by similar methods described in Examples 404 / 405 and were separated by HPLC in the final step.

[0219] Compound 606: LCMS (Roche 5-95 AB, ESI): tR= 0.75 1 min, [M + H]+= 875.5 ;1H NMR (400 MHz,M eOH - d 4) δ 8.54 (br s, 1H), 8.12-8.06 (m, 2H), 7.46-7.40 (m, 2H), 7.25-7.20 (m, 1H), 7.06-6.84 (m, 1H), 6.79-6.74 (m, 3H), 6.43 (br s, 1H), 5.36-5.32 (m, 1H), 4.80-4.75 (m, 4H), 4.32-4.24 (m, 2H),3.28-3.00(m, 8H), 2.42-1.93 (m, 8H), 1.52-1.26 (m, 15H).

[0220] Composition 607: LCMS (Roche 5-95 AB, ESI): tR= 0.75 3 min, [M + H]+= 875.5 ;1H NMR (400 MHz,M eOH - d 4) δ 8.52 (br s, 1H), 8.21-8.14 (m, 2H), 7.46-7.40 (m, 2H), 7.25-7.21(m, 1H), 7.06-7.01 (m, 1H), 6.85-6.61 (m, 3H), 6.43 (br s, 1H), 5.35-5.28 (m, 1H), 4.81-4.76 (m, 4H), 4.30-4.24 (m, 2H), 3.35-3.30(m, 1H), 3.18-2.93 (m, 7H), 2.45-1.93 (m, 8H), 1.48-1.32 (m, 15H) Example: 408 and 409: cents are combinations of 608 and 609.

[0221] Both title compounds (FA salt) were prepared as white solids from 101E and tert-butyl 4-bromopiperidine-1-carboxylate by similar methods described in Examples 404 / 405 and they were separated by HPLC in the final step. 608 compounds: LCMS (method 5-95 AB, ESI): tR= 0.75 1 min, [M + H]+= 901.5; 1H NMR (400 MHz, MeOH-d4) δ 8.50 (br s, 2H), 8.13 (d, J =8.0 Hz, 2H), 7.42 (d, J =8.0 Hz, 2H), 7.10-7.03 (m, 3H), 6.91 (br s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.43 (br s, 1H), 5.38-5.33 (m, 1H), 4.81-4.60 (m, 1H), 4.34-4.12 (m, 4H), 3.57-3.50 (m, 2H), 3.28-3.07 (m, 10H), 2.69-2.10 (m, 4H), 2.41 (s, 6H), 2.00-1.93 (m, 1H), 1.81-1.75 (m, 1H), 1.80 (s, 9H), 1.35 (d, J =6.8Hz, 3H). 609 compounds: LCMS (method 5-95 AB, ESI): tR= 0.748 min, [M + H]+= 901.5; 1H NMR (400 MHz, MeOH - d4 ) 8.54 (br s, 1H), 8.15 (d, J =8.0 Hz, 2H), 7.42 (d, J =8.0 Hz, 2H), 7.28-7.19 (m, 2H), 6.89 (br s, 1H), 6.8 6-6.73 (m, 2H), 6.64 (br s, 1H), 6.38 (s, 1H), 5.33-5.18 (m, 1H), 4.82-4.50 (m, 2H), 4.32-4.15 (m, 3H), 3.61-3.55 (m, 1H), 3.28-2.86 (m, 10H), 2.41 (s, 6H), 2.48-2.09 (m, 6H), 1.38 (s, 9H), 1.34 (d, J =6.8Hz, 3H). Examples 410 and 411: Synthesis of compounds 610 and 611

[0222] Step 1: To a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (1.0 g, 6.84 mmol) and NaH (60% in oil, 0.41 g, 10.3 mmol) in THF (30 mL), BnBr (1.62 mL, 13.7 mmol) was added. The reaction was stirred at 20 °C for 16 h. The reaction was washed with brine (30 mL×2), taken up in ethyl acetate (50 mL), dried over Na2SO4, concentrated, and the residue was purified on a silica gel column, eluting with 10% ethyl acetate in petroleum ether, to give 5-(benzyloxy methyl)-2,2-dimethyl-1,3-dioxane (1.6 g, 99% yield) as a colorless oil.

[0223] Step 2: To a solution of 5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxane (1.5 g, 6.35 mmol) in methanol (20 mL), TsOH (109 mg, 0.63 mmol) was added. The reaction mixture was stirred at 20°C for 1 h. The reaction was washed with brine (20 mL×3), taken up in ethyl acetate (50 mL), dried over Na2SO4, concentrated, and the crude material was purified by silica gel column, eluting with 50% ethyl acetate in petroleum ether, to afford 2-(benzyloxymethyl)propane-1,3-diol (1.0 g, 80% yield) as a colorless oil.

[0224] Step 3: A solution of 2-(benzyloxymethyl)propane-1,3-diol (1.0 g, 5.1 mmol) and Et3N (2.86 mL, 20.4 mmol) in DCM (20 mL) was stirred at 0 °C for 30 min, then MsCl (1.22 mL, 15.7 mmol) was added slowly. The mixture was stirred at 0 °C for another 3 h. After filtration, the filtrate was concentrated and the residue was purified by silica gel column, eluting with 10% ethyl acetate in petroleum ether, to give [2-(benzyloxymethyl)-3-methyl sulfonyloxy-propyl] methanesulfonate (1.5 g, 84% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 4.50 (s, 2H), 4.36-4.29 (m, 4H), 3.55 (d, J=6.0 Hz, 2H), 2.99 (s, 6H), 2.55-2.46 (m, 1H)

[0225] Step 4: A solution of [2-(benzyloxymethyl)-3-methylsulfonyloxy-propyl] methanesulfonate (1.5 g, 4.3 mmol) and NaN3 (2.84 g, 43.7 mmol) in DMF (20 mL) was stirred at 80°C for 16 h. After filtration, the filtrate was washed with brine (100 mL×3), taken up in ethyl acetate (200 mL), dried over Na2SO4, concentrated, and the residue was purified on a silica gel column, eluting with 7% methanol in DCM, to give [3-azido-2-(azidomethyl)propoxy]methyl benzene (1.0 g, 95.4% yield) as a colorless oil.

[0226] Step 5: To a solution of [3-azido-2-(azidomethyl)propoxy]methylbenzene (1.0 g, 4.1 mmol) in methanol (20 mL) was added 10% Pd(OH)2 / C (432 mg, 0.41 mmol). The reaction mixture was stirred at 15 °C for 5 h under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated. The residue, to which Boc2O (4.04 g, 18.5 mmol), Et3N (2.81 g, 27.8 mmol) and DMAP (142 mg, 1.2 mmol) were added, redissolved in THF (10 mL). The reaction mixture was stirred at 20 °C for 16 h. After that, the reaction was washed with brine (100 mL×3), taken up in ethyl acetate (200 mL), dried over Na2SO4, concentrated, and the residue was purified on a silica gel column, eluting with 20% ethyl acetate in petroleum ether, to afford tert-butyl N-[2-(benzyloxymethyl)-3-(tert-butoxycarbonylamino)propyl]carbamate (1.3 g, 71% yield) as a colorless oil.

[0227] Step 6: To a solution of tert-butyl N-[2-(benzyloxymethyl)-3-(tert-butoxycarbonylamino)propyl]carbamate (1.3 g, 3.3 mmol) in methanol (20 mL), 10% Pd / C (351 mg, 0.33 mmol) was added and the reaction mixture was stirred at 60°C for 5 h under hydrogen (40 psi). The mixture was filtered and the filtrate was concentrated. The residue was redissolved in DCM, to which Et3N (740 μL, 5.3 mmol) was added at 0°C for 30 min. MsCl (150 μL, 2.0 mmol) in DCM (2 mL) was then added dropwise to the above solution and the resulting mixture was stirred at 0°C for another 3 h. After filtration, the filtrate was concentrated to afford 3-(tert-butoxy carbonylamino)-2-[(tert-butoxycarbonylamino)methyl]propyl] methanesulfonate (500 mg, low yield) as a colorless oil, which was used directly without further purification.

[0228] Both of these title compounds (FA salt) were prepared as white solids from 101E and [3-(tert-butoxy carbonylamino)-2-[(tert-butoxycarbonylamino)methyl]propyl] methanesulfonate using similar methods described in Examples 404 / 405 and they were separated by HPLC in the final step.

[0229] Composition 610: LCMS (Method 5-95 AB, ESI): tR= 0.743 min, [M + H]+= 904.4; 1H NMR (400 MHz, MeOH-d4) δ 8.48 (br s, 2H), 8.35 (d, J =8.0 Hz, 2H), 7.56 (d, J =8.0 Hz, 2H), 7.35-6.90 (m, 4H), 6.89-6.75 (m, 2H), 6.43 (s, 1H), 5.26-5.25 (m, 1H), 4.80-4.70 (m, 2H), 4.60-4.25 (m, 2H), 4.22 (s, 2H), 3.50 -3.40 (m, 1H), 3.25-2.95 (m, 1 0 H), 2.57 (s, 6H), 2.45-2.35 (m, 1H), 2.30-2.20 (m, 1H), 2.19-2.10 (m, 1H), 1.40 (s, 9H), 1.37 (d, J =6.8 Hz, 3H).

[0230] Compound 611: LCMS (Roche 5-95 AB, ESI): tR= 0.740 min, [M + H]+= 905.0 ;1H NMR (400 MHz, MeOH - d 4) δ 8.57 (br s, 1H), 8.40 - 8.20 (m, 2H), 7.56-7.54 (m, 2H), 7.35-7.00 (m, 3H), 6.98-6.75 (m, 2H), 6.69 (br s, 1H), 6.47 (s, 1H), 5.30-5.15 (m, 1H), 4.80 - 4.70 (m, 2H), 4.41-4.31 (m, 2H), 4.22 (s, 2H), 3.50-3.40 (m, 1H), 3.25- 3.04 (m, 7H), 3.05 (s, 3H), 2.57 (s, 6H), 2.45-2.35 (m, 1H), 2.30-2.20 (m, 1H), 2.19-2.10 (m, 1H), 1.40 (s, 9H), 1.38 -1.25 (m, 3H). Example 412: compound centz 612

[0231] Step 1: A solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (7.77 g, 35.4 mmol) in toluene (80 mL) was added to 2,2-dimethoxypropane (7.38 g, 70.9 mmol) and TsOH (610 mg, 3.54 mmol) and stirred at 110 °C for 0.5 h. The volatiles were distilled off under 1 atmosphere and the residue, which was washed with saturated NaHCO3 and brine (100 mL each), was redissolved with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified by chromatography on silica, eluting with 10% ethyl acetate in petroleum ether, to give (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (7.60 g, 83% yield) as a yellow oil.

[0232] Step 2: To a suspension of lithium aluminum hydride (3.34 g, 87.9 mmol) in tetrahydrofuran (80 mL), a solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine- 3,4- dicarboxylate (7.60 g, 29.3 mmol) in tetrahydrofuran (5 mL) was added dropwise at 0 °C under nitrogen. The reaction was then gradually warmed to 25 °C with stirring and stirred at the same temperature for 2 h. The reaction was quenched with 10% NaOH solution (3.5 mL). After filtration, the filtrate was concentrated and the residue was partitioned between ethyl acetate and water (300 mL each). The organic layer was washed with brine (300 mL), dried over magnesium sulfate, concentrated to give (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (5.51 g, 81% yield) as a colorless oil.

[0233] Step 3: To a solution of (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (4.90 g, 21.2 mmol) and TsCl (6.06 g, 31.8 mmol) in dichloromethane (50 mL) was added Et3N (5.91 mL, 42.4 mmol) and DMAP (259 mg, 2.12 mmol) and the reaction was stirred at 25 °C for 16 h. The reaction mixture was diluted with water and DCM (100 mL each). The organic layer was washed with brine (100 mL×2), concentrated, and the residue was purified on a silica gel column, eluting with 20-50% ethyl acetate in petroleum ether, to afford (R)-tert-butyl 2,2-dimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate (4.73 g, 58% yield) as a white solid.

[0234] Compound 612 (FA salt) was prepared as a white solid from 101E and (R)-tert-butyl 2,2-dimethyl-4-((tosyloxy)methyl)oxazolidine-3-carboxylate by similar methods described in Example 404. LCMS (method 5-95 AB, ESI): tR= 0.611 min, [M + H]+= 891.4; 1H NMR (400 MHz, MeOH-d4) δ 8.60 (br s, 1H), 8.2 8-8.12 (m, 2H), 7.54-7.48 (m, 2H), 7.29-7.02 (m, 3H), 6.88-6.81 (m, 2H), 6.65 (br s, 1H), 6.54 (s, 1H), 5.3-7-5.30 (m, 1H), 4.84-4.80 (m, 2H), 4.73-4.20 (m, 4H), 4.25 (s, 2H), 4.28-4.23 (m, 3H), 3.92-3.77 (m, 2H), 3.64-3.60 (m, 1H), 3.15-3.11 (m, 2H), 3.03 (s, 3H), 2.48 (s, 6H), 2.33-2.29 (m, 1H), 2.21-2.14 (m, 1H), 1.41 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H) Example 413: Synthesis of compound 613

[0235] Compound 613 (TFA salt) was prepared as a white solid from (S)-methyl 2-((tert-butoxy carbonyl)amino)-3-hydroxypropanoate by similar methods described in Example 412. LCMS (Roche 5-95 AB, ESI): tR= 0 .609 min, [M + H]+= 891.4 ;1H NMR (400 MHz, MeOH-d4 ) δ 8.36 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.33-7.30 (m, 1H), 7. 20-7.15 (m, 1H), 7.1 2-7.05 (m, 1H), 6. 72-6.93 (m, 2H), 6. 91-6.85 (m, 1H), 6.78 (br s, 1H), 6.46 (s, 1H), 5.26-5.22(m, 2H), 4.43-4.29 (m, 3H), 4.22 (s, 2H), 4.07-4.02 (m, 2H), 3.85-3.73 (m, 2H), 3.03 (s, 3H), 2.52 (s, 6H), 2.30-2.00 (m, 2H), 1.42 (s, 9H), 1.37 (d, J = 6.8 Hz, 3H) Example 414: compound centz 614

[0236] Step 1: To a solution of compound 614-1 (from Example V (compound 106-A2 (200 mg, 0.31 mmol) and DIEA (507 μL, 3.1 mmol) in DMF (5 mL), SEM-Cl (543 μL, 3.1 mmol) was added and the reaction was stirred at 50 °C for 16 h. The mixture was partitioned between ethyl acetate and H2O (100 mL each). The organic layer was washed with brine, dried over sodium sulfate, concentrated, and the residue was purified on a silica gel column, eluting with 10% methanol in DCM, to give compound 614-2 (200 mg, 83% yield) as a yellow oil. LCMS (Method 5-95 AB, ESI): tR= 1.038 min, [M + Na]+= 804.0 Step 2: To a solution of compound 614-2 (200 mg, 0.26 mmol) in ethanol (20 mL) was added 10% Pd / C (272 mg, 0.26 mmol) and a drop of ammonia, and the mixture was stirred at 30 °C under hydrogen (15 psi) for 3 h. After filtration, the volatiles were concentrated to give compound 614-3 (96 mg, 67% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.758 min, [M + Na]+= 580.0

[0237] Compound 614-4 was prepared as a white solid from compound 614-3 by a similar method described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 1.125 min, [M + Na]+= 1046.3 Compound 614-5 was prepared from compound 614-4 as a white solid using similar methods described in Example 367. LCMS (Method 5-95 AB, ESI): tR= 1.117 min, [M + Na]+= 1219.2

[0238] Compound 614 (FA salt) was prepared as a white solid from compound 614-5 by similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 0.728 min, [M + H]+= 891.4; 1H NMR (400 MHz, MeOH - d 4) δ 8.55 (br s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H). 7.14-6.99 (m, 4H), 6.85 (br s, 1H), 6.69 (br s, 1H), 6.58 (s, 1H), 5.3 5-5.25 (m, 1H), 5.35-5.25 (m , 2H), 4.71-4.40 (m, 2H), 4.31-4.06 (m, 3 H), 3.21-3.17 (m, 1H), 3.15-3.07 (m, 5H), 3.03 (s, 3H), 2.51 (s, 6H), 2.33-2.24 (m, 1H), 2.20-2.11 (m, 1H), 1.41 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H) Example 415: Synthesis of compound 615

[0239] Compound 615 (TFA salt) was prepared as a white solid from compound 615-1 (from Example V (Compound 106-B2)) and 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using similar methods described in Example 374. LCMS (Method 5-95 AB, ESI): tR= 0.702 min, [M + H]+= 982.4; 1H NMR (400 MHz, MeOH-d4) δ 8.24-8.08 (m, 2H), 7.27-7.14 (m, 2H), 6.97-6.69 (m, 6H), 6.45 (s, 1H), 5.33-5.24 (m, 1H), 4.81-4.74 (m, 2H), 4.57-4.37 (m, 4H), 4.28-4.20 (m, 1H), 3.42-3.35 (m, 2H), 3.29-3.19 (m, 2H), 3.05 (s,3H), 2.99-2.74 (m, 2H), 2.44 (s, 6H), 2.24-2.14 (m, 1H), 2.09-1.97 (m, 3H), 1.89-1.79 (m, 2H), 1.66-1.41 (m, 6H), 1.35 (d, J =6.8Hz, 3H) Example 416: Synthesis of compound 616

[0240] Compound 616 (TFA salt) was prepared as a white solid from compound 616-1 (from Example V (Compound 106-B1)) and 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine-5-carboxylic acid (described in Example 137) using similar methods described in Example 374. LCMS (Method 5-95 AB, ESI): tR= 0.831 min, [M + H]+= 968.4; 1H NMR (400 MHz, MeO H- d4 ) δ 8. 7.93-10 (m, 2H), 7.17-6.97 (m, 4H), 6.97-6.81 (m, 3H), 6.72 (br s, 1H), 6.26 (br s, 1H), 5.54-5.50 (m, 1H), 4.83-4.72 (m, 2H), 4.5 1-4.34 (m, 3H), 4.29 (s, 2H), 4.02-3.74 (m, 1H), 3.58-3.37 (m, 4H), 3.12 (s, 3H), 2.85-2.75 (m, 1H), 2.33 (s, 6H), 2.09-2.02 (m, 2H), 1.89-1.85 (m, 2H), 1.67-1.38 (m, 9H) Example 417: Synthesis of compound 617

[0241] Compound 617-2 was prepared as a white solid from compound 617-1 (from Example V (Compound 106-A2)) using similar methods described in Example 367. LCMS (Method 5-95 AB, ESI): tR= 0.817 min, [M + Na]+= 847.2

[0242] Compound 617 (FA salt) was prepared as a white solid from compound 617-2 and (S)-2- (((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butanoic acid was prepared using similar methods described in Example 414 and Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.617 min, [M + H]+= 891.3; 1H NMR (400MHz, MeOH - d4 ) δ 8.45 (br s, 1H), 8.21 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H). 7.31-7.15 (m, 2H), 6.93-6.86 (m, 2H), 6.85-6.81 (m, 1H), 6.59 (br s, 1H), 6.48 (s, 1H), 5.34-5.26 (m, 1H), 4.85-4.76 (m, 2H), 4.30-4.19 (m, 3 H), 4.21 (s, 2H), 3.28-3.08 (m, 4H), 3.00 (s, 3H), 2.97-2.70 (m, 2H), 2.47 (s, 6H), 2.36-2.25 (m, 1H), 2.21-2.11 (m, 1H), 1.39 (s, 9H), 1.34 (d, J) =6.8Hz, 3H) Example 418: Synthesis of compound 618

[0243] Compound 618-2 was prepared as a white solid from compound 618-1 (from Example V (Compound 106-B2)) using similar methods described in Example 371. LCMS (Method 5-95 AB, ESI): tR= 0.944 min, [M + H]+= 1038.9

[0244] Compound 618-3 was prepared as a white solid from compound 618-2 using similar methods described in Example 389. LCMS (Method 5-95 AB, ESI): tR= 0.795 min, [M + H]+= 1052.8

[0245] A solution of compound 618-3 (70 mg, 0.07 mmol), trimethylsilyl isocyanate (153 mg, 1.3 mmol) in DCM (5 mL) was stirred at 25 °C for 5 h. The reaction, which was washed with 0.1 M hydrochloric acid and brine (30 mL each), was added with DCM (30 mL). The organic layer was dried over sodium sulfate, concentrated, and the residue was purified by TLC, eluting with 10% methanol in DCM, to afford compound 618-4 (20 mg, 27% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.989 min, [M + H]+= 1095.6

[0246] Compound 618 (TFA salt) was prepared as a white solid using similar methods described in Example 382. LCMS ( روش 5-95 AB, ESI): tR= 0. 715 min, [M + H ]+= 919.8 ;1H NMR (400 MHz, MeOH- d4)  8.21 (d, J =7.6 Hz, 2H), 7.51 (d, J =7.6 Hz, 2H), 7.29 (d, J =7.2 Hz, 1H), 7.22 (d, J =7.2 Hz, 1H), 7.03 (br s, 1H), 6.95 (br s, 1H), 6.61 (br s, 1H), 6.34 (s, 1H), 5.35-5.27 (m, 1H), 4.63-4.33 (m, 4H), 4.26 (s, 2H), 3.43-3.31 (m, 3H), 3.20-3.08 (m, 2H), 3.03 (s, 3H), 2.99-2.92 (m, 1H), 2.49 (s, 6H), 2.40-2.28 (m, 1H), 2.21-2.10 (m, 1H), 1. 40 (s, 9H), 1. 37 (d, J = 6.8 Hz, 3H) مثال ۴۱۹: سنتز ترکیب ۶۱۹

[0247] Step 1: A solution of compound 619-1 (134 mg, 0.12 mmol), K2CO3 (86 mg, 0.62 mmol) and tert-butyl (2-bromoethyl)carbamate (139 mg, 0.62 mmol) in DMF (5 mL) was stirred at 50 °C for 48 h while four portions of K2CO3 (86 mg, 0.62 mmol) and tert-butyl (2-bromoethyl)carbamate (139 mg, 0.62 mmol) were added every 12 h. After filtration, the filtrate was partitioned between ethyl acetate and water (40 mL each). The organic layer was washed with brine (30 mL×2), dried over Na2SO4, concentrated, and the residue was purified by preparative TLC, eluting with 5% methanol in DCM, to afford compound 619-2 (131 mg, 86% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.214 min, [M + H]+= 1225.8

[0248] Compound 619 (FA salt) was prepared as a white solid using similar methods described in Example 418. LCMS (method 10-80 AB, ESI, 7 min): tR= 1.749 min, [M + H ]+= 962.5; 1H NMR (400 MHz, MeOH-d4)  8.53 (br s, 1H), 8.05 (s, 2H), 7.4 5 (d, J = 8.4 Hz, 2H). 7.34-7.23 (m, 2H), 7.20-7.08 (m, 1H), 6.91 (s, 1H), 6.76 (br s, 1H), 6.09 (br s, 1H), 5.42-5.27 (m, 1H), 4.87-4.72 (m, 2H), 4.59-4.40 (m, 2H), 4.23 (s, 2H), 3.74 (t, J =5.2 Hz, 2H), 3.49-3.45 (m, 2H), 3.32-3.31 (m, 1H), 3.14 (t, J =8.4 Hz, 2H), 3.07-3.03 (m, 2H), 3.02 (s, 3H), 2.92-2.77 (m, 1H), 2.38 (s, 6H), 2.30-2.24 (m, 1H), 2.21-2.07 (m, 1H), 1.38 (s, 9H), 1.35 (d, J = 6.8 Hz, 3H) Example 420: Synthesis of compound 620

[0249] Compound 620-2 was prepared as a white solid from compound 620-1 (from Example V (Compound 106-B1)) using similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 1.161 min, [M + H]+= 1138.1

[0250] Compound 620-3 was prepared as a white solid using similar methods described in Example 418. LCMS (Method 5-95 AB, ESI): tR= 0.986 min, [M + Na]+= 1074.7

[0251] A solution of compound 620-3 (100 mg, 0.10 mmol), Ac2O (30 μL, 0.29 mmol) and pyridine (50 μL, 0.57 mmol) in DCM (2 mL) was stirred at 25 °C for 2 h. The mixture was washed with brine (50 mL), added to ethyl acetate (50 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC, eluting with 5% methanol in DCM, to give compound 620-4 (108 mg, 97% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.059 min, [M + H]+= 1094.8

[0252] Compound 620 (FA salt) was prepared as a white solid using similar methods described in Example 382. LCMS (method 20-80 AB, ESI, 7 min): tR= 2.366 min, [M / 2 + H ]+= 459.9; 1H NMR (400 MHz, MeOH-d4)  8.55 (br s, 1H), 8.2 1 (d, J =8.0 Hz, 2H), 7.54 (s, 1H), 7.46 (d, J =8.0 Hz, 2H), 6.90-7.00 (m, 2H), 6.66 (s, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 5.34-5.31 (m, 1H), 4.86-4.74 (m, 2H), 4.40-4.28 (m, 4H), 3.42-3.32 (m, 2H), 3.31-3.26 (m, 1H), 3.12 (t, J =7.8 Hz, 2H), 2.98 (s, 3H), 2.95-2.89 (m, 1H), 2.43 (s, 6H), 2.36-2.27 (m, 1H), 2. 15 (m, 1H), 2.17-2.11 (s, 3H), 1.39 (s, 9H), 1.36 (d, J =6.8 Hz, 3H) Example 421: Synthesis of compound 621

[0253] Compound 621 (FA salt) was prepared from compound 621-1 (synthesis described in Example 418) as a white solid using similar methods described in Example 418. LCMS (20-80 AB method, ESI, 7 min): tR= 2.372 min, [M + H ]+= 919.5; 1H NMR (400 MHz, MeOH-d4)  8.70 (br s, 1H), 8.10 (d, J =7.6 Hz, 2H), 7.55-7.40 (m, 3H), 6.99 (d, J =8.4 Hz, 1H), 6.90 (br s, 1H), 6.62 (s, 1H), 6.44 (s, 1H), 6.33 (s, 1H), 5.43-5.32 (m, 1H), 4.87-4.70 (m, 2H), 4.44-4.27 (m, 4H), 3.45-3.34 (m, 2H), 3.21-3.04 (m, 2H), 2.98 (s, 3H), 2.93-2.79 (m, 1H), 2.62-2.51 (m, 1H), 2.41 (s, 6H), 2.36-2.28 (m, 1H), 2.22-2.09 (m, 1H), 1.41 (s, 9H), 1.30 (d, J = 6.4 Hz, 3H) Example 422: Synthesis of compound 622

[0254] Compound 622 (FA salt) was prepared from compound 622-1 (synthesis described in Example 418) as a white solid using similar methods described in Example 419. LCMS ( روش 20-80 AB, ESI , 7 min ): tR= 1.930 min, [M + H ]+= 962.6 ;1H NMR (400 MHz, MeOH- d4)  8.49 (br s , 1H), 8.26 (d, J = 8.0 Hz , 2 H) , 7.68 ( s , 1 H), 7.5 0 (d, J = 8.0 Hz , 2 H), 7.20 (d, J =8. 4 Hz , 1H), 7.08 (d, J =8. 4 Hz , 1H), 6. 85 ( s , 1H), 6.6 4 (s, 1H), 6.4 7 (s, 1H), 5.43-5.32 (m, 1H), 4.87-4.70 (m, 2H), 4.44-4.27 (m, 2H), 4.22 (s, 2H), 4.00-3.80 (m, 2H), 3.45-3.34 (m, 2H), 3.21-3.04 (m, 2 H), 2.98 (s, 3H), 2.62-2.40 (m, 2H), 2.51 (s, 6H), 2.36-2.28 (m, 1H), 2.22-2.09 (m, 1H), 1 .38 (s, 9H), 1.36 ( d , J =6.8 Hz, 3 H) مثال ۴۲۳: سنتز ترکیب ۶۲۳

[0255] Step 1: A solution of compound 623-1 (synthesis described in Example 418, 110 mg, 0.10 mmol), 1,1'-carbonyldiimidazole (339 mg, 2.1 mmol) in anhydrous THF (6 mL) was stirred at 25 °C for 16 h. The mixture was partitioned between ethyl acetate and water (40 mL each) and the organic layer was washed with brine (30 mL×2), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC, eluting with 5% methanol in DCM, to afford compound 623-2 (91 mg, 81% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.047 min, [M + H]+= 1078.7

[0256] Compound 623 (FA salt) was prepared from compound 623-2 as a white solid using similar methods described in Example 54. LCMS (method 10-80 AB, ESI, 7 min): tR= 2.188 min, [M + H ]+= 902.5; 1H NMR (400 MHz, MeOH-d4)  8.52 (br s, 1H), 8.34 (d, J =8.4Hz, 2H), 7.53 (d, J =8.4Hz, 2H). 7.29-7.19 (m, 1H), 7.14 (d, J =8.4Hz, 1H), 6.96 (s, 1H), 6.81 (br s, 1H), 6.75 (s, 1H), 6.55 (s, 1H), 5.2 2-5.18 (m, 1H), 4.73-4.56 (m, 2H), 4.51-4.40 (m, 1H), 3.39-4.27 (m, 1H), 4.22 (s, 2H), 3.47-3.38 (m, 2H), 3.38-3.34 (m, 2H), 3.15-3.11 (m, 2H), 3.00 (s, 3H), 2.57 (s, 6H), 2.33-2.22 (m, 2H), 1.41 (s, 9H), 1.37 (d, J = 6.0 Hz, 3H) Example 424: Synthesis of compound 624

[0257] Step 1: 4-bromo-2-methoxy-1-nitrobenzene was prepared as a yellow solid from 5-bromo-2-nitrophenol using the methylation method described in Example 391.

[0258] Step 2: A solution of methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.26 g, 12.9 mmol), zinc (1.69 g, 25.8 mmol) and I2 (100 mg) in DMF (10 mL) was stirred at 20 °C under nitrogen for 30 min, followed by the addition of 4-bromo-2-methoxy-1-nitrobenzene (2.0 g, 8.6 mmol), sphos (354 mg, 0.86 mmol) and Pd2(dba)3 (395 mg, 0.43 mmol) under nitrogen. The mixture was then heated to 60 °C with stirring and stirred at 60 °C for 3 h. The mixture was washed with brine (150 mL×2), taken up in ethyl acetate (200 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column, eluting with 0-20% ethyl acetate in petroleum ether, to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-methoxy-4-nitrophenyl)propanoate (2 g, 66% yield) as a yellow oil.

[0259] Step 3: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-methoxy-4-nitrophenyl) propanoate (2 g, 5.6 mmol) in DCM (10 mL), BBr3 (3.2 mL, 33.9 mmol) was added at 0 °C. The mixture was slowly warmed to 25 °C with stirring and stirred at the same temperature for 16 h. The reaction was slowly added to methanol (20 mL) and the resulting mixture was concentrated. The residue was redissolved in saturated hydrochloric acid / methanol (50 mL) and the mixture was stirred at 25 °C for 5 h. The volatiles were removed and the resulting residue, to which Boc2O (1.44 mL, 6.3 mmol) and 15 mL of saturated NaHCO3 solution were added, was redissolved in THF (15 mL). The reaction mixture was stirred at 25 °C for 16 h. After that, the mixture was washed with brine (100 mL), diluted with ethyl acetate (100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column, eluting with 0-30% ethyl acetate in petroleum ether, to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-hydroxy-4-nitrophenyl)propanoate (1.44 g, 74% yield) as a yellow solid.NMR (400 MHz, CDCl3): δ 10.59 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.07 (d, J=7.6 Hz, 1H, NH), 4.62 (br s, 1H, phenol-OH), 3.76 (s, 3H), 3.27-3.05 (m, 2H), 1.43 (s, 9H).

[0260] Step 4: (S)-Methyl 2-amino-3-(4-nitro-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate was prepared as a white solid from (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-hydroxy-4-nitrophenyl)propanoate using the triflate elimination process (described in Example 10) and elimination method B (described in Example 53).

[0261] Step 5: To a solution of compound 624-1 (10.0 g, 18.4 mmol) in DCM / methanol (150 mL, v / v=1:2), Ag2SO4 (4.0 g, 12.9 mmol) and iodine (5.1 g, 20.2 mmol) were added. The mixture was stirred at 25 °C for 3 h. The mixture was partitioned between ethyl acetate and saturated NaHCO3 solution (300 mL each), and the organic layer was washed with 5% Na2S2O3 and brine (300 mL each), dried over Na2SO4, and concentrated. The residue was purified by silica gel column, eluting with 40-60% ethyl acetate in petroleum ether, to afford compound 624-2 (12.0 g, 97% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): tR= 0.959 min, [M + Na]+= 692.1

[0262] Step 6: A solution of compound 624-2 (12.0 g, 18 mmol), Pd(PPh3)2Cl2 (1.26 g, 1.8 mmol), bis(pinacolato)diboron (22.7 g, 90 mmol), KOAc (12.3 g, 126 mmol) in DMSO (40 mL) was stirred at 60 °C for 3 h under N2. The mixture, washed with brine (500 mL×3), was taken up in ethyl acetate (500 mL), dried over sodium sulfate, concentrated, and the residue was purified on a silica gel column, eluting with 40-60% ethyl acetate in petroleum ether, to give compound 624-3 (9.0 g, 75% yield) as a white solid. Step 7: Compound 624-4 was prepared from compound 624-3 from compound and (S)-methyl-2-amino-3-(4-nitro-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate using the methods described in 101B. LCMS (Method 5-95 AB, ESI): tR= 0.927 min, [M + Na]+= 756.3

[0263] Step 8: A solution of compound 624-4 (100 mg, 0.14 mmol) and SnCl2·2H2O (308 mg, 1.4 mmol) in ethyl acetate (10 mL) was stirred at 75 °C for 2 h. The mixture was washed with saturated Na2CO3 solution and brine (40 mL each), added with ethyl acetate (30 mL), dried over magnesium sulfate, and concentrated. The resulting residue, to which Boc2O (152 μL, 0.66 mmol) and Et3N (147 μL, 1.1 mmol) were added, redissolved in DCM (10 mL). The mixture was stirred at 25 °C for 32 h. Volatiles were removed and the residue was then purified by preparative TLC, eluting with 10% methanol in DCM, to afford compound 624-5 (100 mg, 94% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 0.994 min, [M + Na]+= 826.5

[0264] Compound 624 (FA salt) was prepared from compound 624-5 as a white solid using similar methods described in Example 54. LCMS (method 5-95 AB, ESI): tR= 0.730 min, [M + H ]+= 860.4; 1H NMR (400 MHz, MeOH-d4)  8.55 (br s, 3 H), 8.14 (d, J =8.0 Hz, 2 H), 7.44 (d, J =8.0 Hz, 2 H), 7.30-7.22 (m, 2H), 6.89-6.71 (m, 4H), 6.33 (s, 1H), 5.30 (m, 1H), 4.60-4.50 (m, 2H), 4.39-4.20 (m, 2H), 4.26 (s, 2H), 3.08-2.54 (m, 8H), 3.01 (s, 3H), 2.42 (s, 6H), 2.24-2.11 (m, 2H), 1.38 (s, 9H), 1.35 (d, J =6.4 Hz, 3H) Example 425: Synthesis of compound 625

[0265] Step 1: (S)-methyl 3-(2-(benzyloxy)-4-methoxyphenyl)-2-((tert-butoxycarbonyl)amino) propanoate was prepared as a white solid from 2-bromo-5-methoxyphenol and benzyl bromide by similar methods described in Example 424. 1H NMR (400 MHz, CDCl3) δ 7.47-7.31 (m, 5H), 7.02 (d, J =8.4 Hz, 1H), 6.51 (d, J =2.0 Hz, 1H), 6.44 (dd, J =8.4, 2.0 Hz, 1H), 5.12-5.03 (m, 2H), 4.50-4.45 (m, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 3.12-2.98 (m, 2H), 1.39 (s, 9H)

[0266] Step 2: Compound 625-1 was prepared as a white solid using similar methods described in Example 424. LCMS (Method 5-95 AB, ESI): tR= 0.991 min, [M + Na ]+= 847.5

[0267] Step 3: Compound 625-2 was prepared as a white solid from (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butanoic acid using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.896 min, [M + H ]+= 1068.3

[0268] Compound 625 (FA salt) was prepared as a white solid using similar methods described in Example 382. LCMS (method 5-95 AB, ESI): tR= 0.743 min, [M + Na ]+= 913.5; 1H NMR (400 MHz, MeOH-d4)  8.56 (br s, 2 H), 8.08 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.18 (br s, 2H), 6.77 (br s, 1H), 6.73 (s, 1H), 6.52 (s, 1H), 6.17 (s, 1H), 5.37-5.35 (m, 1H), 4.79-4.74 (m, 2H), 4.39-4.25 (m, 2H), 4.31 (s, 2H), 3.83 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.95 (m, 2H), 3.02 (s, 3H), 2.79-2.71 (m, 2H), 2.38 (s, 6H), 2.28-2.08 (m, 2H), 1.40 (s, 9H), 1.3 4 (d, J = 6.8 Hz, 2H) Example 426: Synthesis of compound 626

[0269] Step 1: Compound 626-2 was prepared as a white solid from compound 626-1 (synthesis described in Example 425) using the triflate formation method described in Example 10. LCMS (Method 5-95 AB, ESI): tR= 1.054 min, [M + H ]+= 1199.6

[0270] Step 2: A solution of compound 626-2 (240 mg, 0.20 mmol), Zn(CN)2 (48 mg, 0.40 mmol), dppf (44 mg, 0.08 mmol) and Pd2(dba)3 (17 mg, 0.04 mmol) in DMF (8 mL) was stirred at 100 °C for 16 h under N2. The mixture was washed with brine (50 mL×2), added with ethyl acetate (80 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC, eluting with 10% methanol in DCM, to give compound 626-3 (160 mg, 74% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.148 min, [M + H ]+= 1077.0

[0271] Step 3: Compound 626-4 was prepared as a white solid from compound 626-3 using the methods described in Example 424 except for the B addition process where Boc2O, Et3N was used (described in Example 395). LCMS (Method 5-95 AB, ESI): tR= 1.174 min, [M + Na ]+= 1184.3

[0272] Step 4: To a solution of compound 626-4 (50 mg, 0.04 mmol), Boc2O (57 mg, 0.26 mmol) and NiCl2·6H2O (15 mg, 0.06 mmol) in methanol (4 mL), NaBH4 (11 mg, 0.30 mmol) was added slowly at 0 °C. The reaction was gradually warmed to 25 °C with stirring and stirred at the same temperature overnight. The mixture was washed with brine (40 mL), added with ethyl acetate (40 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC, eluting with 10% methanol in DCM, to afford compound 626-5 (30 mg, 55% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR= 1.133 min, [M + Na ]+= 1288.3

[0273] Compound 626 (FA salt) was prepared from compound 626-5 as a white solid using similar methods described in Example 54. LCMS (Method 5-95 AB, ESI): tR= 0.760 min, [M + H ]+= 891.0; 1H NMR (400 MHz, MeOH-d4)  8.49 (br s, 2H), 8.32 (d, J =8.4 Hz, 2H), 7.53 (d, J =8.4 Hz, 1H), 7.30 (d, J =8.4 Hz, 1H), 7.18 (d, J =8.4 Hz, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.45 (s, 1H), 5.24-5.21 (m, 2H), 4.85-4.80 (m, 1H), 4.40-4.32 (m, 2H), 4.22 (s, 2H), 4.10-4.04 (m, 2H), 3.35-3.11 (m, 6H), 2.98 (s, 3H), 2.55 (s, 6H), 2.29-2.13 (m, 2H), 1.38 (s, 9H), 1.35 (d, J =6.8 Hz, 3H) Example 427: Synthesis of compound 627

[0274] Compound 627-2 was prepared from compound 627-1 (described in Example 425) and tert-butyl (2-bromoethyl)carbamate using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 1.011 min, [M + H ]+= 1299.6

[0275] Compound 631 (FA salt) was prepared from compound 627-2 as a white solid using the elimination conditions B described in Example 53. LCMS (method 5-95 AB, ESI): tR= 0.785 min, [M + H ]+= 999.6; 1H NMR (400 MHz, MeOH-d4)  8.53 (br s, 3H), 8.19 (d, J =7.6 Hz, 2H), 7.47 (d, J =7.6 Hz, 2H), 7.24-7.16 (m, 3H), 6.77 (s, 1H), 6.72 (s, 1H), 6.62 (br s, 1H), 6.52 (s, 1H), 5.42-5.40 (m, 1H), 4.78-4.62 (m, 2H), 4.27-4.22 (m, 6H), 3.88 (s, 3H), 3.58-3.53 (m, 2H), 3.40-3.38 (m, 1H), 3.05 (s, 3H), 2.99-2.96 (m, 2H), 2.90-2.75 (m, 3H), 2.49 (s, 6H), 1.38 (s, 9H), 1.37 (d, J =6.4) Hz, 3H) Example 428: Synthesis of compound 628

[0276] To a solution of compound 628-1 (synthesis described in Example 427, 50 mg, 0.04 mmol) in DCM (4 mL), BBr3 (36 μL, 0.38 mmol) was added at 0 °C. The reaction was gradually warmed to 25 °C with stirring and stirred at the same temperature for 16 h. The reaction was quenched with water and the resulting mixture was immediately lyophilized. The residue was purified by preparative HPLC (acetonitrile 23-33 / 0.225% FA in water) to afford compound 628 (FA salt) as a white solid (2.3 mg, 5.9% yield). LCMS (Method 5-95 AB, ESI): tR= 0.793 min, [M + Na ]+= 1007.8; 1H NMR (400 MHz, MeOH-d4)  8.5 3 (br s, 3H), 8.22 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H). 7.21 (d, J =8.0 Hz, 1H), 7.16 (d, J =8.0 Hz, 1H), 6.82 (s, 1H), 6.63 (br s, 1H), 6.53 (s, 1H), 6.50 (br s, 1H), 5.39-5.35 (m, 2H), 4.81-4.77 (m, 1H), 4.65-4.15 (m, 6H), 4.2 1 (s, 2H), 3.58-3.53 (m, 2H), 3.39-3.33 (m, 4H), 3.10 (s, 3H), 3.05-2.98 (m, 2H), 2.50 (s, 6H), 1.36 (s, 9H), 1.35 (d, J=6.4 Hz, 3H) Example 429: Synthesis of compound 629

[0277] Step 1: Compound 629-2 was prepared from compound 629-1 (synthesis described in Example 371) using the iodine addition conditions described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.925 min, [M + Na ]+= 853.1

[0278] Step 2: A solution of compound 629-2 (200 mg, 0.24 mmol), Pd2dba3 (11 mg, 0.01 mmol), SPhos (10 mg, 0.02 mmol), potassium tert-butyl N-(difluoroboranylmethyl)carbamate fluoride (63 mg, 0.26 mmol) and K3PO4 (153 mg, 0.72 mmol) in toluene (2 mL) and H2O (0.1 mL) was stirred at 85 °C for 16 h under nitrogen. The volatiles were removed and the residue was triturated with ethyl acetate (30 mL). After filtration, the filtrate was washed with brine (35 mL×3), dried over Na2SO4, concentrated, and the residue was purified by preparative TLC, eluting with 10% methanol in DCM, to afford compound 629-3 (110 mg, 55% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): tR= 0.926 min, [M + Na ]+= 856.1

[0279] Compound 629 (FA salt) was prepared as a white solid using similar methods described in Example 382. LCMS (Method 5-95 AB, ESI): tR= 0.785 min, [M + H ]+= 955.5; 1H NMR (400 MHz, MeOH-d4)  8.44 (brs, 1H), 8.32 (d, J =8.0 Hz, 1H), 7.53 (d, J =8.4 Hz, 2H), 7.23 (d, J =8.0 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J =8.0 Hz, 1H), 6.93 (brs, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 5.30-5.27 (m, 1H), 4.90-4.81 (m, 2H), 4.35 (s, 2H), 4.21 (s, 2H), 4.10-4.00 (m, 2H), 3.60-3.55 (m, 2H), 3.25-3.10 (m, 4H), 3.06 (s, 3H), 2.59 (s, 6H), 1.38 (s, 9H), 1.36 (d, J = 6.0 Hz, 3H) Examples 430-437: Synthesis of compounds 630-637

[0280] The following compounds in Table 4 were prepared using methods similar to those previously described. Table 4 Structure combination number 630 631 632 633 634 635 636 637 Examples 438-449: Synthesis of compounds 638-649

[0281] The following compounds in Table 5 were prepared using methods similar to those previously described. Table 5 Structure Composition Number 638 639 640 641 642 643 644 645 646 647 648 649 Biological assessments: Example B1: Determination of the minimum inhibitory concentration

[0282] The in vitro antimicrobial activity of each compound was determined by measuring the minimum inhibitory concentrations (MICs) using a liquid microdilution method as validated by the Clinical and Laboratory Standards Institute (CLSI) (Methods for Dilute Antimicrobial Stability Tests for Bacteria Growing Aerobically; Approved Standard - 8th Edition - CLSI Document, M07-A8. Wayne, PA: Clinical and Laboratory Standards; 2009). Antimicrobial activity was measured against two bacterial species: a methicillin-resistant Staphylococcus aureus strain, USA 200, (S. aureus) and Escherichia coli ATCC 25922 (E. coli), a clinical Gram-negative strain. Cells were inoculated onto plates of Trypticase Soy Agar or Luria Agar, respectively, and cultured at 35°C for 20 hours. The inoculum was suspended by scraping the cells into 1 mL of test medium (cation adjusted Mueller Hinton Broth supplied with 0.002% v / v of Tween-80) and diluted to a final OD600nm of 0.01.

[0283] Test compounds were prepared in DMSO at a concentration of 10 mg / mL. Compounds were tested under various dilution formats and data are reported in Tables 6, 7 and 8. In Protocol 1, compound stocks were diluted into test media at a concentration of 64 μg / mL and serial 2-fold dilutions were made in the same medium in a 96-well U-bottom microtiter plate for a total of 10 compound concentrations. In Protocol 2, compound stocks were diluted into test media at a concentration of 4 μg / mL and serial 2-fold dilutions were made in the same medium in a 96-well U-bottom microtiter plate for a total of 10 compound concentrations. In Protocol 3, compound stocks were diluted into test media at a concentration of 0.5 μg / mL and serial 2-fold dilutions were made in the same medium as described above. In protocol 4, compound stocks were diluted into test media at a concentration of 0.13 μg / mL and serial 2-fold dilutions were made in the same medium as described above. Inoculum suspensions were added to serial 2-fold dilutions of test compounds to a final OD600nm density of 0.0005 and incubated at 35°C for 22 h.After incubation, the plates were visually inspected and the lowest concentration of the test compound that completely inhibited bacterial growth was recorded as MICs. The results obtained are listed in Tables 6, 7, 8. Table 6 Compound No. MIC S. aureus µM MIC E. coli µM Compound No. MIC S. aureus µM MIC E. coli µM 201 0 . 062 0 . 42 381 0 . 067 4 . 3 202 0 . 023 0 . 37 382 0 . 4 4 . 3 203 0 . 031 0 . 13 383 0 . 1 1 . 1 204 0 . 032 2 . 1 384 0 . 033 0 . 4 205 0 . 012 0 . 066 385 0 . 017 0 . 27 206 0 . 025 0 . 13 386 0 . 75 8 207 0 . 017 0 . 1 387 0 . 25 8 208 0 . 017 0 . 14 388 0 . 031 1 209 0 . 26 2 . 1 389 0 . 13 4 210 0 . 022 0 . 35 390 0 . 094 8 211 0 . 026 0 . 17 391 0 . 031 0 . 25 212 0 . 017 0 . 067 392 0 . 063 3 213 0 . 28 1 . 1 393 0 . 021 8 . 2 214 0 . 034 0 . 41 394 0 . 0083 0 . 2 215 0 . 017 0 . 13 395 0 . 013 0 . 27 216 0 . 0084 0 . 2 396 0 . 016 0 . 5 217 0 . 0082 0 . 099 397 0 . 023 0 . 38 218 0 . 012 0 . 097 398 0 . 025 0 . 27 219 0 . 012 0 . 13 399 0 . 0078 0 . 5 220 0 . 0062 0. 099 400 0. 047 0. 25 221 0. 024 1 401 0. 016 0. 25 222 0. 033 0. 53 402 0. 031 0. 38 223 0. 016 0. 26 403 0. 016 0. 5 224 0. 017 0. 13 404 0. 094 0. 38 225 0. 016 0. 19 405 0. 063 0. 38 226 0.0082 0 . 099 406 0 . 023 0 . 25 227 0 . 017 0 . 077 407 0 . 016 0 . 13 228 0 . 57 2 . 3 408 0 . 023 0 . 38 229 0 . 57 4 . 6 409 0 . 13 0 . 75 230 0 . 012 0 . 066 410 0 . 016 0 . 3 231 0 . 35 1 . 4 411 0 . 016 0 . 25 232 0 . 015 0 . 16 412 0 . 023 0 . 5 233 0 . 016 0 . 13 413 0 . 016 0 . 13 234 0 . 0082 0 . 066 414 0 . 016 0 . 25 235 0 . 016 0 . 26 415 0 . 063 1 . 5 236 0 . 016 0 . 13 416 0 . 094 3 237 0 . 0083 0 . 27 417 0 . 0062 0 . 13 238 0 . 53 2 . 1 418 0 . 008 0 . 064 239 0 . 015 0 . 12 419 0 . 063 8 240 0 . 012 0 . 13 420 0 . 75 3 241 0 . 0081 0 . 097 421 0 . 031 0 . 19 242 0 . 016 0 . 39 422 0 . 031 0 . 38 243 0 . 008 0 . 13 423 0 . 13 2 244 0 . 012 0 . 13 424 0 . 023 0 . 19 245 0 . 0081 0 . 097 425 0 . 016 0 . 19 246 0 . 067 0 . 4 426 0 . 023 0 . 12 247 0 . 016 0 . 19 427 NT 0 . 094 248 0 . 016 0 . 13 428 NT 0 . 5 249 0 . 043 0 . 35 429 0 . 023 1 250 0 . 066 0 . 35 430 0 . 15 4 . 7 251 0 . 067 1 . 1 431 0 . 18 3 . 9 252 0 . 0081 0 . 097 432 0 . 045 1 . 4 253 0 . 012 0 .14 433 0 . 016 0 . 096 254 0 . 061 0 . 24 434 0 . 023 0 . 21 255 0 . 0082 0 . 066 435 0 . 012 0 . 094 256 0 . 0078 0 . 1 436 NT 0 . 063 257 0 . 016 0 . 13 437 0 . 031 0 . 38 258 0 . 012 0 . 13 438 0 . 012 0 . 16 259 0 . 025 0 . 26 439 0 . 016 0 . 076 260 0 . 079 0 . 45 440 NT 1 261 0 . 014 0 . 1 441 NT 0 . 38 262 0 . 0081 0 . 097 442 0 . 042 0 . 91 263 0 . 016 0 . 53 443 0 . 27 4 . 2 264 0 . 52 1 . 6 444 0 . 064 4 . 1 265 0 . 068 0 . 41 445 0 . 13 4 . 1 266 0 . 033 0 . 2 446 0 . 032 4 . 1 267 0 . 39 1 447 0 . 033 4 . 2 268 0 . 016 0 . 12 448 0 . 13 4 . 1 269 0 . 016 0 . 094 449 0 . 016 0 . 5 270 0 . 012 0 . 064 450 0 . 016 2 . 1 271 0 . 032 0 . 26 451 0 . 047 0 . 76 272 0 . 012 0 . 065 452 0 . 13 1 . 3 273 0 . 0082 0 . 099 453 0 . 026 1 . 1 274 0 . 023 0 . 063 454 0 . 55 4 . 4 275 0 . 012 0 . 094 455 NT NT 276 0 . 016 0 . 063 456 0 . 56 3 . 3 277 0 . 016 0 . 13 457 0 . 025 0 . 27 278 0 . 0078 0 . 094 458 0 . 033 1 . 1 279 0 . 023 0 . 13 459 0 . 083 0 . 71 280 0 . 031 0 . 13 460 0 .13 4 . 1 281 0 . 016 0 . 065 461 0 . 051 1 . 1 282 0 . 016 0 . 094 462 0 . 027 5 . 4 283 0 . 012 0 . 094 463 NT NT 284 0 . 016 0 . 13 464 0 . 063 4 285 0 . 047 0 . 19 465 0 . 047 4 286 0 . 016 0 . 13 466 0 . 047 1 . 5 287 0 . 065 1 467 0 . 19 8 288 0 . 023 1 . 5 468 0 . 063 1 289 0 . 016 0 . 75 469 0 . 13 6 290 0 . 19 0 . 75 470 0 . 047 4 291 0 . 094 0 . 25 471 0 . 04 5 . 1 292 0 . 13 0 . 75 472 0 . 0085 0 . 11 293 0 . 13 1 . 5 473 0 . 31 4 . 9 294 0 . 031 0 . 19 474 0 . 11 4 . 8 295 0 . 0078 0 . 063 475 0 . 6 4 . 8 296 0 . 016 0 . 38 476 0 . 025 1 . 1 297 0 . 016 0 . 75 477 0 . 26 3 . 2 298 0 . 016 0 . 13 478 0 . 071 1 . 1 299 0 . 047 0 . 38 479 0 . 027 0 . 77 300 0 . 031 0 . 25 480 0 . 061 1 . 6 301 0 . 016 0 . 094 481 0 . 037 2 . 3 302 NT 0 . 5 482 0 . 036 0 . 24 303 NT 0 . 13 483 0 . 036 0 . 29 304 NT 0 . 13 484 NT NT 305 NT 0 . 13 485 0 . 023 0 . 5 306 0 . 84 14 486 0 . 023 0 . 38 307 0 . 033 0 . 2 487 0 . 016 0 . 38 308 0 . 012 0 . 096 488 NT 0 . 5 309 0 . 27 1 . 1 489 0 .016 0 . 38 310 0 . 066 0 . 53 490 0 . 023 1 311 1 8 . 2 491 0 . 049 3 . 1 312 0 . 024 0 . 063 492 0 . 016 2 313 0 . 016 0 . 13 493 0 . 047 1 314 0 . 033 0 . 2 494 0 . 068 1 . 1 315 0 . 016 0 . 25 495 0 . 031 1 316 0 . 38 1 . 5 496 0 . 094 1 317 0 . 047 0 . 5 497 0 . 047 0 . 75 318 0 . 016 0 . 38 498 0 . 063 1 319 1 8 499 0 . 063 1 . 5 320 0 . 016 0 . 19 500 0 . 031 0 . 48 321 0 . 047 0 . 38 501 0 . 063 1 322 0 . 15 0 . 6 502 0 . 078 0 . 24 323 0 . 38 1 503 0 . 047 1 324 0 . 047 0 . 13 504 0 . 063 0 . 75 325 0 . 016 0 . 13 505 0 . 094 1 . 5 326 0 . 031 0 . 13 506 0 . 094 0 . 83 327 NT 0 . 13 507 0 . 063 0 . 38 328 0 . 0093 0 . 07 508 1 6 329 0 . 011 0 . 11 509 0 . 047 0 . 5 330 0 . 033 0 . 26 510 0 . 023 1 . 5 331 0 . 0081 0 . 13 511 NT 2 332 0 . 0078 0 . 063 512 NT 1 333 1 2 513 0 . 0061 0 . 097 334 0 . 5 4 514 0 . 031 0 . 19 335 0 . 032 0 . 19 516 0 . 19 2 336 0 . 016 0 . 15 517 0 . 19 0 . 75 337 0 . 012 0 . 11 518 0 . 028 0 . 16 338 0 . 012 0 . 13 519 NT 0 . 13 339 0 . 047 0 .25 520 NT 1 340 0 . 023 0 . 063 521 0 . 047 0 . 2 341 0 . 016 0 . 13 522 NT 0 . 13 342 0 . 097 0 . 39 523 0 . 044 0 . 28 343 0 . 13 0 . 75 524 0 . 56 4 . 5 344 0 . 063 0 . 38 525 0 . 053 0 . 56 345 0 . 023 0 . 25 526 0 . 047 0 . 33 346 0 . 016 0 . 13 527 NT 0 . 38 347 0 . 047 0 . 25 528 NT 0 . 063 348 0 . 023 0 . 19 529 NT 4 349 0 . 023 0 . 094 530 0 . 063 0 . 35 350 0 . 016 0 . 094 531 0 . 047 0 . 25 351 NT 0 . 25 532 NT 0 . 063 352 0 . 023 0 . 094 533 NT 1 . 5 353 0 . 047 2 534 NT 0 . 5 354 0 . 016 1 . 5 535 0 . 029 0 . 23 355 0 . 094 4 536 0 . 016 0 . 13 356 NT 0 . 13 537 NT 0 . 25 357 NT 0 . 19 538 NT 0 . 063 358 0 . 033 0 . 2 539 0 . 023 0 . 15 359 0 . 008 0 . 064 540 NT 1 . 5 360 0 . 066 0 . 26 541 NT 0 . 75 361 0 . 016 0 . 13 542 0 . 55 4 . 4 362 0 . 063 0 . 25 543 0 . 063 0 . 35 363 0 . 016 0 . 19 544 NT 0 . 13 364 0 . 016 0 . 25 545 NT 1 365 0 . 063 0 . 31 546 NT 0 . 38 366 0 . 016 0 . 13 547 NT 0 . 094 367 NT 0 . 5 548 0 . 047 0 . 46 368 0 . 047 0 . 5 549 0 . 035 0 .21 369 0 . 047 0 . 75 550 NT 2 370 0 . 031 0 . 19 551 NT 1 371 0 . 031 0 . 19 552 0 . 25 1 . 4 372 0 . 023 0 . 38 553 0 . 055 0 . 21 373 NT 0 . 13 554 NT 0 . 094 374 0 . 016 0 . 25 555 NT 0 . 19 375 0 . 031 0 . 5 556 NT 0 . 19 376 0 . 016 0 . 25 557 NT 0 . 25 377 0 . 031 0 . 5 558 0 . 046 0 . 73 378 0 . 031 0 . 38 379 0 . 26 1 380 0 . 045 0 . 48. جدول 7 شماره ترکیب MIC S. aureus µM MIC E. coli µM شماره ترکیب MIC S. aureus µM MIC E. coli µM 559 NT 0 . 38 597 NT 0 . 26 560 NT 0 . 25 598 NT 0 . 094 561 NT 0 . 75 599 NT 0 . 58 562 NT 0 . 094 600 NT 0 . 38 563 NT 0 . 25 601 NT 0 . 50 564 NT 0 . 063 602 NT 0 . 063 565 NT 0 . 13 603 NT 0 . 44 566 NT 0 . 094 604 NT 0 . 75 567 NT 0 . 094 605 NT 0 . 75 568 NT 0 . 063 606 NT 0 . 50 569 NT 0 . 50 607 NT 0 . 50 570 NT 0 . 063 608 NT 0 . 38 571 NT 0 . 094 609 NT 0 . 50 572 NT 0 . 28 610 NT 0 . 19 573 NT 0 . 50 611 NT 0 . 19 574 NT 0 . 50 612 NT 0 . 25 575 NT 0 . 31 613 NT 0 . 75 576 NT 0 . 50 614 NT 0 . 19 577 NT 0 . 21 615 NT 1 . 0 578 NT 0 . 19 616 NT 0 . 50 579 NT 0 . 75 617 NT 0 . 19 580 NT 0 . 58 618 NT 0 . 19 581 NT 0 . 25 619 NT 0 . 13 582 NT 0 . 75 620 NT 0 . 50 583 NT 0 . 17 621 NT 0 . 25 584 NT 0 . 50 622 NT 0 . 50 585 NT 0 . 38 623 NT 0 . 50 586 NT 0 . 19 624 NT 0 . 38 587 NT 0 . 094 625 NT 0 . 38 588 NT 0 . 094 626 NT 0 . 25 589 NT 1 . 0 627 NT 0 . 50 590 NT 0 . 38 628 NT 0 .44 591 NT 0. 25 630 NT 0. 25 592 NT 0. 19 631 NT 0. 19 593 NT 1. 5 632 NT 0. 50 594 NT 0. 13 633 NT 0. 047 595 NT 0. 33 634 NT 0. 25 596 NT 0. 50. Table 8 Compound No. MIC S. aureus µM MIC E. coli µM 638 0. 19 0. 22 639 0. 75 0. 38 640 NT 0. 25 641 0. 047 0. 094 642 0. 21 0. 23 643 1. 1 2. 3 644 1. 2 0. 58 645 0. 52 0. 4 646 1. 1 0. 37 647 0. 19 0. 25 648 0. 28 0. 1 NT = Not tested Example B2: Evaluation of whole-cell SpsB biochemical screening

[0284] A kinetic fluorogenic enzyme activity assay is used to evaluate the inhibition of SpsB (Staphylococcus aureus signal peptidase) activity and IC50s are determined. This method is performed using a S. aureus cell suspension system as a source of SpsB instead of recombinant SpsB protein.

[0285] Cell preparation: Luria broth (LB) was inoculated with Staphylococcus aureus (USA300 background, overexpressing SpsB) and shaken at 37°C until an OD600nm of 1.5-2.0 was obtained (up to 4 hours). The culture medium was then diluted to an OD600nm of 1.0 with LB, aliquoted, and centrifuged at 10,000x g for 2 minutes. The supernatant was removed and the pellet was resuspended in phosphate buffer (1x PBS, 12.5 mg / L MgCl2, 25 mg / L CaCl2, 0.1% Tween-80) to an OD600nm of 0.5, and then centrifuged again at 10,000x g for 2 minutes. The supernatant was removed and the pellets were frozen at -20°C.

[0286] Test compounds were prepared in DMSO at a concentration of 10 mg / mL. These compound stocks were diluted into DMSO to a concentration of 25 μg / mL, and 3-fold dilutions were made in DMSO for a total of 11 compound concentrations. 20 nL of each compound solution was spotted into a 384-well white plate (50 μL / well of polypropylene, Nunc) using acoustic fluid transfer (Echo).

[0287] Frozen S. aureus pellets were resuspended in assay buffer (1x PBS, 12.5 mg / L MgCl2, 25 mg / L CaCl2, 0.1% Tween-80) to an OD600nm of 0.05, then mixed 1:1 (v / v) with 20 µM substrate in assay buffer ((Dabcyl)βAla-KPAKAAE(Edans)), and this solution (20 µL / well) was added to a 384-well plate pre-spotted with the compound. Fluorescence intensity was then read kinetically for 30 min with 2 min reading intervals to monitor the breakdown of the internally quenched peptide substrate (excitation wavelength = 340 nm, emission wavelength = 490 nm, Spectramax M5 Molecular Devices). The reaction rate (slope) was plotted against inhibitor concentration to extract the IC50. Example B3: Activity in a highly neutropenic infection model

[0288] The ability of a compound to inhibit bacterial pathogen infection can be measured using a highly neutropenic mouse infection model. Reduction of bacterial load is a measure of antibacterial activity in vivo.

[0289] Jugular vein cannulated CD-1 mice were induced to neutropenia (<100 cells / mm3) by injection of 150 mg / kg and 100 mg / kg cyclophosphamide on day 5 and day 2, respectively. On day 1, saline was infused at 20 µL / hour for 12 hours using a Harvard PHD 2000 device with infusion pumps. On day 0, mice were infected in the thigh muscle with 1X105CFU / 50 µL of Escherichia coli strain ATCC 25922. There were four test groups and one challenge group, which were dosed 1 hour after infection: Group 1 - Stimulant control (3% HP-beta-cyclodextrin in PBS) Group 2 - The group of the compound disclosed herein dosed at a concentration of 0.62 mg / mL of solution, infused at 80 µL / hour for 23 hours, with a target steady-state concentration (Css) of 13 µg / mL. Group 3 - The group of compounds disclosed herein dosed at a concentration of 0.21 mg / mL of solution, infused at 80 µL / hour for 23 hours, to achieve a target steady-state concentration (Css) of 3.4 µg / mL. Group 4 - The compound disclosed herein was administered at a concentration of 0.07 mg / mL of solution (Css 1.2 ug / mL) infused at 80 µL / hour for 23 hours. Group 5 - The compound disclosed herein was administered at a concentration of 0.02 mg / mL of solution (Css 0.31 ug / mL) infused at 80 µL / hour for 23 hours.

[0290] At 24 hours post-infection, bacterial load in thigh muscle was determined by culturing tissue homogenates at serial dilutions on blood agar plates. Example B4: Clinical Treatment Safety and Efficacy of Compounds of Formula I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) in Patients with C. Difficile-Associated Diarrhea.

[0291] Objective: The purpose of the present study is to determine the safety and efficacy of the compounds presented here for treating symptoms of Clostridium difficile-associated diarrhea and reducing the risk of recurrent diarrhea. The compounds will be evaluated in comparison to current standard antibiotic therapy, such that all patients will receive active drug. All study care, including doctor visits, physical examinations, laboratory tests, and study medication, will be provided. The total length of participation is approximately 10 weeks.

[0292] Patients: Eligible individuals are men and women 18 years of age or older.

[0293] Criteria Inclusion criteria: At least 18 years of age. C. difficile-associated diarrhea (CDAD) with mild to moderate activity. Able to tolerate oral medication; not be pregnant or breastfeeding; and Sign and date an informed consent form.

[0294] Study Design: This is an active-controlled, double-blind, randomized study of the efficacy, safety, and tolerability of the combination of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) in patients with C. difficile-associated diarrhea. Example B5: Clinical trial comparison of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) with vancomycin for the treatment of MRSA staphylococcus.

[0295] Objective: The objective of the present study is to determine the efficacy of the compounds presented herein compared to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis.

[0296] Patients: Eligible individuals will be males and females 18 years of age and older.

[0297] Criteria: Inclusion criteria: MRSA confirmed in culture obtained in the operating room or during a sterile biopsy procedure from a bone site. The site of infection and sampling is either within the bone or a deep soft tissue site that is contiguous with the bone, or a radiographic abnormality consistent with osteomyelitis in association with a positive blood culture for MRSA; Surgery to remove dead tissue from the site of infection, if needed; The subject is able to provide written informed consent; and Subject is able to receive outpatient injectable treatment for 12 weeks. Barrier criteria: Sensitivity to a combination of formulas (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or vancomycin; Staphylococcus aureus resistant to a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or vancomycin; Osteomyelitis that develops directly from a chronic, open wound. Polymicrobial culture medium (the only exception is when coagulase-negative staphylococcus is present in the culture medium and clinical evaluation indicates it is a contaminant); The subject has a positive pregnancy test on the registration form; Kidney or liver failure that worsens with study medication; Injecting active ingredients without safety conditions for administering intravenous antibiotics for 3 months; and Use of antibiotics for more than 14 days in the presence of an infection other than osteomyelitis.

[0298] Study Design: This is a randomized, open-label, active-controlled study, testing the efficacy of vancomycin compared with a combination of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) for the treatment of MRSA osteomyelitis. Example B5: Clinical Trial Evaluation of a Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) in Selected Serious Infections Caused by Vancomycin-Resistant Enterococcus (VRE)

[0299] Objective: This study was conducted to determine the safety and efficacy of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) for the treatment of serious infections caused by VRE.

[0300] Patients: Eligible subjects are males and females 18 years of age or older.

[0301] Criteria:

[0302] Inclusion criteria: Isolation of one of the following multi-antibiotic-resistant bacteria: vancomycin-resistant Enterococcus faecium, vancomycin-resistant Enterococcus faecalis alone or as part of a multi-microbial infection; and Having a definite diagnosis of serious infection (eg, bacterial [unless ruled out by an infection], complicated intra-abdominal infection, skin and skin structure infection, or pneumonia) requiring intravenous (IV) antibiotic therapy. Exclusion criteria: Subjects with any concurrent condition taking any medication that, in the opinion of the investigator, would prevent the assessment of response or make it unlikely that the intended period of treatment or assessment would be completed, or would significantly increase the risk associated with the subject's participation in this study. The expected duration of antibiotic treatment is less than 7 days.

[0303] Study Design: This is a randomized, double-blind, active-controlled study, testing the efficacy of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) for the treatment of serious infections caused by VRE. Pharmaceutical compounds Example C1: Parent compounds

[0304] To prepare an injectable pharmaceutical composition suitable for administration by injection, 100 mg of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) was dissolved in DMSO and then mixed with 10 mL of sterile 0.9% saline. The mixture was incorporated into a unit dose suitable for administration by injection.

[0305] In another configuration, the following ingredients are mixed together to form an injectable formulation: Ingredient Amount Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) 1.2 g Sodium acetate buffer solution (0.4 M) 2.0 mL HCl (1 N) or NaOH (1 M) qs to appropriate pH Water (sterile, distilled) qs to 20 mL

[0306] All the above ingredients, except water, are combined and stirred together, and if necessary, heated slightly. Sufficient water is then added. Example C2: Oral composition

[0307] To prepare a pharmaceutical composition for oral administration, 100 mg of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) was mixed with 750 mg of starch. The mixture was incorporated into an oral dosage unit, such as a gelatin pharmaceutical capsule, suitable for oral administration.

[0308] In another configuration, the following materials were mixed together and compressed into round tablets. Ingredient Amount per tablet, mg Compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) 200 Corn starch 50 Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5

[0309] In another configuration, the following ingredients were mixed together and loaded into a hard-shell gelatin capsule. Ingredient Amount per tablet, mg Compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) 200 Spray-dried lactose 148 Magnesium stearate 2

[0310] In another configuration, the following ingredients were mixed together and formed into a solution / suspension for oral administration: Ingredient Amount Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) Sodium carbonate anhydrous 1 g 0.1 g Ethanol (200 proof), USP 10 mL Purified water, USP 90 mL Aspartame 0.003 g Example C3: Topical gel composition

[0311] To prepare a topical pharmaceutical gel composition, 100 mg of a compound of formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V) or (Va)-(Vc) was mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of pure USP alcohol. The resulting gel was then placed in a tube-like container suitable for topical application.

[0312] While preferred configurations of the present disclosure have been described and illustrated herein, it will be apparent to those skilled in the art that these configurations are provided by way of example only. Numerous changes, modifications, and substitutions will now occur to those skilled in the art without departing from the scope of the invention. It is to be understood that various alternatives to the configurations described herein may be used in practicing the invention. It is intended that the claims define the scope of the invention and methods and structures that fall within the scope of the claims, and that equivalents thereof are also covered by the claims.

Claims

PROPOSED CLAIM AMENDMENTS WHAT IS CLAIMED IS:

1. A compound of Formula (V): Formula (V); wherein: R1 and R2 are each independently H, -(C1 -C6 )alkyl, -(C1 -C6 )alkyl-OR23 , -CH2 CH(OH)CH2 NH2 , -CH2 CH(heterocycloalkyl)CH2 NH2 , -CH2 C(O)NH2 , -CH2 C(O)N(H)CH2 CN, -(C1 -C6 )alkyl-C(O)OR23 , -(C1 -C6 )alkyl-NR21 R22 , -(C1 -C6 )alkyl-C(O)NR25 R26 , -(C1 -C6 )alkyl-N(R23 )C(O)(C1 -C6 )alkylNR21 R22 , -(C1 -C6 )alkyl-N(R23 )C(O)(C1 -C6 )alkyl, -(C1 -C6 )alkyl-C(O)N(R23 )(C1 -C6 )alkyl, -(C1 -C6 )alkyl-C(O)N(R23 )(C1 -C6 )alkyl-heterocycloalkyl, -(C1 -C6 )alkyl-NR23 C(=NH)NR21 R22 , -(C1 -C6 )alkyl-NR23 C(=NH)R23 , -(C1 -C6 )alkyl-[(C1 -C6 )alkyl-NR21 R22 ]2 , -(C1 -C6 )heteroalkyl, or optionally substituted heterocycloalkyl; or R1 and R2 and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring; R6 , R7 , and R8 are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl,heteroalkyl, or -(C1 -C6 )alkyl; R9 is H, -(C1 -C6 )alkyl, -(C1 -C6 )haloalkyl, or -(C3 -C6 )cycloalkyl; R10 is H, -(C1 -C6 )alkyl, -(C1 -C6 )haloalkyl, or -(C3 -C6 )cycloalkyl; or R9 and R10 are combined to form a heterocycloalkyl or cycloalkyl ring R11 and R12 are each independently H, -NH2 , -(C1 -C6 )alkyl, -(C1 -C6 )alkyl-OR23 , -(C1 -C6 )alkyl-SR23 , -(C1 -C6 )alkyl-C(O)OR23 , -(C1 -C6 )alkyl-NR21 R22 , -(C1 -C6 )alkyl-NR23 OR23 , -(C1 -C6 )alkyl-NHC(O)NR23 OR23 , -(C1 -C6 )alkyl-O-(C1 -C6 )alkyl-NR25 R26 , -(C1 -C6 )alkyl-CN, -(C1 -C6 )alkyl-NR23 C(O)R23 , -(C1 -C6 )alkyl-C(O)NR25 R26 , -(C1 -C6 )heteroalkyl-CO2 H, -(C1 -C6 )alkyl-S(O)(C1 -C6 )alkyl, -(C1 -C6 )alkyl-N(H)CH=NH, -(C1 -C6 )alkyl-C(NH2 )=NH, -(C1 -C6 )alkyl-N(H)C(=NH)NH2 , -(C1 -C6 )alkyl-N(H)S(O)2 NR25 R26 , -(C1 -C6 )alkyl-N(H)S(O)2 (C1 -C6 )alkyl, -(C1 -C6 )alkyl-N(H)-C(O)NR25 R26 , -(C1 -C6 )alkylC(O)N(H)[optionally substituted(C2 -C6 )alkyl]-OR23 , -(C1 -C6 )alkylN(H)C(O)(C1 -C6 )alkyl-OR23 , -(C1 -C6 )alkylC(O)N(H)heterocycloalkyl, -(C1 -C6 )alkylC(O)NR25 R26 , -(C1 -C6 )alkyl-N(H)-C(O)-(C1 -C6 )alkyl-NR25 R26 , -(C1 -C6 )alkyl-N(H)-(C1 -C6 )alkylC(O)NR25 R26 , -(C1 -C6 )alkyl-heterocycloalkyl, optionally substituted -(C1 -C6 )alkyl-N(H)heterocycloalkyl, or -(C1 -C6 )alkyl-heteroaryl; or R11 and R18 are combined to form an optionally substituted heterocycloalkyl ring; and R12 is H; R15 , R16 , R17 , and R18 are each independently H, -(C1 -C6 )alkyl, -(C3 -C6 )cycloalkyl, -(C1 -C6 )alkyl-OR23 , -(C1 -C6 )alkyl-C(O)OR23 , or -(C1 -C6 )alkyl-NR21 R22 ; X is optionally substituted heteroaryl; Y is a bond, -O-, -S-, optionally substituted -(C1 -C6 )alkyl-, -(C2 -C6 )alkenyl-, -(C2 -C6 )alkynyl, -(C1 -C6 )alkyl-N(R24 )(C1 -C6 )alkyl-, -O-(C1 -C6 )alkyl-, -O(C6 -C10 )aryl-, -N(R24 )(C1 -C6 )alkyl-, -N(R24 )SO2 (C1 -C6 )alkyl-, -N(R24 )C(O)(C1 -C6 )alkyl-, -C(O)(C1 -C6 )alkyl-, -S(C1 -C6 )alkyl-, -SO2 (C1 -C6 )alkyl-, -C(O)NH(C1 -C6 )alkyl-, optionally substituted -(C3 -C7 )cycloalkyl-, optionally substituted -C(O)N(R24 )aryl-, optionally substituted -N(R24 )C(O)aryl-, optionally substituted -N(R24 )SO2 aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Z is H, halogen, -NH2 , -CN, -CF3 , -CO2 H, -(C1 -C12 )alkyl, -(C2 -C12 )alkenyl, -CH=((C3 -C7 )cycloalkyl), -(C2 -C12 )alkynyl, -C(O)NR25 R26 , -O-(C1 -C12 )alkyl, -S-(C1 -C12 )alkyl, -O-(C3 -C10 )[optionally substituted (C3 -C7 )cycloalkyl], -O-(C1 -C6 )alkyl-OR23 , -(C1 -C12 )alkyl-OR23 , -(C1 -C12 )alkyl-CN, -S-(C1 -C12 )alkyl, -N(R24 )(C1 -C12 )alkyl, -N(R24 )C(O)(C1 -C12 )alkyl, optionally substituted -(C3 -C7 )cycloalkyl, -(C1 -C6 )alkyl-(C3 -C7 )cycloalkyl, -(C1 -C6 )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R21 and R22 is independently H, -(C1 -C6 )alkyl, -(C1 -C6 )heteroalkyl, -(C1 -C6 )alkyl-CO2 H, -C(O)(C1 -C6 )alkyl, -C(O)O(C1 -C6 )alkyl, -C(O)O(C1 -C6 )haloalkyl, -C(=NH)(C1 -C6 )alkyl, -C(=NH)N(R31 )2 , -C(O)N(R31 )2 , or -SO2 N(R31 )2 ; or R21 and R22 and the nitrogen atom to which they are attached form a heterocycloalkyl ring; each R31 is independently H or -(C1 -C6 )alkyl; or two R31 and the nitrogen atom to which they are attached form a heterocycloalkyl ring; each R23 is independently H or -(C1 -C6 )alkyl; each R24 is independently H or -(C1 -C6 )alkyl; each R25 and R26 is independently H or optionally substituted -(C1 -C6 )alkyl; or R25 and R26 and the nitrogen atom to which they are attached form a heterocycloalkyl ring; each R27 is independently halogen, -NR23 R24 , -NHC(O)R23 , -NHC(O)NR23 R24 , nitro, hydroxyl, optionally substituted -(C1 -C6 )alkyl, optionally substituted -(C1 -C6 )heteroalkyl, optionally substituted -(C1 -C6 )heteroalkyloxy, optionally substituted -(C1 -C6 )heteroalkylamino, -(C1 -C6 )alkoxy, -C(O)(C1 -C6 )alkyl, or -S(O)2 (C1 -C6 )alkyl; or R1 and R27 and the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl ring; each R28 is independently halogen, -NR23 R24 , -NHC(O)R23 , -NHC(O)NR23 R24 , nitro, hydroxyl, optionally substituted -(C1 -C6 )alkyl, optionally substituted -(C1 -C6 )heteroalkyl, optionally substituted -(C1 -C6 ) heteroalkyloxy , optionally substituted -(C1 -C6 )heteroalkylamino, -(C1 -C6 )alkoxy, -C(O)(C1 -C6 )alkyl, or -S(O)2 (C1 -C6 )alkyl; or R2 and R28 and the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl ring; p is 0, 1, or 2; and q is 0, 1, or 2; or a pharmaceutically acceptable salt, solvate, or prodrug thereof .

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R6 , R7 , and R8 are H.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R15 and R16 are H.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R17 is -CH3 .

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R18 is H.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R9 is -(C1 -C6 )alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R9 is -CH3 .

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R11 is -(C1 -C6 )alkyl-OR23 .

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R11 is -CH2 CH2 OH.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R11 is -(C1 -C6 )alkyl.

11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R11 is -(C1 -C6 )alkyl-NR21 R22 .

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R11 is -(C1 -C6 )alkyl-NH2 .

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is heteroaryl monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally substituted -(C1 -C6 )alkyl, optionally substituted -O-(C1 -C6 )alkyl, OR23 , -NR25 R26 , and -NO2 .

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is pyridinyl or pyrimidinyl monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally substituted -(C1 -C6 )alkyl, optionally substituted -O-(C1 -C6 )alkyl, OR23 , -NR25 R26 , or -NO2 .

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Y is optionally substituted aryl.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Y is optionally substituted heteroaryl.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Y is optionally substituted (C3 -C7 )cycloalkyl.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Y is optionally substituted heterocycloalkyl.

19. A pharmaceutical composition comprising the compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

20. Use of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for preparation of a medicament for treatment of a bacterial infection in a patient.