ZHONG MIN (US)
WALKER MICHAEL (US)
BURES MARK (US)
PAJOUHESH HASSAN (US)
ZHANG KEN (US)
WO2021110883A1 | 2021-06-10 | |||
WO2020194531A1 | 2020-10-01 | |||
WO2021110883A1 | 2021-06-10 | |||
WO2021110884A1 | 2021-06-10 | |||
WO2021110885A1 | 2021-06-10 | |||
WO2021110886A1 | 2021-06-10 | |||
WO2021110887A1 | 2021-06-10 | |||
WO2020161216A1 | 2020-08-13 | |||
WO2020161217A1 | 2020-08-13 | |||
WO2019234077A1 | 2019-12-12 | |||
WO2014037480A1 | 2014-03-13 | |||
WO2014184328A1 | 2014-11-20 | |||
WO2013006394A1 | 2013-01-10 | |||
WO2014089296A2 | 2014-06-12 | |||
WO2014106019A2 | 2014-07-03 | |||
WO2013102655A1 | 2013-07-11 | |||
WO2014184350A1 | 2014-11-20 | |||
WO2014184365A1 | 2014-11-20 | |||
WO2014161888A1 | 2014-10-09 | |||
WO2014131847A1 | 2014-09-04 | |||
WO2014033176A1 | 2014-03-06 | |||
WO2014033167A1 | 2014-03-06 | |||
WO2014033170A1 | 2014-03-06 | |||
WO2013010069A1 | 2013-01-17 | |||
WO2014074906A1 | 2014-05-15 |
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CLAIMS: 1. A compound of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is NRx or CR2R3; Rx is hydrogen or C1-4alkyl; R0 is -C(O)OH, -C(O)OC1-6alkyl or -S(O)2OH; R1 is hydrogen, halo, C1-4alkyl or haloC1-4alkyl; R2 and R3 are independently selected from the group consisting of hydrogen, halo and methyl; R4 is independently selected from the group consisting of hydrogen, halo, cyano, C1- 4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio; R5 is haloC3-4alkyl, hydroxyC3-4alkyl, aminoC3-4alkyl, cyanoC2-4alkyl, C3-5alkenyl, C3- 4alkynyl, methoxyethyl, ethoxymethyl, and C3-6cycloalyl-ethylene-; R6 is hydrogen; or R5 and R6 together with the carbon atom to which they are attached form a C3-7monocycloalkyl or C5-12bicycloalkyl group; and R7 is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, and C1-4alkylthio. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is NRx. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein M is NH or NCH3. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is CH2, CHF, CF2 or C(CH3)2. 5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R0 is -C(O)OH or -C(O)OC1-4alkyl. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R0 is -C(O)OH. 7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or F. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R1 is F. 9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is methylthio. 10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 is haloC3-4alkyl, hydroxyC3-4alkyl, aminoC3-4alkyl, cyanoC2-4alkyl, C3-5alkenyl, C3-4alkynyl, methoxyethyl, ethoxymethy or C3-6cycloalyl- ethylene-. 11. The compound according to any one of claims 10, or a pharmaceutically acceptable salt thereof, wherein R5 is haloC3-4alkyl. 12. The compound according to any one of claims 11, or a pharmaceutically acceptable salt thereof, wherein R5 is n-butyl substituted with 1 to 6 halo atoms. 13. The compound according to any one of claims 12, or a pharmaceutically acceptable salt thereof, wherein R5 is n-butyl substituted with 1 to 6 F atoms. 14. The compound according to any one of claims 13, or a pharmaceutically acceptable salt thereof, wherein R5 is -CH2CH2CF2CH3. 15. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are attached form a C3-7monocycloalkyl or C5-12bicycloalkyl group. 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are attached form a or group. 17. A compound selected from the group consisting of: , and . 18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 19. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof. 20. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 18. 21. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof. 22. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 18. |
[0143] Step 1. Synthesis of spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2). Bicyclo[2.2.1]heptan-2-one (1-1) (15 g, 136.4 mmol) was dissolved in EtOH/H 2 O = 50 mL/50 mL, TMSCN (20 g, 204.5 mmol), CsF (31 g, 204.5 mmol), and (NH 4 ) 2 CO 3 (39 g, 409.1 mmol) were added. Then the reaction mixture was stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2) (21 g, 85%) as a white solid. MS (ESI): calcd.: 180.1, Found: 181.3 [M+1] + . [0144] Step 2. Synthesis of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3). Spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2) (21 g, 117.0 mmol) was dissolved in saturated aq. NaOH (200 mL). Then the reaction mixture was reflux for 3 days and acidified with 6N HCl solution to pH = 5. The reaction mixture was concentrated under reduced pressure to afford 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3) as a white solid (27 g, 30%). MS (ESI): calcd.: 155.1, Found: 156.3 [M+1] + . [0145] Step 3. Synthesis of 2-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2- carboxylic acid (1-4). To a solution of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3) (27 g, 35.1 mmol) and NaOH (3 g, 77.2 mmol) in H 2 O (70 mL) was added Boc 2 O (9 g, 40 mmol) in acetone dropwise between 10 - 20 °C. The reaction mixture was stirred at rt overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidified with 6N aq. HCl solution to pH = 2 and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford 2-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2- carboxylic acid (1-4) (9 g, 89%) as a white solid. MS (ESI): calcd.: 255.2, Found: 156.3 [M - 100+1] + . [0146] Step 4. Synthesis of tert-butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5). A 250 mL flask was charged with 2-(tert- butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (1-4) (9 g, 35.3 mmol), TEA (3.2 g, 32.1 mmol) and THF (100 mL). Then isobutyl carbonochloridate (4.4 g, 32.1 mmol) was added at 0 °C. The reaction mixture was stirred at rt for 0.5 h. Then aniline (3 g, 32.1 mmol) was added. The reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was diluted with water and extracted with EA (100 mL x 3). The combined organic layers were dried by Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford tert-butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5) (4.95 g, 43%) as a white solid. TLC: 10% PE/DCM (v/v) (R f : 0.6); MS (ESI): calcd.: 330.2, Found: 275.2 [M-56+1] + . [0147] Step 5. Synthesis of 2-amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide (1- 6). To a stirred solution of tert-Butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5) (4.95 g, 15 mmol) in DCM (50 mL) was added CF 3 COOH (6 mL) at 0 °C. The reaction mixture was stirred at rt overnight. After completion of the reaction (monitored by TLC), the reaction mixture was basified with K 2 CO 3 solution to pH = 9. Then reaction mixture was extracted with DCM (70 mL x 3). The combined organic layers were dried by Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford 2-amino-N- phenylbicyclo[2.2.1]heptane-2-carboxamide (1-6) (2.9 g, 85%) as a white solid. TLC: 5 % PE/DCM (v/v) (R f : 0.5); MS (ESI): calcd.: 230.1, Found: 231.3 [M+1] + . [0148] Step 6. Synthesis of 2-((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1- 7).2-amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide (1-6) (2.9 g, 12.6 mmol) was dissolved in THF (50mL), LiAlH 4 (1.9 g, 50.4 mmol) was added at 0 °C slowly. The reaction mixture was warmed up to 75 °C and stirred overnight. After completion of the reaction by TLC, the reaction mixture was cooled to 0 °C, quenched with 1.9 mL water and 1.9 mL 15 % aqueous NaOH, filtered, washed with THF (50 mL). The organic layer was dried by Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford 2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1-7) (2.5 g, 95%) as a white solid. MS (ESI): calcd.: 216.2, Found: 217.4 [M+1] + . [0149] Step 7. Synthesis of 2,4-dibromo-5-methoxy-N-(2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)benzenesulfon amide (1-8). To a mixture of 2-((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1-7) (2.4 g, 11.1 mmol) and TEA (2.8 g, 27.8 mmol) in THF (50mL), was added, 2,4-dibromo-5-methoxybenzenesulfonyl chloride (6.03 g, 16.7 mmol) at 0 °C slowly. The reaction mixture was stirred at rt rt overnight. The reaction mixture was quenched with water (50 mL), extracted with EA (70 mL x 3). The combined organic layers were dried by Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with PE in DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v) to afford 2,4-dibromo-5-methoxy-N-(2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)benzenesulfon amide (1-8) (2.97 g, 50%) as a white solid. TLC: 20% PE/DCM (v/v) (R f : 0.4); MS (ESI): calcd.: 542.0, Found: 543.0 [M+1] + . [0150] Step 8. Synthesis of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan e] 1,1-dioxide (1-9). To a solution of 2,4-dibromo-5-methoxy-N-(2-((phenylamino)methyl)bicyclo[2.2. 1]heptan-2- yl)benzenesulfonamide (1-8) (2.7 g, 5.0 mmol) in DMF (30 mL), K 2 CO 3 (1.95 g, 10.0 mmol) and CuI (95 mg, 0.5 mmol) were added. The reaction mixture was stirred at rt under N 2 atmosphere for 15 min. TDA-1 (323.5 mg, 1.0 mmol) was added, and the reaction mixture was stirred at 130 °C overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with EA (3x70 ml). The combined organic layers were washed with brine (30 ml), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2 ,5]thiadiazepine-3,2'- bicyclo[2.2.1]heptane] 1,1-dioxide (1-9) (1.97 g, 85%) as a white solid. TLC: 20% PE/DCM (v/v) (R f : 0.5); MS (ESI): calcd.: 462.1, Found: 463.2 [M+1] + . [0151] Step 9. Synthesis of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan e] 1,1-dioxide (1-10). To a stirred solution of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan e] 1,1-dioxide (1-9) (500 mg, 1.1 mmol) in NMP (10 ml), Cs 2 CO 3 (705 mg, 2.2 mmol) was added at 0 °C and reaction mixture was stirred for 15 minutes. Methyl iodide (768 mg, 5.4 mmol) was then added at 0 °C. The reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EA (50 mL) and the organic layer was washed with water (40 mL). The organic part was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2 .2.1]heptane] 1,1-dioxide (1-10) (506 mg, 98%) as a white solid. TLC: 20% PE/DCM (v/v) (R f : 0.7); MS (ESI): calcd.: 476.1, Found: 477.2 [M+1] + . [0152] Step 10. Synthesis of 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro- 2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]hep tane] 1,1-dioxide (1-11). To a solution of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan e] 1,1-dioxide (1-10) (506 mg, 1.06 mmol) in DMF (10mL), CH 3 SNa (744 mg, 10.63 mmol) was added and the reaction mixture was stirred for 6 hours at 80 °C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (30 ml) and the aqueous laver was extracted with EA (30 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na 2 SO 4, filtered , and concentrated under vacuum. The residue was purified by column chromatography, eluting with 25% PE in DCM, then 100% DCM to afford 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan e] 1,1-dioxide (1-11) (299 mg, 66%) as a white solid. TLC: 10% PE/DCM (v/v) (R f : 0.4); MS (ESI): calcd.: 430.1, MS Found: 431.2 [M+1] + . [0153] Step 11. Synthesis of ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3 ,2'-bicyclo[2.2.1]heptan]- 8-yl)oxy)acrylate (1-12). To a stirred solution of ethyl 3-bromo-2,2-difluoropropanoate (389 mg, 1.79 mmol) in THF (4 mL), NaH (72 mg, 1.79 mmol) was added slowly under N 2 atmosphere. The reaction mixture was stirred at 30 °C for 2 hours.8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]th iadiazepine-3,2'- bicyclo[2.2.1]heptane] 1,1-dioxide (1-11) (155 mg, 0.36 mmol) was disoolved in DMF (2 mL) and added to the above reaction mixture slowly. Cs 2 CO 3 (350 mg, 1.08 mmol) was added. The reaction mixture was warmed up to 70 °C and stirred for 2 hours. The reaction mixture was partitioned between water and EA (30 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL) and dried over anhydrous Na 2 SO 4 , filtered, concentrated under vacuum. The residue was purified by prep-HPLC to afford ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-pheny l-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan ]-8-yl)oxy)acrylate (1-12) (122 mg, 62%) as a white solid. MS (ESI): calcd.: 546.2; Found: 547.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.84 ‒ 7.74 (m, 1H), 7.56 (s, 1H), 7.23 ‒ 7.21 (m, 2H), 7.06 ‒ 6.84 (m, 4H), 4.42 ‒ 4.24 (m, 3H), 2.96 ‒ 2.62 (m, 4H), 2.33 ‒ 2.13 (m, 4H), 2.09 ‒ 1.37 (m, 6H), 1.29 ‒ 1.05 (m, 6H) ppm. [0154] Step 12. Synthesis of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2 '-bicyclo[2.2.1]heptan]-8- yl)oxy)acrylic acid (Example 1). Ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadia zepine-3,2'- bicyclo[2.2.1]heptan]-8-yl)oxy)acrylate (1-12) (122 mg, 0.22 mmol) was dissolved in 1,4- dioxane/H 2 O (9 mL/3 mL), LiOH (28 mg, 0.67 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water and acidified with KHSO 4 solution to pH = 4, extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried by Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3 ,2'-bicyclo[2.2.1]heptan]-8- yl)oxy)acrylic acid (Example 1) (70 mg, 59%) as a white solid. MS (ESI): calcd.: 518.1, Found: 519.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.52 (s, 1H), 7.31 ‒ 7.27 (m, 3H), 7.03 ‒ 6.86 (m, 4H), 4.39 ‒ 4.26 (m, 1H), 3.00 ‒ 2.70 (m, 4H), 2.28 ‒ 2.03 (m, 5H), 1.99 ‒ 1.10 (m, 8H) ppm. [0155] Example 2. (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-pheny l-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobuta n]-8-yl)oxy)acrylic acid
[0156] Step 1. Synthesis of tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2). To a solution of 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (2-1) (20 g, 93 mmol) in THF (400 mL) was added TEA (7.6 g, 84 mmol), then the isobutyl carbonochloridate (8.6 g, 84 mmol) was added at 0 °C slowly. The mixture was stirred for 0.5 h followed by addition of a solution of aniline (7.8 g, 84 mmol) in THF (80 mL) dropwise. The mixture was stirred at rt for 16 h. The reaction mixture was then concentrated under reduced pressure to afford tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2) (15 g, 56%) as a white solid, which was used for next step without further purification. MS (ESI): calcd.: 290.1, Found: 235.1 [M-56+1] + . [0157] Step 2. Synthesis of 1-amino-N-phenylcyclobutanecarboxamide (2-3). To a solution of tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2) (15 g, 51.72 mmol) in DCM (150 mL) was added TFA (30 mL) at rt. The mixture was stirred at rt for 16 h. The reaction solution was concentrates under reduced pressure. The residue was diluted with DCM and basified with aqueous K 2 CO 3 solution to pH = 9. The aqueous layer was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-amino-N- phenylcyclobutanecarboxamide (2-3) (7.5 g) as a yellow solid, which was used for next step without further purification. MS (ESI): calcd.: 190.1, Found: 191.1. [0158] Step 3. Synthesis of N-((1-aminocyclobutyl)methyl)aniline (2-4). To a solution of 1-amino-N-phenylcyclobutanecarboxamide (2-3) (7.5 g, 39.47 mmol) in THF (75 mL) at 0 °C was added LiAlH 4 (4.5 g, 118.42 mmol) slowly. The reaction mixture was stirred at 75 °C for 4 h. The reaction mixture was cooled to rt and quenched by adding water (4.5 mL) and then 15% aqueous NaOH solution (4.5 mL) at 0 °C. The reaction mixture was concentrated under reduced pressure to afford N-((1-aminocyclobutyl)methyl)aniline (2-4) (6.5 g, 94%) as a celadon solid, which was used for next step without further purification. MS (ESI): calcd.: 176.1, Found: 177.4 [M+1] + . [0159] Step 4. Synthesis of 2,4-dibromo-5-methoxy-N-(1- ((phenylamino)methyl)cyclobutyl)benzenesulfonamide (2-5). To a solution of N-((1- aminocyclobutyl)methyl)aniline (2-4) (6.5 g, 36.93 mmol) in DCM (70 mL) was added TEA (9.32 g, 92.32 mmol) at rt, then 2,4-dibromo-5-methoxybenzenesulfonyl chloride (20 g, 55.4 mmol) was added at 0 °C slowly. The mixture was stirred at rt for 2 h. The reaction mixture was extracted with DCM (150 mL x 3), washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: DCM = 100:1 ~ 0:1 (v/v)) to afford 2,4-dibromo-5- methoxy-N-(1-((phenylamino)methyl)cyclobutyl)benzenesulfonam ide (2-5) as a white solid (6.8 g, 37%). TLC: PE/DCM = 1/2 (v/v) (R f : 0.4); MS (ESI): calcd.: 504.2, Found: 505.0 [M+1] + . [0160] Step 5. Synthesis of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-6). To a solution of 2,4-dibromo-5-methoxy-N-(1-((phenylamino)methyl)cyclobutyl)b enzenesulfonamide (2-5) (3 g, 5.95 mmol) in DMF (20 mL) was added K 2 CO 3 (1.64 g, 11.9 mmol) and CuI (114 mg, 0.6 mmol). The mixture was stirred at rt for 15 min under N 2 , TDA-1 (1.03 mg, 1.19 mmol) was added at rt. The mixture was stirred at 130 °C for 16 h under N 2 . The reaction was cooled to rt, diluted with ethyl acetate (80 mL x 3), and filtered. The filtrate was washed with brine and dried over sodium sulfate. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 100% PE to 100% EA to afford 7-bromo- 8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiad iazepine-3,1'-cyclobutane] 1,1-dioxide (2-6) as a white solid (2.53 g, 89%). TLC: PE/EA = 5/1 (v/v) (R f : 0.4); MS (ESI): calcd.: 422.2, Found: 423.2 [M+1] + . [0161] Step 6. Synthesis of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-7): To a solution of 7- bromo-8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5 ]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-6) (2.53 g, 5.99 mmol) in DMF (25 mL) was added Cs 2 CO 3 (2.16 g, 6.59 mmol) and MeI (4.13 g, 29.95 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was extracted with EA (80 mL x 3), washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: EA = 100:1 ~ 0:1 (v/v)) to afford 7-bromo-8- methoxy-2-methyl-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2, 5]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-7) as a yellow solid (1.8 g, 69%). TLC: PE/EA = 5/1 (v/v) (R f : 0.5); MS (ESI): calcd.: 436.1, Found: 437.1 [M+1] + . [0162] Step 7. Synthesis of 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro- 2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-8). To a solution of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-7) (1.8 g, 4.13 mmol) in DMF (20 mL) was added NaSMe (2.9 g, 41.3 mmol) at rt. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (40 mL) and filtered. The filtrate was washed with brine and dried over sodium sulfate. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 100% PE to 100% EA to afford 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobuta ne] 1,1-dioxide (1-8) as a white solid (900 mg, 56%). TLC: PE/EA = 2/1 (v/v) (R f : 0.5); MS (ESI): calcd.: 390.1, Found: 391.2 [M+1] + . [0163] Step 8. Synthesis of ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3 ,1'-cyclobutan]-8- yl)oxy)acrylate (2-9). A mixture of ethyl 3-bromo-2,2-difluoropropanoate (1.09 g, 5 mmol) and NaH (60%, 200 mg, 5 mmol) in DMF (10 mL) was stirred at 25 °C for 3 h.8-Hydroxy-2- methyl-7-(methylthio)-5-phenyl-4,5-dihydro-2H-spiro[benzo[f] [1,2,5]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-8) (400 mg, 1.03 mmol) and Cs 2 CO 3 (1.01 g, 3.09 mmol) in DMF (4 mL) were added. The reaction mixture was stirred at 70 °C for 16 h. After the reaction was cooled to rt, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution at 0 °C, then extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: EA = 100:1 ~ 0:1 (v/v)) to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-pheny l-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobuta n]-8-yl)oxy)acrylate (2-9) as a yellow solid (380 mg, 75%). TLC: PE/EA = 4/1 (v/v) (R f : 0.4); MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] + . [0164] Step 9. Synthesis of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1 '-cyclobutan]-8- yl)oxy)acrylic acid (Example 2). To a solution of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thi adiazepine-3,1'-cyclobutan]-8- yl)oxy)acrylate (2-9) (200 mg, 0.40 mmol) in dioxane (18 mL) and H 2 O (6 mL) was added LiOH (28 mg, 1.2 mmol) at 0 °C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was acidified with aqueous NaHSO4 solution to pH = 4, extracted with ethyl acetate (50 mL x 3), and filtered. The filtrate was washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by prep-HPLC to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-pheny l-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8-yl)oxy )acrylic acid (Example 2) as a white solid (20 mg, 10%). MS (ESI): calcd.: 478.1, Found: 479.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.53 (s, 1H), 7.33-7.26 (m, 3H), 7.07-7.06 (m, 2H), 6.96 (s, 1H), 6.92- 6.89 (m, 1H), 4.90 (s, 1H), 2.50 (s, 3H),2.32-2.29(M, 2H), 2.26 (s, 3H), 1.85-1.76 (m, 4H) ppm. [0165] Example 3, 3a and 3b. (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 3), (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1 -dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)-2-fluoroacrylic acid (Example 3a), and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1 -dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl) oxy)-2-fluoroacrylic acid (Example 3b)
[0166] Step 1. Synthesis of 2-cyclopropylethyl trifluoromethanesulfonate (3-2). A solution of 2-cyclopropylethanol (3-1) (5.5 g, 62.7 mmol) in anhydrous DCM (120 mL) was added 2,6-Lutidine (10 g, 94.0 mmol) and stirred for 30 min at 0 °C. Tf 2 O (25 g, 87.8 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with ice water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford 2-cyclopropylethyl trifluoromethanesulfonate (3-2) (12 g, 87%) as a brown oil, which was used for next step directly without further purification. [0167] Step 2. Synthesis of ethyl 4-cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3). A solution of ethyl 2-(diphenylmethyleneamino)acetate (10 g, 37.4 mmol) in anhydrous THF (200 mL) was added t-BuOK (5 g, 44.6 mmol) at 0 °C and stirred for 30 min. 2-cyclopropylethyl trifluoromethanesulfonate (3-2) (12 g, 55.0 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ice water (200 mL) and extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford ethyl 4- cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3) (12 g, 96%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 335.2, Found: 336.3 [M+1] + . [0168] Step 3. Synthesis of ethyl 2-amino-4-cyclopropylbutanoate (3-4). A mixture of ethyl 4-cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3) (12 g, 35.8 mmol) and HCl (6 N, 60 mL, 360 mmol) in EA (50 mL) was stirred at rt for 2 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EA (80 mL x 2). The aqueous phase was basified with NH 3 . H 2 O to pH = 9 - 10 and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford ethyl 2-amino-4-cyclopropylbutanoate (3-4) (4.6 g.75%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 171.1, Found: 172.3 [M+1] + . [0169] Step 4. Synthesis of ethyl 2-(tert-butoxycarbonylamino)-4- cyclopropylbutanoate (3-5). A mixture of ethyl 2-amino-4-cyclopropylbutanoate (3-4) (4.6 g, 26.9 mmol), Et 3 N (4.0 g, 40.4 mmol), and Boc 2 O (7.0 g, 32.3 mmol) in anhydrous DCM (150 mL) was stirred at rt overnight. The reaction mixture was quenched with ice water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford ethyl 2-(tert- butoxycarbonylamino)-4-cyclopropylbutanoate (3-5) (6.9 g, 94%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 271.2, Found: 216.2 [M–56+1] + . [0170] Step 5. Synthesis of 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6). To a solution of ethyl 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoate (3-5) (6.9 g, 25.4 mmol) in MeOH/H 2 O (50 mL/ 50 mL) was added LiOH (3 g, 71.4 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (100 mL), acidified with 3N aq. HCl solution to pH = 4, extracted with DCM (150 mL x 3), The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6) (4.38 g, 71%) as a yellow solid, which was used for next step directly without further purification. MS (ESI): calcd.: 243.2, Found: 188.2 [M–56+1] + . [0171] Step 6. Synthesis of tert-butyl 4-cyclopropyl-1-oxo-1-(phenylamino)butan-2- ylcarbamate (3-7). A mixture of 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6) (4.38 g, 18 mmol), HATU (10 g, 26.3 mmol), and DIEA (7 g, 54 mmol) in anhydrous DMF (100 mL) was stirred at rt for 30 min, then to this mixture was added PhNH 2 (2 g, 21.5 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (150 mL), and filtrated. The filtrate was concentrated under reduced pressure to afford tert-butyl 4- cyclopropyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (3-7) (5.5 g, 96%) as a yellow solid, which was used for next step directly without further purification. MS (ESI): calcd.: 318.2, Found: 263.2 [M-56+1] + . [0172] Step 7. Synthesis of 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8). To a solution of tert-butyl 4-cyclopropyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (3-7) (5.5 g, 17.3 mmol) in EA (50 mL) was added 4N HCl in dioxane (43 mL, 173 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (100 mL), basified with NaHCO 3 to PH = 8, and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 10% to 20% MeOH in DCM to afford 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8) (3.2 g, 85%) as a yellow oil. MS (ESI): calcd: 218.1, Found: 219.2 [M+1] + . [0173] Step 8. Synthesis of 4-cyclopropyl-N’-phenylbutane-1,2-diamine (3-9). To a solution of 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8) (3.2 g, 14.7 mmol) in anhydrous THF (100 mL) was added LiAlH 4 (2.8 g, 73.4 mmol) slowly at rt. Then reaction mixture was allowed warm to 70 °C and stirred for 3 h. The reaction mixture was cooled to rt, quenched with ice water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 15% to 20% MeOH in DCM to afford 4-cyclopropyl-N’-phenylbutane-1,2-diamine (3-9) (3 g, 100%) as a yellow oil. MS (ESI): calcd.: 204.2, Found: 205.4 [M+1] + . [0174] Step 9. Synthesis of 2,4-dibromo-N-(4-cyclopropyl-1-(phenylamino)butan-2-yl)- 5-metho xybenzenesulfonamide (3-10). To a solution of 4-cyclopropyl-N’-phenylbutane- 1,2-diamine (3-9) (3 g, 14.7 mmol) in DCM (100 mL) was added Et3N (3.7 g, 36.7 mmol) and 2,4-dibromo-5-methoxybenzenesulfonyl chloride (8 g, 22 mmol). The reaction mixture was stirred at rt for 3 h, quenched with ice water (100 mL), extracted with EA (100 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (40 % - 45 % EA in PE) to afford 2,4-dibromo-N-(4-cyclopropyl-1-(phenylamino)butan-2-yl)-5- methoxybenzenesulfonamide (3-10) (4.5 g, 58%) as a yellow solid. MS (ESI): calcd.: 530.0, Found: 531.0 [M+1] + . [0175] Step 10. Synthesis of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11). To a solution of 2,4- dibromo-N-(4-cyclopropyl-1-(phenyl amino)butan-2-yl)-5-methoxybenzenesulfonamide (3- 10) (4.5 g, 8.5 mmol) in anhydrous DMF (40 mL) was added K 2 CO 3 (2.35 g, 17 mmol) and CuI (323 mg, 1.7 mmol). The reaction mixture was degassed for 5 minutes under N 2 atmosphere and stirred at rt for 30 min. To the mixture was then added TDA-1 (550 mg, 1.7 mmol). The reaction mixture was stirred at 130 °C overnight. The reaction mixture was quenched with ice water (50 mL), extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% to 35% EA in PE) to afford 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11) (2.5 g, 65%) as a yellow solid. MS (ESI): calcd.: 450.1, Found: 450.9 [M+1] + . [0176] Step 11. Synthesis of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12). To a solution of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11) (1.5 g, 3.3 mmol) in NMP (5 mL) was added Cs 2 CO 3 (2.2 g, 6.6 mmol) and MeI (2.3 g, 18 mmol). The reaction mixture was stirred at rt for 3 h, quenched with ice water (30 mL), and extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (65% to 80% MeCN in H 2 O) to afford 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12) (880 mg, 57%) as a yellow solid. MS (ESI): calcd.: 464.1, Found: 465.1 [M+1] + . [0177] Step 12. Synthesis of 3-(2-cyclopropylethyl)-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiad iazepine 1,1-dioxide (3-13). To a solution of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5-phenyl-2 ,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12) (880 mg, 1.9 mmol) in anhydrous DMF (8 mL) was added MeSNa (1.4 g, 19 mmol). The reaction mixture was stirred at 80 °C overnight, quenched with ice water (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (50% to 60% MeCN in H 2 O) to afford 3-(2-cyclopropylethyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-13) (700 mg, 88%) as a yellow solid. MS (ESI): calcd.: 418.1, Found: 419.1 [M+1] + . [0178] Step 13. Synthesis of ethyl (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylate (3-14). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (1.1 g, 5.0 mmol) in anhydrous DMF (5 mL) was added NaH (200 mg, 60%, 5.0 mmol) and stirred at 30 °C for 2 hours. To the mixture was added 3-(2-cyclopropylethyl)-8-hydroxy-2- methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1, 2,5]thiadiazepine 1,1-dioxide (3-13) (420 mg, 1.0 mmol). The reaction mixture was then stirred at 70 °C overnight, quenched with ice water (50 mL), extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (80% MeCN in H 2 O) to afford (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1-d ioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry late (3-14) (400 mg, 75%) as a white solid. MS (ESI): calcd.: 534.2, Found: 535.2 [M+1] + . [0179] Step 14. Synthesis of (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadi azepin-8-yl)oxy)-2- fluoroacrylic acid (Example 3). To a solution of (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (3-14) (400 mg, 0.75 mmol) in dioxane (5 mL) and H 2 O (1.5 mL) was added LiOH (95 mg, 2.25 mmol). The reaction mixture was stirred at rt for 4 h and extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by reverse column (40% to 43% MeCN in H 2 O) to afford (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 3) (80 mg, 21%) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.56 (s, 1H), 7.26 (d, J = 17.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 4.10 - 4.00 (m, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 1.74 - 1.65 (m, 2H) , 1.42 - 1.28 (m, 3H), 0.78 - 0.68 (m, 1H), 0.45 – 0.42 (m, 2H), 0.14 - 0.03 (m, 2H) ppm. [0180] Step 15. Synthesis of (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadi azepin-8-yl)oxy)-2- fluoroacrylic acid (Example 3a) and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 3b): The racemic sample (Example 3) (70 mg) was separated by SFC to afford: (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1 - dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 3a) (10 mg, 2.6 %) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.53 (s, 1H), 7.30 (d, J = 17.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 4.13 - 3.98 (m, 2H), 2.57 (s, 3H), 2.34 (s, 3H), 1.75 - 1.65 (m, 2H) , 1.40 - 1.26 (m, 3H), 0.77 - 0.69 (m, 1H), 0.45 - 0.41 (m, 2H), 0.14 - 0.03 (m, 2H) ppm and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl- 7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[ f][1,2,5]thiadiazepin-8-yl)oxy)- 2-fluoroacrylic acid (Example 3b) (10 mg, 2.6%) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.54 (s, 1H), 7.30 (d, J = 17.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 4.14 - 3.98 (m, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 1.74 - 1.65 (m, 2H) , 1.40 - 1.32 (m, 3H), 0.78 - 0.68 (m, 1H), 0.45 - 0.41 (m, 2H), 0.14 - 0.03 (m, 2H) ppm. [0181] Example 4, 4a and 4b. (E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)acrylic acid (Example 4), (S,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acryl ic acid (Example 4a), and (R,E)- 3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4b)
[0182] Step 1. Synthesis of diethyl 2-acetamido-2-(but-3-enyl)malonate (4-2). A stirred suspension of sodium hydride (60%, 4.60 g, 115 mmol) in anhydrous DMF (100 ml) at 0 °C was added a solution of diethyl acetamidomalonate (22.68 g, 105 mmol) in anhydrous DMF (80 mL) dropwise. The reaction mixture was stirred for 20 minutes at rt and then 4- bromo-1-butene (4-1) (7.5 mL, 74.1 mmol) was added. The light brown solution was then stirred at 90 °C for 4 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl and extracted with EA (3 × 200 mL). The combined organic layers were washed with water (200 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (40% EA in PE) to afford diethyl 2-acetamido-2-(but-3-enyl)malonate (4-2) (15.1 g, 75%) as a yellow oil. TLC: 40% EA/PE (v/v) (R f : 0.4); MS (ESI): calcd.: 271.1, Found: 272.1 [M + 1] + . [0183] Step 2. Synthesis o 2-aminohex-5-enoic acid (4-3). A mixture of diethyl 2- acetamido-2-(but-3-enyl)malonate (4-2) (15.1 g) was refluxed in 100 mL of 10 w% NaOH for 4 h. The solution was neutralized with 6N HCl and the solvent was evaporated. The residue was diluted with 100 mL of methanol and filtered. The filtrate was evaporated. The residue was added 100 mL of 1N HCl. The resulting mixture was refluxed for 3 h. The solvent was evaporated, and the residue was taken up in 150 mL of methanol and the mixture was stirred overnight at rt. The precipitate was filtered and dried in vacuo to afford 2- aminohex-5-enoic acid (4-3) (4.53 g, 63%) as a white solid. MS (ESI): calcd.: 129.0, Found: 130.2 [M+1] + . [0184] Step 3. Synthesis of 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4). A mixture of 2-aminohex-5-enoic acid (4-3) (4.53 g, 35 mmol), Et3N (10.5 g, 100 mmol), and Boc 2 O (21.8 g, 100 mmol) in MeOH (50 mL) was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and acidified with 1.5N HCl. The reaction mixture was extracted with EA (150 mL x 2). The combined organic layers were washed with ice-cold water (150 mL), brine (150 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated to afford 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4) (6.65 g.83%) as a white solid. MS (ESI): calcd.: 229.0, Found: 174 [M-56+1] + . [0185] Step 4. Synthesis of tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5). To a stirred solution of 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4) (6.55 g, 28.6 mmol) in DMF (50 mL) was added Et 3 N (5.78 g, 57.2 mmol) and T3P (50 w%, 43.5 g, 68.6 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then aniline (3.46 g, 37.2 mmol) was added. The reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (50 mL) and diluted with EA (200 mL). The organic layer was washed with ice-cold water (200 mL), brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to afford tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5) as a yellow solid (7.13 g, 82%) TLC: 5% MeOH/DCM (v/v) (R f : 0.4); MS (ESI): calcd.: 304.0, Found: 249.2 [M- 56+1] + . [0186] Step 5. Synthesis of 2-amino-N-phenylhex-5-enamide (4-6). To a solution of tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5) (7.13 g, 23.4 mmol) in DCM (50 mL) at 0 °C was added a solution of CF 3 COOH (14 mL). The reaction mixture was stirred for 3 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The residue was quenched with saturated NaHCO 3 solution. The aqueous layer was extracted with EA (200 mL x 2). The combined organic layers were washed brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentered to afford 2-amino-N-phenylhex-5-enamide (4-6) as a colorless gum (4.53 g, 95%). TLC: 40% EA/PE (v/v) (R f : 0.4); MS (ESI): calcd.: 204.0, Found: 204 [M + 1] + . [0187] Step 6. Synthesis of N1-phenylhex-5-ene-1,2-diamine (4-7). To a solution of 2- amino-N-phenylhex-5-enamide (4-6) (4.53 g, 22.2 mmol) in THF (50mL) at 0 °C was added LiAlH 4 (2M solution in THF, 55.5ml, 111 mmol). The reaction mixture was heated for 4 hours at 75 °C. The reaction mixture was cooled to 0 °C and quenched with methanol at 0 °C. The reaction mixture was concentrated under vacuum. The residue was partitioned between water (50 mL) and EA (50 mL). The aqueous laver was extracted with EA (250 mL x 2). The combined organic layers were washed with water (250 mL), brine (250 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was purified by column chromatography (10% MeOH in DCM) to afford N1-phenylhex-5-ene-1,2-diamine (4-7) as a yellow oil (3.92 g, 93%). TLC: 40% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 190.0, Found: 191.2 [M+1] + . [0188] Step 7. Synthesis of 4-dibromo-5-methoxy-N-(1-(phenylamino)hex-5-en-2- yl)benzenesulfonamide (4-8). To a stirred solution of N1-phenylhex-5-ene-1,2-diamine (4-7) (3.92 g, 20.6 mmol) in DCM (50 mL) and Et 3 N (5.2 g, 51.5 mmol) and 2,4-dibromo-5- methoxybenzenesulfonyl chloride (11.2 g, 30.9 mmol) were added and the reaction mixture was stirred for 2 hours at rt. After completion of the reaction (monitored by TLC), the organic part was filtered and concentrated under vacuum to afford 2,4-dibromo-5-methoxy-N-(1- (phenylamino)hex-5-en-2-yl)benzenesulfonamide (4-8) as a yellow solid (6.91 g, 65%). TLC: 20% EA/PE (v/v) (R f : 0.6); MS (ESI): calcd.: 515.9, Found: 517.1 [M+1] + . [0189] Step 8. Synthesis of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-9). To a solution of 2,4-dibromo-5- methoxy-N-(1-(phenylamino)hex-5-en-2-yl)benzenesulfonamide (4-8) (6.91 g, 13.4 mmol) in DMF (30 mL), K 2 CO 3 (3.6 g, 26.8 mmol) and CuI (255 mg, 1.34 mmol) were added. The reaction mixture was degassed for 5 minutes under N 2 atmosphere and TDA-1 (866 mg, 2.68 mmol) were added. The reaction mixture was heated for 16 hours at 130 °C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (25 mL). The aqueous layer was extracted with a 1:1 mixture of EA and PE (50 mL x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (15% EA in PE) to afford 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine (4-9) as a brown gum (3.0 g, 51%). TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 436.0, Found: 437.1 [M+1] + . [0190] Step 9. Synthesis of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10). To a stirred solution of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine (4-9) (3.0 g, 6.9 mmol) in NMP (10 mL), Cs 2 CO 3 (4.5 g, 13.8 mmol) was added at 0 °C and reaction mixture was stirred for 15 minutes. Methyl iodide (4.9 g, 34.5 mmol) was then added drop wise at 0 °C and the reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EA (100 mL) and the organic layer was washed with water (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was purified by column chromatography, eluting with 18% EA /PE (v/v) to afford 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl-2,3,4, 5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10) as a white solid (2.33 g, 75%). TLC: 20% EA/PE (v/v) (R f : 0.7); MS (ESI): calcd.: 450.0, Found: 451.1 [M+1] + . [0191] Step 10. Synthesis of 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11). To a solution of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl-2,3,4, 5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10) (2.33 g, 5.18 mmol) in DMF (10mL), CH 3 SNa (1.8 g, 25.9 mmol) was added and the reaction mixture was stirred for 6 hours at 80 °C. After completion of the reaction (monitored by TLC) the reaction mixture was quenched with ice water (30 ml) and the aqueous layer was extracted with EA (2 x 30 mL). The combined organic layers were washed with water (30mL), brine (30 m), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (35% EA in PE) to afford 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiad iazepine 1,1-dioxide (4-11) as a white solid (1.4 g, 68%). TLC: 20% EA/PE (v/v) (R f : 0.4); MS (ESI): calcd.: 404.0, Found: 405.1 [M+1] + . [0192] Step 11. Synthesis of (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadi azepin-8-yl)oxy)acrylate (4-12). A mixture of 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl -2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11) (1.4g, 3.46 mmol), DABCO (194 mg, 1.73 mmol), and tert-butyl propiolate (680 mg, 5.4mmol) in THF (5 mL) was stirred for 3 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layers were extracted with EA (20 mL x 2). The combined organic layers were washed with water (10 mL x 2), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (12% EA/PE (v/v)) to afford the title compound (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl- 7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[ f][1,2,5]thiadiazepin-8- yl)oxy)acrylate (4-12) as a white solid (1.6 g, 89%). TLC: 10% EA/PE (v/v) (R f : 0.4); MS (ESI): calcd.: 530.2, Found: 531.1 [M+1] + . [0193] Step 12. Synthesis of (E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)acrylic acid (Example 4). A mixture of (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)- 1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)acrylate (4-12) (160 mg, 0.3 mmol) and TFA (0.4 mL) in DCM (5 mL) stirred for 3 h at rt. The reaction mixture was quenched with H 2 O (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford (E)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4) (75 mg, 53%) as a white solid. TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.72 (d, J = 12 Hz, 1H), 7.47 (s, 1H), 7.18 (t, J = 7.2 Hz, 3H), 6.75 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 5.87-5.80 (m, 1H), 5.54 (d, J = 12 Hz, 1H), 5.10 (d, J = 16 Hz, 1H), 5.00 (d, J = 8.4 Hz, 1H), 4.08 (d, J = 16 Hz, 1H), 3.86 (brs, 1H), 3.41-3.32 (m, 1H), 2.51-2.49 (m, 3H), 2.40 (s, 3H), 2.20-2.09 (m, 2H), 1.74-1.59 (m, 2H) ppm. [0194] Step 13. Synthesis of (S,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)acrylic acid (Example 4a) and (R,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido-5- phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4b). Racemic Example 4 (75 mg) was separated by SFC to afford: (S,E)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4a) (11 mg, 7.7%) as a white solid. TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 12 Hz, 1H), 7.60 (s, 1H), 7.29 (s, 2H), 6.95-6.91 (m, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.87-5.77 (m, 1H), 5.60 (d, J = 12 Hz, 1H), 5.08 (d, J = 16 Hz, 1H), 5.02 (d, J = 9.6 Hz, 1H), 4.05 (d, J = 17.2 Hz, 1H), 3.87 (brs, 1H), 3.60-3.47 (m, 1H), 2.68 (s, 3H), 2.29 (s, 3H), 1.82- 1.74 (m, 2H) , 1.62-1.52 (m, 2H) ppm and (R,E)-3-((3-(but-3-en-1-yl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4b) (16 mg, 11.3%) as a white solid. TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.78 (d, J = 12 Hz, 1H), 7.60 (s, 1H), 7.29 (s, 2H), 6.95-6.91 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.87-5.77 (m, 1H), 5.60 (d, J = 12 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 5.03 (d, J = 12 Hz, 1H), 4.05 (d, J = 14.4 Hz, 1H), 3.95-3.84 (m, 1H), 3.60-3.46 (m, 1H), 3.09-3.02 (m,1H), 2.68 (s, 3H), 2.29 (s, 3H), 1.84-1.71 (m, 2H) , 1.62-1.47 (m, 2H) ppm. [0195] Example 5, 5a and 5b. (Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 5), (S,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylic acid (Example 5a), and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry lic acid (Example 5b) [0196] Step 1. Synthesis of (Z)-ethyl 3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadi azepin-8-yl)oxy)-2- fluoroacrylate (5-1). Into an 8 mL vial purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-bromo-2, 2-difluoropropanoate (540 mg, 2.5 mmol), anhydrous DMA (5 mL), and NaH (100 mg, 2.5 mmol) at 60 °C. After completion of the reaction (monitored by GCMS), 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl - 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11) (202 mg, 0.5 mmol) and CS 2 CO 3 (652 mg, 2 mmol) was added into the vial. The resulting mixture was stirred for 3 h at 60 °C. The reaction mixture was then cooled to 0 °C and quenched with aqueous NH 4 Cl. The resulting mixture was extracted with EA (50 mL x3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (1/5) (v/v) to afford (Z)-ethyl 3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylate (5-1) (180 mg, 69%) as a light yellow solid. TLC: 10% EA/PE (v/v) (R f : 0.4); MS (ESI): calcd.:520.2, Found: 521.1 [M + 1] + . [0197] Step 2. Synthesis of (Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 5). Into a 50-mL round-bottom flask, was placed (Z)-ethyl 3-((3-(but-3-en-1- yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry late (5-1) (180 mg, 0.35 mmol), dioxane (12 mL) and H 2 O (4 mL). The reaction mixture was cooled to 0 °C. Then the LiOH (40 mg, 1.0 mmol) was placed into the flask. The resulting solution was stirred for 6 h at rt. The resulting solution was quenched with H 2 O (20 mL) and acidified with aqueous NaHSO 4 solution to pH = 5. The resulting solution was extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford (Z)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 5) (95 mg, 55%) as a white solid. TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 492.1, Found: 493.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.53 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.78 (t, J = 7.6 Hz, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.81-5.74 (m, 1H), 5.04 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10 Hz, 1H), 3.93-3.90 (m, 1H), 3.34-3.26 (m, 1H), 2.54 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H), 2.18-2.10 (m, 2H), 1.71-1.58 (m, 1H) , 1.54-1.48 (m, 1H) ppm. [0198] Step 3. Synthesis of (S,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 5a) and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl) oxy)-2-fluoroacrylic acid (Example 5b): Racemic Example 5 (95 mg) was separated by SFC to afford (S,Z)-3-((3- (but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl -2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry lic acid (Example 5a) (32 mg, 19%) as a white solid, TLC: 20% EA/PE (v/v) (R f : 0.5); MS (ESI): calcd.: 492.1, Found: 493.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.60 (s, 1H), 7.35 (d, J = 17.2 Hz, 1H), 7.23 (t, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.86-5.76 (m, 1H), 5.07 (d, J = 17.2 Hz, 1H), 5.01 (d, J = 10 Hz, 1H), 4.03-3.96 (m, 1H), 3.94-3.84 (m, 1H), 3.52-3.39 (m, 1H), 2.64 (s, 3H), 2.28 (s, 3H), 2.25-2.13 (m, 2H), 1.77-1.71 (m, 1H), 1.60-1.52 (m, 1H) ppm and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-diox ido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl) oxy)-2-fluoroacrylic acid (Example 5b) (26 mg, 15%) as a white solid, TLC: 20% EA/PE (v/v) (R f : 0.5); MS Calcd.: 492.1, Found: 493.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.56 (s, 1H), 7.40 (d, J = 17.2 Hz, 1H), 7.20 (t, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (t, J = 6.8 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.84-5.77 (m, 1H), 5.07 (d, J = 17.2 Hz, 1H), 5.01 (d, J = 10 Hz, 1H), 4.03-3.96 (m, 1H), 3.94-3.84 (m, 1H), 3.52-3.39 (m, 1H), 2.61 (s, 3H), 2.26 (s, 3H), 2.21-2.13 (m, 2H), 1.80-1.64 (m, 1H) , 1.60-1.49 (m, 1H) ppm. [0199] Examples 6 and 7. (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl - 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylamide (Example 6) and (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl -2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry lonitrile (Example 7)
[0200] Step 1. Synthesis of 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2). То а solution of 2-aminohexanoic acid (6-1) (25 g, 0.19 mol) in water (250 mL) and THF (250 mL), NаНСО 3 (48 g, 0.57 mol) and Boc 2 O (52.2 ml, 0.23 mol) were added. The reaction mixture was stirred for 16 h at rt. After completion of the reaction, the reaction was acidified using NaHSO 4 . The reaction mixture was extracted with EtOAc (150 mL x 2). The combined organic layer was washed with ice-cold water (150 mL) and brine (150 mL), dried over anhydrous Na 2 SO 4 , and concentrated to afford 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2) (42 g, 95%). [0201] Step 2. Synthesis of tert-butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (6- 3). A solution of 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2) (5 g, 0.02 mol) in CH 2 Cl 2 (150 mL) was cooled and then added EDC·HCl (5g, 26 mmol), HOBt (7.2 g, 22 mmol), and TEA (5 g, 50 mmol). The mixture was stirred for 1 h. Then aniline (1.86 g, 20 mmol) was added. The resulting mixture was stirred at rt overnight. The organic layer was washed with water and concentrated to afford tert-butyl (1-oxo-1-(phenylamino)hexan-2- yl)carbamate (6-3) (6 g, 90%). [0202] Step 3. Synthesis of 2-Amino-N-phenylhexanamide (6-4). To а solution of tert- butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (6-3) (6 g, 19.6 mol) in 1,4-dioxane (500 mL) at 0 °C was added а solution of HCl in 1,4-dioxane (4 М, 199 mL). The reaction mixture was stirred for 16 h at rt. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was basified with saturated NаНСО 3 solution. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layer was washed brine (200 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to afford 2-Amino-N-phenylhexanamide (6-4) (3.8 g, 95%). [0203] Step 4. Synthesis of Nl-Phenylhexane-1,2-diamine (6-5). То а solution of 2- amino-N-phenylhexanamide (6-4) (10 g, 0.05 mol) in THF (320 mL) at 0 °C was added borane dimethylsulfide (2М solution in THF, 117 ml, 0.23 mol). The reaction mixture was heated at 75 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with methanol (150 mL) and then stirred for 30 min at rt. The reaction mixture was concentrated under vacuum. To the resulting crude material was added solution of HCl (3 М, 100 mL). The obtained residue was quenched with saturated NаOН solution. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layer was washed brine (200 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to afford Nl-Phenylhexane-1,2-diamine (6-5) (8 g, 85%). [0204] Step 5. Synthesis of 2,4-Dibromo-5-methoxy-N-1-{phenylamino)hexan-2- yl)benzenesulfonamide (6-6). То а solution of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (52 g, 0.14 mol) in THF (500 mL) at 0 °C were added N 1 -phenylhexane-1,2-diamine (6-5) (21 g, 0.11 mol) and triethylamine (45.5 ml, 0.33 mol). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated under vacuum and the obtained residue was dissolved in EtOAc (400 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum to afford 2,4-Dibromo-5-methoxy-N-1-{phenylamino)hexan-2- yl)benzenesulfonamide (6-6) (65 g, 65%). [0205] Step 6. Synthesis of 7-Bromo-З-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine 1,1-dioxide (6-7). То а solution of 2,4-dibromo-5-methoxy-N-(1- (phenylamino)hexan-2-yl)benzenesulfonamide (6-6) (65 g, 0.11 mol) in DMF (200 mL), К 2 СO 3 (58 g, 0.42 mol) and copper powder (14.1 g, 0.22 mol) were added. The reaction mixture was degassed for 5 minutes under N 2 atmosphere, and the reaction mixture was then heated at 115 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (500 mL). The aqueous layer was extracted with MTBE (250 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum. The residue was purified by column chromatography to afford 7-Bromo-З-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5 - benzothiadiazepine 1,1-dioxide (6-7) (20 g, 43%). MS (ESI): calcd.: 440.0, 441.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.60 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.20 – 7.11 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.1 Hz, 2H), 4.34 (d, J = 15.5 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 2.86 (s, 1H), 1.57 (s, 1H), 1.49 – 1.24 (m, 5H), 0.89 (td, J = 7.2, 2.0 Hz, 3H) ppm. [0206] Step 7. Synthesis of 7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (6-8). То а stirred solution of 7-bromo-3- butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothia- diazepine 1,1-dioxide (6-7) (10 g, 22.75 mmol) in DMFA (50 mL) were added Сs 2 СO 3 (14.75 g, 45.67 mmol) and then iodomethane (7.1 ml, 0.11 mol). The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and the aqueous layer was extracted with MTBE (150 mL x 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na 2 SO 4 and concentrated under vacuum to afford 7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahyd ro-1,2,5- benzothiadiazepine 1,1-dioxide (6-8) (7 g, 68%). MS (ESI): calcd.: 452.0, Found 453.0 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.51 (d, J = 2.2 Hz, 2H), 7.20 (t, J = 7.9 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 2H), 4.08 (d, J = 16.0 Hz, 1H), 3.99 (s, 4H), 3.26 (s, 1H), 2.59 (s, 3H), 1.61 (d, J = 8.2 Hz, 2H), 1.53 – 1.34 (m, 4H), 0.97 (t, J = 6.5 Hz, 3H) ppm. [0207] Step 8. Synthesis of 3-Butyl-8-hydroxy-2-methyl-7-{methylthio)-5-phenyl- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (6-9). To a mixture of NaH (1.6 g, 33.3 mmol) in DMF (20 mL) was bubbled CH 3 SH (5 eq). This mixture added tо а solution of 7 -bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydr o-1,2,5-benzothia- diazepine 1,1-dioxide (6-8) (3 g, 6.61 mmol) in DMF (50 mL). The reaction mixture was heated at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL) and dried over anhydrous Na 2 SO 4 . The organic part was concentrated under vacuum to afford 3- butyl-8-hydroxy-2-methyl-7-{methylthio)-5-phenyl-2,3,4,5-tet rahydro-1,2,5- benzothiadiazepine 1,1-dioxide (6-9) (2.3 g, 77%). MS (ESI): calcd.: 406.0, Found 407.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.75 (s, 1H), 7.27 (s, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.98 (s, 1H), 6.66 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 2H), 3.97 (d, J = 16.1 Hz, 1H), 3.89 (s, 1H), 3.17 (s, 1H), 2.41 (s, 3H), 2.33 (s, 3H), 1.66 – 1.55 (m, 1H), 1.48 (s, 1H), 1.34 (q, J = 7.7, 7.2 Hz, 4H), 1.00 – 0.81 (m, 3H) ppm. [0208] Step 9. Synthesis of ethyl (2Z)-3-[3-butyl-2-methyl-7-(methylsulfanyl)-1,1- dioxo-5-phenyl-2,3,4,5-tetrahydro-1-lambda-6,2,5-benzothiadi azepin-8-yl]oxy)-2- fluoroprop-2-enoate (6-10). To a stirred mixture of 3-butyl-8-hydroxy-2-methyl-7- (methylthio)-5)phenyl-2,3,4,5_tetrahydro-1,2,5-benzothiadiaz epine 1,1-dioxide (6-9) (1 g, 2.46 mmol) in DMA (15ml) at 0 °C, NaH (50%, 0.35 g, 7.38mmol) was added portion wise. The reaction mixture was stirred for 30 min. at 0 °C. A solution of 3-bromo-2,2- difluoropropanoate (1.2 g, 5.56mmol) in DMA (5ml) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 2N HCl to pH ~ 3. The aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 . The organic part was concentrated under vacuum. The residue was purified by HPLC to afford ethyl (2Z)-3-[3-butyl-2-methyl-7-(methylsulfanyl)-1,1-dioxo-5-phen yl- 2,3,4,5-tetrahydro-1-lambda-6,2,5-benzothiadiazepin-8-yl]oxy )-2-fluoroprop-2-enoate (6-10) (0.22 g, 17%). MS (ESI): calcd.: 522.2, Found 523.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 CN): δ 7.63 (s, 1H), 7.53 (d, J = 18.1 Hz, 1H), 7.29 – 7.17 (m, 3H), 6.82 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.12 – 3.93 (m, 2H), 3.27 (t, J = 13.1 Hz, 1H), 2.54 (d, J = 5.0 Hz, 3H), 2.43 (s, 3H), 1.62 (d, J = 8.8 Hz, 2H), 1.44 (dq, J = 17.2, 6.8 Hz, 4H), 1.35 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0209] Step 10. Synthesis (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)-2-fluoroacrylic acid (6- 11). То а stirred solution of ethyl (Z}-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)- 2-fluoroacrylate (6-10) (180 mg, 0.35 mmol) in 1, 4-dioxane/water (4/1, 5 mL), lithium hydroxide (4 mg, 0.95 mmol) was added. The reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction mixture was acidified with 1.5 N aq. HCl solution to рН ~ 4. The aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with water (5 mL) and brine solution (5 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylic acid (6-11) (60 mg, 35%). MS (ESI): calcd.: 494.2, Found 493.2 [M-1]-; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.33 (s, 1H), 7.15 (dd, J = 13.5, 6.0 Hz, 3H), 6.99 (d, J = 18.2 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 8.1 Hz, 2H), 4.03 (d, J = 16.0 Hz, 1H), 3.87 (s, 1H), 2.39 (s, 3H), 1.55 (d, J = 44.6 Hz, 2H), 1.35 (s, 4H), 0.92 (d, J = 7.1 Hz, 3H) ppm. [0210] Step 11. Synthesis of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)-2-fluoroacrylamide (Example 6): To a stirring suspension of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (6-11) (90 mg, 181.97 µmol), ammonium chloride (19.46 mg, 363.85 µmol), and DIPEA (141.07 mg, 1.09 mmol) in anhydrous DMF (2 mL) HATU (89.92 mg, 236.5 µmol) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under educed pressure. The residue was purified by HPLC to afford (Z)-3-((3- butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry lamide (Example 6) (36 mg, 40%). MS (ESI): calcd.: 493.1, Found: 492.0 [M-1]-; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.90 (s, 1H), 7.65 (s, 1H), 7.63 – 7.51 (m, 2H), 7.23 – 7.11 (m, 3H), 6.74 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 8.1 Hz, 2H), 4.05 (d, J = 16.0 Hz, 1H), 3.86 (s, 1H), 2.41 (s, 3H), 1.61 (d, J = 7.2 Hz, 1H), 1.51 (s, 1H), 1.35 (s, 4H), 0.92 (d, J = 6.9 Hz, 3H) ppm. [0211] Step 12. Synthesis of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)-2-fluoroacrylonitrile (Example 7): A mixture of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl - 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylamide (Example 6) (36 mg, 0.072 mmol) and DIPEA (28.29 mg, 0.219 mmol) was dissolved in CH 2 Cl 2 (2 mL) at 0 °C. Trifluoroacetyl 2,2,2-trifluoroacetate (19.92 mg, 0.095 mmol) was then added. The resulting mixture was stirred at rt overnight and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl - 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylonitrile (Example 7) (19.7 mg, 57%). MS (ESI): calcd.: 475.1, Found: 476.2 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.19 (d, J = 19.9 Hz, 1H), 7.76 (d, J = 2.9 Hz, 1H), 7.18 (q, J = 7.6, 5.7 Hz, 3H), 6.75 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.06 (d, J = 16.2 Hz, 1H), 3.85 (s, 1H), 2.56 (d, J = 16.3 Hz, 3H), 2.41 (s, 3H), 1.62 (s, 1H), 1.52 (s, 1H), 1.35 (s, 4H), 0.92 (d, J = 6.9 Hz, 3H) ppm. [0212] Example 8. (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1-dioxido -5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylic acid
[0213] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2- fluoroacrylate (7-2). To a stirred solution of 3-butyl-2-(2-fluoroethyl)-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiad iazepine 1,1-dioxide (7-1) (100 mg, 0.24 mmol) in DMA (5mL) at 0 °C, NaH (50%, 35 mg, 0.73 mmol) was added portion wise and the reaction mixture was stirred for 30 min at 0 °C. A solution of 3-bromo-2,2- difluoropropanoate (0.12 g, 0.55 mmol) in DMA (2 mL) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 2N HCl to pH ~ 3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by HPLC to afford ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylate (7-2) (38 mg, 30%). MS (ESI): calcd. for C 26 H 32 F 2 N 2 O 5 S 2 : 554.1, Found: 555.2 [M+1] + ; 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.78 (d, J = 18.6 Hz, 1H), 7.57 (s, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.05 (s, 1H), 6.86 – 6.68 (m, 3H), 4.50 (dq, J = 9.6, 5.5, 4.8 Hz, 1H), 4.43 (dt, J = 9.5, 5.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 3.71 (s, 2H), 2.97 (s, 2H), 2.52 (s, 1H), 2.33 (s, 3H), 1.64 (s, 1H), 1.57 (d, J = 7.5 Hz, 1H), 1.40 (dd, J = 14.7, 7.5 Hz, 2H), 1.29 (s, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H) ppm. [0214] Step 2. Synthesis of (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylic acid (Example 8). То а stirred solution of ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (7-2) (30 mg, 0.058 mmol) in 1, 4-dioxane/ water (4/1, 5 mL), lithium hydroxide (1 mg, 0.25 mmol) was added and the reaction mixture was stirred 2 h at rt. After completion of the reaction, the reaction mixture was acidified with 1.5 N aq. HCl solution to рН ~ 4. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl- 2-(2-fluoroethyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4, 5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry lic acid (Example 8) (14 mg, 50%). MS (ESI): calcd. for C 24 H 28 F 2 N 2 O 5 S 2 : 526.1, Found: 525.2 [M −1] − ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.71 (s, 1H), 7.74 (d, J = 18.5 Hz, 1H), 7.55 (s, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.07 (s, 1H), 6.80 (d, J = 8.9 Hz, 3H), 4.54 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 3.72 (s, 1H), 3.02 (s, 2H), 2.35 (s, 4H), 1.73 – 1.52 (m, 2H), 1.41 (d, J = 7.4 Hz, 2H), 1.29 (s, 2H), 0.88 (t, J = 7.4 Hz, 3H) ppm. [0215] Example 9. (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1-yl)oxy)-2-meth yl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiad iazepine 1,1-dioxide [0216] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl) oxy)-2-fluoroacrylate (8-2). To a reactor containing a solution of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (8-1) (250.0 mg, 614.91 µmol) in DMA (3mL) at 0 °C was added sodium hydride (73.69 mg, 3.07 mmol). The mixture was stirred for 10 minutes. After that, the reaction mixture was cooled to -30 °C and ethyl 3- bromo-2,2-difluoropropanoate (533.13 mg, 2.46 mmol) was added. The resulting mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by HPLC to afford ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl -2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry late (8-2) (151 mg, 47%). [0217] Step 2: Synthesis of (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1-yl)oxy)-2- methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1, 2,5]thiadiazepine 1,1- dioxide (Example 9). To a solution of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylate (8-2) (75.0 mg, 143.5 µmol) in DCM (2 mL) at -78 °C was added diisobutylaluminum hydride (61.25 mg, 430.7 µmol) dropwise. The resulting mixture was stirred at -78 °C for 30 minutes. The reaction was then quenched with water at rt and concentrated in vacuo. The residue was purified by HPLC to afford (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1- yl)oxy)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrob enzo[f][1,2,5]thiadiazepine 1,1-dioxide (Example 9) (15.8 mg, 22%). MS (ESI): calcd.: 480.62, Found: 481.0 [M+1] + ; 1 H NMR (400 MHz, CD 3 CN): δ 7.52 (s, 1H), 7.26 - 7.17 (m, 3H), 6.79 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 20.4 Hz, 1H), 4.19 (s, 1H), 4.14 (s, 1H), 4.03 (d, J = 15.7 Hz, 2H), 3.24 (s, 1H), 2.51 (s, 3H), 2.42 (s, 3H), 1.67 – 1.57 (m, 2H), 1.42 (dq, J = 14.2, 9.0, 7.5 Hz, 4H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0218] Example 10. (E)-(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-pheny l- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)vinyl )phosphonic acid
[0219] Step 1. Synthesis of diethyl ethynylphosphonate (9-2). Ethynylmagnesium bromide (0.5 M in THF, 37.67 mmol, 75.34 mL) was added dropwise to a solution diethyl phosphorochloridate (9-1) (6.5 g, 37.67 mmol) in anhydrous THF (75 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. the reaction mixture was quenched with saturated NH 4 Cl (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with H 2 O (100 mL), brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford diethyl ethynylphosphonate (9-2) (150 mg, 2.5%). MS (ESI): calcd.: 162.0, Found: 163.0 [M+1] + . [0220] Step 2. Synthesis of (E)-diethyl (2-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8- yl)oxy)vinyl)phosphonate (9-3). To a solution of 3-Butyl-8-hydroxy-2-methyl-7- {methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiaz epine 1,1-dioxide (90 mg, 221.37 µmol) and diethyl ethynylphosphonate (9-2) (108 mg, 664.69 µmol) in THF (2 mL) was added DABCO (4.97 mg, 44.31 µmol). The reaction mixture was stirred at rt overnight. Then the mixture was diluted with Н 2 O (10 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na 2 SO 4 , filtered, and evaporated in vacuo. The residue was purified with prep-HPLC to afford (E)-diethyl (2-((3-butyl-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)vinyl)phosphonate (9-3) (75 mg, 60%). MS (ESI): calcd.: 568.2, Found: 569.0 [M+1] + ; 1 H NMR (400 MHz, CD 3 CN): δ 7.57 (s, 1H), 7.36 (dd, J = 13.2, 10.5 Hz, 1H), 7.30 – 7.17 (m, 3H), 6.83 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H), 5.24 (dd, J = 13.2, 9.3 Hz, 1H), 4.18 – 3.93 (m, 6H), 3.28 (d, J = 26.8 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H), 1.62 (q, J = 7.5, 6.9 Hz, 2H), 1.54 – 1.36 (m, 4H), 1.38 – 1.20 (m, 6H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0221] Step 3. Synthesis of (E)-(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)vinyl)phosphonic acid (Example 10). To a solution of (E)-diethyl(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl) oxy)vinyl)phosphonate (9-3) (30.0 mg, 52.75 µmol), pyridine (526.75 µmol, 40 µl) in anhydrous DCM (2 mL) was added TMSBr (1.05 mmol, 140.0 µl). The reaction mixture was stirred at rt overnight. After completion of the reaction (monitored by LCMS), the mixture was poured into water (10 mL). The resulting solution was acidified with 5 N aq. HCl solution to pH ~ 2 and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified with prep-HPLC to afford (E)-(2-((3-butyl-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepin-8- yl)oxy)vinyl)phosphonic acid (Example 10) (20.5 mg, 76%). MS (ESI): calcd.: 512.1, Found: 511.0 [M−1] − ; 1 H NMR (400 MHz, CD 3 CN): δ 7.52 (s, 1H), 7.28 (s, 1H), 7.18 (dd, J = 13.7, 5.5 Hz, 3H), 6.78 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.0 Hz, 2H), 5.42 (s, 1H), 3.99 (d, J = 17.7 Hz, 2H), 3.22 (s, 1H), 2.54 (d, J = 10.1 Hz, 3H), 2.35 (s, 3H), 1.56 (s, 2H), 1.38 (d, J = 23.2 Hz, 4H), 0.94 (t, J = 7.0 Hz, 3H) ppm. [0222] Example 11, 11a and 11b. (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11), (S,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11a), and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b) [0223] Step 1. Synthesis of ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2). A solution of ethyl 2-[(diphenylmethylidene)amino]acetate (10-1) (30 g, 112.22 mmol), K 2 CO 3 (46.53 g, 336.66 mmol), 1-bromo-4-fluorobutane (34.79 g, 224.44 mmol), and tetrabutylammonium bromide (7.24 g, 22.44 mmol) in CH 3 CN (500 mL) was stirred for 72 h at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/THF (1/1) (v/v) to afford ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2) (30 g, 78%) as a brown oil. MS (ESI): calcd. for C 21 H 24 FNO 2 : 341.1, Found: 342.1 [M+1] + . [0224] Step 2. Synthesis of 2-[(diphenylmethylidene)amino]-6-fluorohexanoic acid (10- 3). A mixture of ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2) (30 g, 87.87 mmol) and NaOH (5.27 g, 131.80 mmol) in methanol (300 mL) and water (75 mL) was stirred for 5 h at 50 °C. The mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL). The aqueous layer was acidified with 0.5 M aq. HCl solution to pH = 6 and then extracted with CH 2 Cl 2 (100 mL x 3). The combined organic layers were concentrated under reduced pressure to afford 2-[(diphenylmethylidene)amino]- 6-fluorohexanoic acid (10-3) (15 g, 54%) as a yellow oil. MS calcd. for C 19 H 20 FNO 2 : 313.1, Found: 314.1 [M+1] + . [0225] Step 3. Synthesis of 2-[(diphenylmethylidene)amino]-6-fluoro-N- phenylhexanamide (10-4). A solution of 2-[(diphenylmethylidene)amino]-6-fluorohexanoic acid (10-3) (14 g, 44.68 mmol), aniline (4.99 g, 53.61 mmol), T3P (28.43 g, 89.35 mmol) and TEA (13.56 g, 134.03 mmol) in CH 3 CN (300 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) (v/v) to afford 2- [(diphenylmethylidene)amino]-6-fluoro-N-phenylhexanamide (10-4) (14 g, 81%) as a yellow oil. MS (ESI): calcd. for C 25 H 25 FN 2 O: 388.2, Found: 389.2 [M+1] + . [0226] Step 4. Synthesis of 2-amino-6-fluoro-N-phenylhexanamide (10-5). A solution of 2-[(diphenylmethylidene)amino]-6-fluoro-N-phenylhexanamide (10-4) (14 g, 36.04 mmol) in 4N HCl/methanol (70 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (100 mL x 3), basified with sodium bicarbonate solution (100 mL), and extracted with EtOAc (100 mL x 3). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/10) (v/v) to afford 2-amino-6-fluoro-N-phenylhexanamide (10-5) (4.5 g, 56%) as a yellow solid. MS (ESI): calcd. for C12H17FN 2 O: 224.1, Found: 225.1 [M+1] + . Step 5. Synthesis of 6-fluoro-N1-phenylhexane-1,2-diamine (10-6). A solution of 2-amino- 6-fluoro-N-phenylhexanamide (10-5) (4 g, 17.84 mmol) and BH 3 -Me 2 S (2.72 mL, 28.71 mmol) in THF (100 mL) was stirred for 16 h at 75 °C under nitrogen atmosphere. The reaction was quenched with MeOH (100 mL). The resulting mixture was stirred for 1 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 6-fluoro-N1-phenylhexane-1,2-diamine (10-6) (2 g, 53%) as a yellow oil. MS (ESI): calcd. for C 12 H 19 FN 2 : 210.2, Found: 211.2 [M+1] + . [0227] Step 6. Synthesis of 2,4-dibromo-N-[6-fluoro-1-(phenylamino)hexan-2-yl]-5- methoxybenzenesulfonamide (10-7). A solution of 6-fluoro-N1-phenylhexane-1,2-diamine (10-6) (2 g, 9.51 mmol), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (3.81 g, 10.46 mmol), and TEA (3.85 g, 38.04 mmol) in THF (40 mL) was stirred for 4 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 2,4-dibromo-N-[6-fluoro-1- (phenylamino)hexan-2-yl]-5-methoxybenzenesulfonamide (10-7) (2.1 g, 41%) as a white solid. MS (ESI): calcd. for C 19 H 23 Br 2 FN 2 O 3 S: 536.0, Found: 537.0 [M+1] +. [0228] Step 7. Synthesis of 7-bromo-3-(4-fluorobutyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-8). A solution of 2,4-dibromo-N- [6-fluoro-1-(phenylamino)hexan-2-yl]-5-methoxybenzenesulfona mide (10-7) (2.1 g, 3.90 mmol), K 2 CO 3 (2 g, 14.47 mmol), TMEDA (100 mg, 0.86 mmol), and CuI (2 g, 10.50 mmol) in dioxane (40 mL) was stirred for 4 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) (v/v) to afford 7-bromo-3-(4-fluorobutyl)- 8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiaz epine 1,1-dioxide (10-8) (1.1 g, 62%) as a yellow oil. MS (ESI): calcd. for C 19 H 22 BrFN 2 O 3 S: 456.1, Found: 457.1 [M+1] + . [0229] Step 8. Synthesis of 7-bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9). A solution of 7-bromo- 3-(4-fluorobutyl)-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo [f][1,2,5]thiadiazepine 1,1- dioxide (10-8) (1.1 g, 2.41 mmol), Cs 2 CO 3 (1.57 g, 4.81 mmol), and MeI (0.51 g, 3.61 mmol) in DMF (30 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 7- bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9) (1.3 g, 90%) as a brown solid. MS (ESI): calcd. for C 20 H 24 BrFN 2 O 3 S: 470.1, Found: 471.1[M+1] + . [0230] Step 9. Synthesis of 3-(4-fluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10). A solution of 7-bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4, 5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9) (1.25 g, 2.65 mmol) and MeSNa (557.50 mg, 7.96 mmol) in DMF (20 mL) was stirred for 2 h at 80 °C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 3-(4-fluorobutyl)- 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10) (800 mg, 71%) as a brown yellow oil. MS (ESI): calcd. for C 20 H 25 FN 2 O 3 S 2 : 424.1, Found: 425.1 [M+1] + . [0231] Step 10. Synthesis of ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylate (10-11). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (92.01 mg, 0.42 mmol) in DMA (5 mL) was added sodium hydride (28.26 mg, 0.71 mmol) at 0 °C. The mixture was stirred at for 1 h.3-(4-fluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10) (60 mg, 0.14 mmol) in DMA (5 mL) was added. The resulting mixture was stirred for 3 h at 70 °C. The mixture was acidified with 1N HCl to pH = 1. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 2/1 (v/v) to afford ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7-(methylthio)-1 ,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)acrylate (10-11) (40 mg, 52%) as a brown solid. MS (ESI): calcd. for C 25 H 30 F 2 N 2 O 5 S 2 : 540.2, Found: 541.2 [M+1] + . [0232] Step 11. Synthesis of (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11). A mixture of ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylate (10-11) (40 mg, 0.07 mmol) and LiOH (3.66 mg, 0.15 mmol) in dioxane/H 2 O (4 mL/1 mL) was stirred at rt for 3 h. The mixture was acidified with 2N HCl to pH = 4. The resulting mixture was extracted with EA (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19 x 150mm; mobile phase, Water (0.05% FA) and ACN (45% PhaseB up to 75% in 8 min); Detector, UV 254 nm) to afford (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7-(methylthio)-1 ,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)ox y)acrylic acid (Example 11) (12 mg, 32%) as a white solid. MS (ESI): calcd. for C 23 H 26 F 2 N 2 O 5 S 2 : 512.2, Found: 513.2 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6, ): δ 7.66 (d, J = 18.0 Hz, 1H), 7.53 (s, 1H), 7.23-7.12 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.05 (d, J = 15.9 Hz, 1H), 3.88-3.86 (m, 1H), 3.31-3.21 (m, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 1.97-1.30 (m, 6H) ppm. [0233] Step 12. Synthesis of (S,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11a) and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b): Racemic (Example 11) (30 mg) was purified by Chiral- HPLC using the following conditions: column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; M obile Phase A: Hex (0.1% TFA), M obile Phase B: CAN (0.1% isopropyl amine); Flow rate: 35 mL/min; Gradient: 50% B to 50% B in 12 min to afford (S,Z)-2-fluoro-3-((3-(4- fluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2, 3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 11a) (13.1 mg, 48%) as a white solid. MS (ESI): calcd. for C 23 H 26 F 2 N 2 O 5 S 2 : 512.2, Found: 513.2 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 , ): δ 7.66 (d, J = 18.6 Hz, 1H), 7.54 (s, 1H), 7.35-7.12 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.06 (d, J = 15.3 Hz, 1H), 3.88-3.86 (m, 1H), 3.29-3.24 (m, 1H), 2.50 (s, 3H), 2.41 (s,3H), 1.78-1.37 (m, 6H) ppm and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f] [1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b) (14.1 mg, 49%) as a white solid. MS (ESI): calcd. for C 23 H 26 F 2 N 2 O 5 S 2 : 512.2, Found: 513.2 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.66 (d, J =19.2 Hz, 1H), 7.53 (s, 1H), 7.20-7.15 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.88-3.86 (m, 1H), 3.32 (s, 1H), 2.50 (s, 3H), 2.41 (s, 3H), 1.75-1.44 (m, 6H) ppm. [0234] Example 12. Synthesis of (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid [0235] Step 1. Synthesis of 2-{[(2-amino-5-methoxyphenyl) sulfanyl] methyl} hexanoic acid (11-2). Into a 500 mL round-bottom flask were added 2-amino-6-methoxybenzothiazole (11-1) (28.1 g, 155.91 mmol), ethylene glycol (140 mL), and 50% aqueous KOH (150 mL) at 0 °C. The resulting mixture was stirred for 16 h at 120 °C under nitrogen atmosphere. The mixture was cooled down to rt. The resulting mixture was added 2-(bromomethyl) hexanoic acid (27.17 g, 129.92 mmol) in 50 mL THF. The resulting mixture was stirred for 3 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The mixture was acidified with 4 N aq. HCl solution to pH 2. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) (v/v) to afford 2-{[(2-amino-5-methoxyphenyl) sulfanyl] methyl} hexanoic acid (11-2) (21.6 g, 59%) as a yellow solid. MS (ESI): calcd. for C 14 H 21 NO 3 S: 283.1, Found: 284.1 [M+1] + ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.09 – 6.99 (m, 1H), 6.87 – 6.74 (m, 2H), 3.77 (s, 3H), 3.09 – 3.01 (m, 1H), 2.96 – 2.88 (m, 1H), 2.65 – 2.49 (m, 1H), 1.74 – 1.57 (m, 1H), 1.38 – 1.23 (m, 5H), 0.94 – 0.83 (m, 3H) ppm. [0236] Step 2. Synthesis of 3-butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4- one (11-3). Into a 1000 mL 3-necked round-bottom flask were added 2-{[(2-amino-5- methoxyphenyl) sulfanyl] methyl}hexanoic acid (11-2) (21.6 g, 76.22 mmol) and DCM (400 mL) at rt. To a stirred solution was added HATU (34.78 g, 91.464 mmol) batchwise under nitrogen atmosphere. The resulting mixture was stirred for 10 min at rt. To the above mixture was added DIPEA (11.82 g, 91.464 mmol) dropwise. The resulting mixture was stirred for 4 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (100 mL) at 0 °C. The resulting mixture was extracted with DCM (400 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) to afford 3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-3) (17.9 g, 89%) as a yellow solid. MS (ESI): calcd. for C 14 H 19 NO 2 S: 265.1, Found: 266.1 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ): δ 7.31 (s, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.7, 3.2 Hz, 1H), 3.83 (s, 3H), 3.53 – 3.48 (m, 1H), 3.02 - 2.94 (m, 1H), 2.66 – 2.57 (m, 1H), 1.97 – 1.85 (m, 1H), 1.43 – 1.12 (m, 6H), 0.86 (t, J = 8.0 Hz, 3H) ppm. [0237] Step 3. Synthesis of 7-bromo-3-butyl-8-methoxy-3,5-dihydro-2H-1,5- benzothiazepin-4-one (11-4). Into a 500 mL 3-necked round-bottom flask were added 3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-3) (17.9 g, 67.45 mmol), DCM (200 mL), and NBS (18.01 g, 101.18 mmol) at rt. The resulting mixture was stirred for 4 h at rt under nitrogen atmosphere. The reaction was quenched with water at rt. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-8- methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-4) (13.9 g, 60%) as a dark yellow solid. MS (ESI): calcd. for C 14 H 18 BrNO 2 S: 343.0, Found: 344.1 [M+1] + . [0238] Step 4. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3-dihydro-1,5- benzothiazepin-4-one (11-5). Into a 500 mL round-bottom flask were added 7-bromo-3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-4) (13.9 g, 40.375 mmol), copper(I) iodide (1.54 g, 8.07 mmol), DMSO (280 mL), iodophenyl (12.36 g, 60.56 mmol), and K 2 CO 3 (11.24 g, 80.75 mmol) at rt. The resulting mixture was stirred for 1 h at 130 °C under nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) to afford 7-bromo-3-butyl-8-methoxy-5-phenyl- 2,3-dihydro-1,5-benzothiazepin-4-one (11-5) (10.4 g, 61%) as a brown oil. MS (ESI): calcd. for C 20 H 22 BrNO 2 S: 419.1, Found: 420.1 [M + 1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.45 – 7.33 (m, 3H), 7.39 – 7.21 (m, 2H), 7.17 – 7.06 (m, 2H), 3.91 (s, 3H), 2.95 (t, J = 12 Hz, 1H), 2.71 – 2.60 (m, 1H), 1.81 – 1.69 (m, 1H), 1.43 – 1.19 (m, 6H), 0.90 – 0.79 (m, 3H) ppm. [0239] Step 5. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H-1,5- benzothiazepine (11-6). Into a 500 mL round-bottom flask were added 7-bromo-3-butyl-8- methoxy-5-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one (11-5) (13.8 g, 32.82 mmol) and BH 3 -Me 2 S (10 mL, 105.45 mmol) at rt. The resulting mixture was stirred for 16 h at 75 °C. The reaction was quenched with MeOH at 0 °C. The resulting mixture was stirred for 2 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (200 mL) and DCM (100 mL). The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous MgSO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4- dihydro-2H-1,5-benzothiazepine (11-6) (9.3 g, 70%) as a colorless oil, which was used for the next step directly without further purification. MS (ESI): calcd. for C 20 H 24 BrNOS: 405.1, Found: 406.1 [M+1] + . [0240] Step 6. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H- 1lambda6,5-benzothiazepine-1,1-dione (11-7). Into a 500 mL 3-necked round-bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H-1,5-benzot hiazepine (11- 6) (9.3 g, 22.88 mmol), tetrahydrofuran (186 mL), water (93 mL), and Oxone (98.45 g, 160.19 mmol) at 0 °C. The resulting mixture was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford 7-bromo-3-butyl-8- methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-7) (5 g, 50%) as an off-white solid. MS (ESI): calcd. for C 20 H 24 BrNO 3 S: 437.1, Found: 438.1 [M+1] + . [0241] Step 7. Synthesis of 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-8). Into a 100 mL 3-necked round- bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-7) (500 mg, 1.14 mmol) and THF (10 mL) at rt. To the above mixture was added LiHMDS (572.55 mg, 3.42 mmol) dropwise at - 78 °C. The resulting mixture was stirred for additional 1 h at -78 °C. The reaction was added methyl iodide (178.08 mg, 1.25 mmol) at -78 °C. The resulting mixture was stirred for 6 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of sat. aqueous NH 4 Cl (10 mL) at -30 °C. The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-8) (450 mg, 87%) as a yellow solid. MS (ESI): calcd. for C 21 H 26 BrNO 3 S: 451.1, Found: 452.1 [M+1] + . [0242] Step 8. Synthesis of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9). Into a 8 mL vial were added 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahyd robenzo[b][1,4]thiazepine 1,1-dioxide (11-8) (200 mg, 0.44 mmol), DMF (5 mL) and (methylsulfanyl)sodium (170.39 mg, 2.43 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) (v/v) to afford 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9) (130 mg, 73%) as a colorless oil. MS (ESI): calcd. for C 21 H 27 NO 3 S 2 : 405.1, Found: 406.1 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.74 (s, 1H), 7.37 (s, 1H), 7.17 - 7.11 (m, 2H), 7.00 (d, J = 4.0 Hz, 1H), 6.70 – 6.61 (m, 1H), 6.56 – 6.47 (m, 2H), 4.20 (d, J = 16.0 Hz, 1H),3.43 – 3.35 (m, 1H) 3.08 - 3.02 (m, 1H), 2.35 (s, 3H), 2.30 (s, 1H), 1.45 - 1.25 (m, 6H), 0.95 – 0.82 (m, 3H) ppm. [0243] Step 9. Synthesis of tert-butyl (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylate (11-10). Into a 8 mL vial were added 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9) (130 mg, 0.32 mmol), THF (3 mL), tert-butyl prop-2-ynoate (60.66 mg, 0.48 mmol) and DABCO (3.60 mg, 0.032 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) to afford tert-butyl(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxid o-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (11-10) (100 mg, 59%) as an off-white solid. MS (ESI): calcd. for C 28 H 37 NO 5 S 2 : 531.2, Found: 532.2 [M+1] + . [0244] Step 10. Synthesis of (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 12). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxid o-5- phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (11-10) (100 mg, 0.18 mmol), DCM (2 mL, 31.46 mmol) and trifluoroacetic acid (0.3 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 60% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 12) (17.1 mg, 19%) as a white solid. MS (ESI): calcd. for C 24 H 29 NO 5 S 2 : 475.1, Found: 476.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.23 (s, 1H), 7.77 (d, J = 24.5, 12.4 Hz, 1H), 7.57 (s, 1H), 7.23 - 7.10 (m, 3H), 6.84 – 6.69 (m, 3H), 5.53 (d, J = 16 Hz, 1H), 4.29 - 4.07 (m, 1H), 2.37 (s, 3H), 2.05 - 1.93 (m, 1H), 1.63 - 1.55 (m, 1H), 1.37 - 1.23 (m, 6H), 0.87 (t, J = 8 Hz, 3H) ppm. [0245] Example 13. Synthesis of (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)a crylic acid [0246] Step 1. Synthesis of 7-bromo-3-butyl-8-methoxy-2,2-dimethyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (2-2). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][ 1,4]thiazepine 1,1-dioxide (12-1) (100 mg, 0.228 mmol) and tetrahydrofuran (3 mL) at room temperature. To a stirred mixture were added LiHMDS (57.26 mg, 0.342 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution was added MeI (97.13 mg, 0.684 mmol) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt. The reaction was quenched with sat. NH 4 Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA = 5/1 (v/v) to afford 7-bromo-3-butyl-8-methoxy-2,2- dimethyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-2) (60 mg, 56%) as a light yellow solid. [0247] Step 2. Synthesis of 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-2,2-dimethyl-5-phenyl-2,3,4,5-tetrah ydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-2) (60 mg, 0.129 mmol), DMF (2 mL) and NaSMe (49.58 mg, 0.710 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl-2,3,4 ,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3) (52 mg, 96%) as a colorless oil. MS (ESI): calcd. for C 22 H 29 NO 3 S 2 : 419.2, Found: 420.2 [M+1] + . [0248] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylate (12-4). Into a 8 mL vial were added 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl-2,3,4 ,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3) (52 mg, 0.124 mmol), THF (2 mL), tert-butyl prop-2-ynoate (23.45 mg, 0.186 mmol), and DABCO (2.78 mg, 0.025 mmol) at rt. The resulting mixture was stirred for 5 h at tt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (6/1) to afford tert- butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5-ph enyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (12-4) (50 mg, 74%) as a white solid. MS (ESI): calcd. for C 29 H 39 NO 5 S 2 : 545.2, Found: 546.2 [M+1] + . [0249] Step 4. Synthesis of (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 13). Into a 8 mL vial were added tert-butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylate (12-4) (50 mg, 0.092 mmol), DCM (1 mL), and trifluoroacetic acid (1 mL) at rt. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150 mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylic acid (Example 13) (10 mg, 22%) as a white solid. MS (ESI): calcd. for C 25 H 31 NO 5 S 2 : 489.2, Found: 490.3 [M + 1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.34 (s, 1H), 7.75 (d, J = 12.4 Hz, 1H), 7.55 (s, 1H), 7.19 (t, J = 7.7 Hz, 3H), 6.76 - 6.67 (m, 3H), 5.53 (d, J = 12.4 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H), 3.31 - 3.17 (m, 1H), 2.41 (s, 3H), 2.11 - 2.05 (m, 1H), 1.69 - 1.63 (m, 1H), 1.48 - 1.23 (m, 8H), 1.06 (s, 3H), 0.96 - 0.76 (m, 4H) ppm. [0250] Example 14. (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-ph enyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid [0251] Step 1. Synthesis of 7-bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][ 1,4]thiazepine 1,1-dioxide (13-1) (150 mg, 0.342 mmol) and THF (4 mL) at rt. To a stirred mixture were added LiHMDS (114.51 mg, 0.684 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added NFSI (539.48 mg, 1.710 mmol,) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt under nitrogen atmosphere. The reaction was quenched with sat. aqueous NH 4 Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 7- bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5-tetrah ydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2) (90 mg, 55%) as a light yellow solid. [0252] Step 2. Synthesis of 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3). Into a 8 mL vial were added 7-bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5-tetr ahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2) (90 mg, 0.190 mmol), DMF (2 mL) and NaSMe (73.13 mg, 1.045 mmol) at rt. The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4 ,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3) (80 mg, 99%) as a colorless oil. [0253] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylate (13-4). Into a 8 mL vial were added 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4 ,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3) (80 mg, 0.187 mmol), THF (2 mL), tert-butyl prop-2-ynoate (35.41 mg, 0.280 mmol) and DABCO (4.20 mg, 0.037 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) to afford tert- butyl (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-ph enyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (13-4) (60 mg, 58%) as a white solid. MS (ESI): calcd. for C 27 H 33 F 2 NO 5 S 2 : 553.2, Found: 576.2 [M+23] + . [0254] Step 4. Synthesis of (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 14). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-di oxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylate (13-4) (60 mg, 0.108 mmol), DCM (2 mL) and trifluoroacetic acid (2 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-ph enyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 14) (10 mg, 19%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.32 (s, 1H), 7.81 (d, J = 12 Hz, 1H), 7.71 (s, 1H), 7.28 - 7.21 (m, 3H), 6.81 (t, J = 7.2 Hz, 1H), 6.79 - 6.70 (m, 2H), 5.57 (d, J = 12 Hz, 1H), 4.35 - 4.31 (m, 1H),3.49 - 3.41 (m, 1H), 2.83 - 2.79 (m, 1H), 2.44 (s, 3H), 1.72 - 1.62 (m, 2H), 1.58 - 1.33 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H) ppm. [0255] Examples 15, 15a, 15b, 16, 16a and 16b. rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15), rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 16), (E)-3- (((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15a), (E)-3-(((2R,3R)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b), (E)-3-(((2S,3R)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a), and (E)-3-(((2R,3S)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 - tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b) [0256] Step 1. Synthesis of 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-2). Into a 50 mL 3-necked round- bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-1) (1 g, 2.28 mmol) and THF (10 mL) at rt. To a stirred mixture were added LiHMDS (1145.10 mg, 6.84 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added NFSI (863.17 mg, 2.73 mmol) portion wise at -78 °C. The resulting mixture was stirred at rt for 6 h. The reaction was then quenched with sat. aqueous NH 4 Cl at 0 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl- 2-fluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]t hiazepine 1,1-dioxide (14-2) (600 mg, 58%) as a pale-yellow solid. MS (ESI): calcd. for C 20 H 23 BrFNO 3 S: 455.1, Found: 456.2 [M+1] + . [0257] Step 2. Synthesis of 3-butyl-2-fluoro-8-hydroxy-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-3). Into a 40 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-2) (600 mg, 1.31 mmol), DMF (12 mL) and NaSMe (506.75 mg, 7.23 mmol) at rt. The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-2-fluoro-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazep ine 1,1-dioxide (14-3) (400 mg, 74%) as a colorless oil. MS (ESI): calcd. for C 20 H 24 FNO 3 S 2 : 409.1, Found: 409.1 [M+1] + . [0258] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylate (14-4). Into a 40 mL vial were added 3-butyl-2-fluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-3) (400 mg, 0.97 mmol), THF (16 mL), tert-butyl prop-2-ynoate (184.83 mg, 1.46 mmol) and DABCO (21.91 mg, 0.19 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) (v/v) to afford tert-butyl (E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl -2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (14-4) (390 mg, 75%) as an off-white solid. MS (ESI): calcd. for C 27 H 34 FNO 5 S 2 : 535.2, Found: 536.2 [M+1] + . [0259] Step 4. Synthesis of rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylic acid (Example 15) and rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid (Example 16). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxid o-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylate (14-4) (200 mg, 0.37 mmol), DCM (2 mL) and trifluoroacetic acid (1 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated to afford rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15) (85 mg, 47%) as a white solid. MS (ESI): calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.75 (d, J = 12.3 Hz, 1H), 7.61 (s, 1H), 7.24 (t, J = 8.1 Hz, 3H), 7.12 (s, 1H), 6.84 (t, J = 7.8 Hz, 3H), 5.84 - 5.69 (m, 1H), 5.54 (d, J = 12.3 Hz, 1H), 3.96 - 3.80 (m, 2H), 2.44 - 2.37 (m, 4H), 1.61 (s, 1H), 1.46 - 1.20 (m, 5H), 0.86 (t, J = 7.1 Hz, 3H) ppm and rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16) (72 mg, 40%) as a white solid. MS (ESI): calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.75 (d, J = 12.3 Hz, 1H), 7.61 (s, 1H), 7.24 (t, J = 8.1 Hz, 3H), 7.12 (s, 1H), 6.84 (t, J = 7.8 Hz, 3H), 5.84 - 5.69 (m, 1H), 5.54 (d, J = 12.3 Hz, 1H), 3.96 - 3.80 (m, 2H), 2.44 - 2.37 (m, 4H), 1.61 (s, 1H), 1.46 - 1.20 (m, 5H), 0.86 (t, J = 7.1 Hz, 3H) ppm. [0260] Step 5. Synthesis of (E)-3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)a crylic acid (Example 15a), (E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b), (E)-3-(((2S,3R)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 - tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a), and (E)-3- (((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b): Rac-(E)-3- (((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15) (85 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: ACN=3: 1; Injection Volume: 0.8 mL; The collected fractions were combined and concentrated under vacuum to afford (E)-3-(((2S,3S)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15a) (21.7 mg, 26%) as a white solid. MS (ESI): calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.38 (s, 1H), 7.75 (d, J = 12.2 Hz, 1H), 7.62 (s, 1H), 7.25 - 7.21 (m, 2H), 7.12 (s, 1H), 6.85 - 6.81 (m, 3H), 5.77 (d, J = 44 Hz, 1H), 5.54 (d, J = 12.0 Hz, 1H), 4.03 - 3.76 (m, 2H), 2.37 (s, 4H), 1.62 - 1.58 (m, 1H), 1.46 - 1.21 (m, 5H), 0.86 (t, J = 7.2 Hz, 3H) ppm and (E)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b) (32.7 mg, 39%) as a white solid. MS calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 7.74 (d, J = 12.2 Hz, 1H), 7.61 (s, 1H), 7.25 - 7.23 (m, 2H), 7.12 (s, 1H), 6.85 - 6.81 (m, 3H), 5.77 (d, J = 40.0 Hz, 1H), 5.53 (d, J = 12.2 Hz, 1H), 3.95 - 3.76 (m, 2H), 2.37 (s, 4H), 1.62 - 1.59 (m, 1H), 1.46 - 1.24 (m, 6H), 0.86 (t, J = 7.2 Hz, 3H) ppm. Rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16) (72 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; M obile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: ACN=3: 1; Injection Volume: 0.8 mL; The collected fractions were combined and concentrated under vacuum to afford (E)-3- (((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a) (11.1 mg, 15%). MS (ESI): calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (400 MHz, DMSO- d6): δ 12.26 (s, 1H), 7.79 (d, J = 12.0 Hz, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.22 - 7.18 (m, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 44.0 Hz, 1H), 5.55 (d, J = 12.0 Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 3.30 - 3.15 (m, 1H), 2.66 - 2.56 (m, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.37 - 1.29 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm and (E)-3-(((2R,3S)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b) (12.1 mg, 17%) as a white solid. MS calcd. for C 23 H 26 FNO 5 S 2 : 479.1, Found: 480.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.20 - 7.18 (m, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.68 - 6.66 (m, 2H), 5.90 (d, J = 44 Hz, 1H), 5.55 (d, J = 12.0 Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 3.22 - 3.16 (m, 1H), 2.63 - 2.55 (m, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. [0261] Example 17. (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido -5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acr ylic acid
[0262] Step 1. Synthesis of 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2). Into a 8 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahyd robenzo[b][1,4]thiazepine 1,1-dioxide (15-1) (150 mg, 0.329 mmol) and tetrahydrofuran (5 mL) at rt. To a stirred mixture were added LiHMDS (110.00 mg, 0.658 mmol) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added methyl iodide (93.31 mg, 0.658 mmol) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt. The reaction was quenched with sat. aqueous NH 4 Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl-2,3,4,5 - tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2) (100 mg, 65%) as a light yellow solid. [0263] Step 2. Synthesis of 3-butyl-2-fluoro-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-3). Into a 8 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl-2,3,4,5 - tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2) (100 mg, 0.213 mmol), DMF (3 mL) and NaSMe (81.94 mg, 1.171 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4:1) (v/v) to afford 3-butyl-2-fluoro-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazep ine 1,1-dioxide (15-3) (70 mg, 78%) as a colorless oil. MS (ESI): calcd. for C 21 H 26 FNO 3 S 2 : 423.1, Found: 424.1 [M+H] + . [0264] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepi n-8-yl)oxy)acrylate (15-4). Into a 8 mL vial were added 3-butyl-2-fluoro-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-3) (70 mg, 0.165 mmol), THF (3 mL), tert-butyl prop-2-ynoate (31.27 mg, 0.247 mmol), and DABCO (3.71 mg, 0.033 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (6/1) (v/v) to afford tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido -5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (15-4) (40 mg, 44%) as a white solid. MS (ESI): calcd. for C 28 H 36 FNO 5 S 2 : 549.2, Found: 572.2 [M+23] + . [0265] Step 4. Synthesis of (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylic acid (Example 17). Into a 8 mL vial were added tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8- yl)oxy)acrylate (15-4) (40 mg, 0.073 mmol), DCM (2 mL) and trifluoroacetic acid (2 mL) at rt. The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following condition: Column: XBridge Prep C18 OBD 19 x 150 mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated to afford (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido -5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 17) (9.5 mg, 26%) as a white solid. MS (ESI): calcd. for C 24 H 28 FNO 5 S 2 : 493.1, Found: 494.3 [M+1] + ; 1 H NMR (400 MHz, Methanol-d 4 ): δ 7.77 - 7.68 (m, 1H), 7.67 (s, 1H), 7.29 - 7.15 (m, 3H), 6.99 - 6.77 (m, 4H), 5.55 (s, 1H),4.36 - 4.30 (m, 1H), 2.30 (s, 3H), 1.74 - 1.28 (m, 11H), 0.87 (s, 3H) ppm. [0266] Examples 18, 18a, 18b, 19, 19a and 19b. rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 18), rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 19), (Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18a), (Z)-3- (((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18b), (Z)-3- (((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19a), and (Z)-3- (((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phen yl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19b)
[0267] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- fluoroacrylate (16-2). Into a 40 mL vial were added ethyl 3-bromo-2,2-difluoropropanoate (278 mg, 1.28 mmol), DMA (10 mL), and sodium hydride (92.64 mg, 3.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at rt. To a stirred solution was added 3-butyl-2-fluoro-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazep ine 1,1-dioxide (16-1) (527 mg, 1.28 mmol) at rt. The resulting mixture was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was acidified with 1N aq. HCl solution to pH 5 at rt. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford ethyl (Z)-3-((3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)-2- fluoroacrylate (16-2) (408 mg, 60%) as a brown oil. MS (ESI): calcd. for C 20 H 24 FNO 3 S 2 : 525.1, Found: 526.1 [M+1] + . [0268] Step 2. Synthesis of rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 18) and rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)- 2-fluoroacrylic acid (Example 19). Into a 40 mL vial were added ethyl (Z)-3-((3-butyl-2-fluoro-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepi n-8-yl)oxy)-2-fluoroacrylate (16-2) (408 mg, 0.78 mmol), dioxane (10 mL), water (2 mL) and lithiumol (55.77 mg, 2.32 mmol) at rt. The resulting mixture was stirred for 2 h at rt. The mixture was acidified with 1N HCl to pH 5 and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepi n-8-yl)oxy)-2-fluoroacrylic acid (Example 18) (130 mg, 34%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.62 - 7.54 (m, 2H), 7.25 - 7.18 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 5.90 (d, J= 44 Hz, 1H), 4.15 (d, J = 16 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 (s, 3H), 1.54 - 1.45 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm and rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 19) (130 mg, 34%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.62 - 7.54 (m, 2H), 7.25 - 7.18 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 5.90 (d, J= 44 Hz, 1H), 4.15 (d, J = 16 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 (s, 3H), 1.54 - 1.45 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. [0269] Step 3. Synthesis of (Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)- 2-fluoroacrylic acid (Example 18a), (Z)-3-(((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroa crylic acid (Example 18b), (Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19a), and (Z)- 3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-ph enyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19b): Rac-(Z)- 3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-ph enyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18) (130 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1 (min): 10; RT2 (min): 12; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected fractions was combined and concentrated under vacuum to afford (Z)-3-(((2R,3S)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 - tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18a) (36.2 mg, 38%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.65 (s, 1H), 7.74 - 7.67 (d, J = 4.9 Hz, 1H), 7.26 (s, 1H), 7.22 - 7.18 (m, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 5.90 (d, 40 Hz, 1H), 4.17 (d, J = 16 Hz, 1H), 3.19 (dd, J = 16.0, 12.0 Hz, 1H), 2.50 (s, 1H), 2.45 (s, 3H), 1.52 - 1.48 (m, 4H), 1.37 - 1.30 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H) ppm and (Z)-3-(((2S,3R)-3-butyl- 2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahy drobenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 18b) (27.5 mg, 21%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.59 (s, 1H), 7.71 - 7.66 (m, 2H), 7.25 (s, 1H), 7.21 - 7.17 (m, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 5.89 (d, J = 44 Hz, 1H), 4.17 (d, J = 16.0 Hz, 1H), 3.20 - 3.14 (m, 1H), 2.57 (s, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.36 - 1.31 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. Rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-diox ido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19) (10 mg) was purified by Prep-HPLC with the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected fractions was combined and concentrated under vacuum to afford (Z)-3-(((2R,3R)-3-butyl-2- fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydr obenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 19a) (1.1 mg.11%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 8.50 (s, 1H), 7.65 (s, 1H), 7.31 - 7.21 (m, 3H), 6.98 (s, 1H), 6.96 - 6.86 (m, 3H), 5.40 (d, J = 40 Hz, 1H), 4.10 - 3.85 (m, 2H), 2.39 (s, 1H), 2.30 (s, 3H), 1.70 - 1.63 (m, 1H), 1.55 - 1.21 (m, 5H), 0.87 (m, 3H) ppm and (Z)-3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroa crylic acid (Example 19b) (2 mg, 21%) as a white solid. MS (ESI): calcd. for C 23 H 25 F 2 NO 5 S 2 : 497.1, Found: 498.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD): δ 7.68 (s, 1H), 7.46 (d, J = 16 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.00 - 6.89 (m, 4H), 5.42 (d, J = 44 Hz, 1H), 4.10 - 3.84 (m, 2H), 2.39 (s, 1H), 2.30 (s, 3H), 1.69 - 1.63 (m, 1H), 1.56 - 1.54 (m, 1H), 1.54 - 1.21 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H) ppm. [0270] Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. Table 1: Representative Examples of the present invention 115 V. Biological Data [0271] HepG2-NTCP infection protocol [0272] HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture using HepG2-NTCP growth medium (DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 µg/mL G418 (Alfa Aesar, Cat# J62671), 50U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 µg/mL blasticidin (Sigma, Cat# 15205)). Prior to infection, the cells were washed twice with 1× DPBS (Invitrogen, Cat# 14190-136) and treated with 3 mL of 0.05% trypsin (Invitrogen, Cat# 25200-056) to dissociate the cells. Following dissociation, 10 mL of HepG2-NTCP growth medium was added to the cells to neutralize the trypsin and the cells were then centrifuged at 1,300 rpm for 5 minutes. Following centrifugation, the cells were resuspended in 10 mL of HepG2-NTCP growth medium, counted, and then centrifuged at 1,300 rpm for 5 minutes. The cell pellet was resuspended in DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540) to a density of 5.6 × 10 5 cells/mL and infected with HBV at an MOI of 50. Immediately after infection, 90 µL of the cell/HBV mixture was added to a 96-well plate containing 10 µL of compound and incubated at 37⁰C for 24 hours (2% final DMSO concentration). After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 72 hours. At the end of the incubation, the plates were spun at 1,800 rpm for 8 minutes and the supernatant was removed for HBeAg quantification using electrochemiluminescence enzyme-linked immunosorbent assays (ECL-ELISA). [0273] To conduct the HBeAg ECL-ELISA, Lumitrack high-binding 96-well plates (Greiner, Cat# 655074) were treated with 625 ng/mL HBeAg mAb (Biocheck, Cat# 70426) in 1× DPBS for 2 hours at 25⁰C with shaking. The HBeAg mAb solution was then removed and the plates treated with 1× DPBS containing 0.5% bovine serum albumin (BSA) (Sigma, Cat# A7030-100g) for 2 hours at 25⁰C with shaking. The HBeAg-coated plates were then washed 4 times with 1× DPBS containing 0.05% Tween 20 (DPBS-T) (Thermo Fisher Scientific, Cat# J61544-K2). Following the wash, 90 µL of HRP-conjugated antibody (Fitzgerald, Cat# 61-H10K), diluted 1:8,000 in 1× DPBS-T containing 0.5% BSA, was added to the HBeAg-coated plates along with 10 µL of sample. The plates were then incubated for 2 hours at 25 ⁰C with shaking. Following the incubation, the sample was then removed and 200 µL of 1× PBS-T was added and the plates were incubated for 10 minutes at 25⁰C with shaking. The plates were then washed 6 times with 1× PBS-T and blotted dry.80 µL of ECL substrate (Millipore, Cat# WBKLS0500) was then added to the plate and the luminescence was measured using a Tecan M1000 Pro plate reader. [0274] Other assays are known in the art, see for example, Lempp et al., Nature Communications, 2019, 10:2265, https://doi.org/10.1038/s41467-019-10211-2, Grosser et al., Frontiers in Molecular Biosciences, 2021, 8: doi: 10.3389/fmolb.2021.689757. [0275] Following the described HepG2-NTCP infection protocol, assay data for exemplified compounds of the invention can be grouped in the following ranges: A indicates EC 50 < 100 nM; B indicates EC 50 of ≥100 to <1,000 nM; C indicates EC 50 of ≥1,000 to <5,000 nM. INCORPORATION BY REFERENCE [0276] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0277] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0278] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.