5-alkyl pyrrolidine orexin receptor agonists

Abstract

The present invention is directed to 5-alkyl pyrrolidine compounds which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

Claims

1. A compound of the formula Ib′″: ##STR00119## wherein: X is —O— or —NH—, or X may be a direct bond to R.sup.1; R.sup.1 is selected from: (1) —C.sub.1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, and (2) —C.sub.3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4; R.sup.2 is selected from: (1) hydrogen, (2) —C.sub.1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, (3) —C.sub.3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, (4) -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R.sup.4, and (5) -heteroaryl, where the heteroaryl is selected from: pyridyl, pyrimidinyl, and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R.sup.4; R.sup.3 is selected from: (1) —C.sub.1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, (2) —C.sub.3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, (3) -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R.sup.4, (4) —NR.sup.10R.sup.11, wherein R.sup.10 and R.sup.11 are independently selected from: (a) hydrogen, and (b) C.sub.1-6alkyl, which is unsubstituted or substituted with one to six R.sup.4; R.sup.4 is selected from: (1) hydroxyl, (2) halogen, (3) C.sub.1-6alkyl, which is unsubstituted or substituted with one to six fluoro, (4) C.sub.2-4alkenyl, (5) C.sub.2-4alkynyl, (6) —C.sub.3-6cycloalkyl, (7) —O—C.sub.1-6alkyl, (8) —O(C═O)—C.sub.1-6alkyl, (9) —NH.sub.2, (10) —NH—C.sub.1-6alkyl, (11) —NO.sub.2, (12) phenyl, (13) —CO.sub.2H, (14) —SO.sub.2—C.sub.1-6alkyl, (15) —C.sub.3-5cycloalkyl(SO.sub.2), and (16) —CN; R.sup.5 is: (1) C.sub.1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4, and (2) —C.sub.3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R.sup.4; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is —O—.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X is —NH—.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.1 is selected from: (1) methyl, (2) ethyl, (3) —CH.sub.2OH, (4) —CH.sub.2CF.sub.3, (5) —CH.sub.2CHF.sub.2, (6) —CH(CH.sub.3).sub.2, (7) —CH.sub.2CH.sub.2CH.sub.2F, (8) cyclopropyl, (9) —CH.sub.2-cyclopropyl, (10) —CH.sub.2-cyclobutyl, and (11) —CH.sub.2O(C═O)CH.sub.3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.2 is selected from: (1) hydrogen, (2) —CH.sub.2(CH.sub.3).sub.2, (3) —CF.sub.3, (4) —CH.sub.2CHF.sub.2, (5) —CH.sub.2CF.sub.3, and (6) phenyl, which is unsubstituted or substituted with —CF.sub.3, —CH.sub.2CF.sub.3, or one to three fluoro.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.3 is selected from: (1) —C.sub.1-6alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro, (2) —C.sub.3-6cycloalkyl, (3) —NH.sub.2, (4) —NH(C.sub.1-6alkyl), (5) —N(C.sub.1-6alkyl)(C.sub.1-6alkyl), and (6) -phenyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.5 is selected from: (1) al methyl, (2) ethyl, (3) —CHF.sub.2, (4) —CF.sub.3, (5) —CH.sub.2OH, (6) —CH.sub.2OCH.sub.3, and (7).sub.0 cyclopropyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.5 is methyl.

9. A compound which is selected from: (2R,3S,5R)-N-ethyl-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxamide; (2R,3S,5R)-N-ethyl-5-methyl-3-(methylsulfonamido)-2-(((4-(trifluoromethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide; methyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-isopropylcyclohexyl)oxy)-methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; isopropyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; isopropyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate; ethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; ethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((4-isopropylcyclohexyl)-oxy)methyl)-5-methylpyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; 2-fluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((4-(trifluoromethyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((4-(2,2,2-trifluoroethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((4-isopropylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; 2,2-difluoroethyl (2R,3S,5R)-2-((((1r,4R)-4-(2,5-difluorophenyl)-cyclohexyl)oxy)-methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(2-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methylsulfamoyl)amino)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-5-methyl-2-((((1r,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)-oxy)methyl)-5-methylpyrrolidine-1-carboxylate; isopropyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate; isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (CIS)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)-pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-5-cyclopropyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2S,3R,5S)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate; methyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-vinylpyrrolidine-1-carboxylate; methyl (CIS)-5-(2-hydroxyethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (CIS)-5-(hydroxymethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N-(cyanomethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N-(2-cyanoethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((N-(2-methoxyethyl)-N-methylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((N-(2-hydroxyethyl)-N-methylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methyl-N-(2-(methylsulfonyl)ethyl)sulfamoyl)amino)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N-((1,1-dioxidothietan-3-yl)methyl)-N-methylsulfamoyl)-amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-((N-methyl-N-(2-(trifluoromethoxy)ethyl)sulfamoyl)amino)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((2,2-difluoroethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N-(2-cyanoethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((fluoromethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)-methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1r,4R)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxymethyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1r,4R)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3R,4R)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3S,4S)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; methyl (2R,3S,5R)-2-((((1r,4R)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; and methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,4-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A method for treating narcolepsy in a mammalian subject which comprises administering to the patient an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. A method for treating hypersomnia in a mammalian subject which comprises administering to the patient an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

Description

INTERMEDIATE A

1-benzyl 2-methyl (5R)-5-methyl-3-oxopyrrolidine-1,2-dicarboxylate

(1) ##STR00019##

Step 1: methyl (R)-5-(((benzyloxy)carbonyl)amino)-3-oxohexanoate (A-2)

(2) To a solution of (R)-3-(((benzyloxy)carbonyl)amino)butanoic acid (A-1) (6.25 g, 26.3 mmol) in anhydrous THF (100 mL) under N.sub.2 was added di(1H-imidazol-1-yl)methanone (6.41 g, 39.5 mmol). After stirring at rt for 1 h, previously mixed MgCl.sub.2 (4.64 mL, 52.7 mmol) and potassium 3-methoxy-3-oxopropanoate (8.23 g, 52.7 mmol) was added. The resulting mixture was stirred at rt for additional 18 h under N.sub.2. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL), followed by brine (20 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc in hexane) to afford methyl (R)-5-(((benzyloxy)carbonyl)amino)-3-oxohexanoate. LC-MS 294 (M+1).

Step 2: methyl (R)-5-(((benzyloxy)carbonyl)amino)-2-diazo-3-oxohexanoate (A-3)

(3) To a solution of methyl (R)-5-(((benzyloxy)carbonyl)amino)-3-oxohexanoate (A-2) (6.2 g, 21.14 mmol) in DCM (200 mL) was added Et.sub.3N (6.42 g, 63.4 mmol) and 4-acetamido-benzene-sulfonyl azide (5.08 g, 21.14 mmol) at rt under N.sub.2. The reaction mixture was stirred for 12 h. LC-MS showed that the reaction was completed. The crude material was diluted with 200 mL of DCM, washed with 50 mL of H.sub.2O. The organic phase was collected and dried (MgSO.sub.4), concentrated and chromatographed over silica gel (0-100% Ethyl acetate in hexanes) to give the title compound methyl (R)-5-(((benzyloxy)carbonyl)amino)-2-diazo-3-oxohexanoate. LC-MS 320 (M+1).

Step 3: 1-benzyl 2-methyl (5R)-5-methyl-3-oxopyrrolidine-1,2-dicarboxylate (A)

(4) To a solution of methyl (R)-5-(((benzyloxy)carbonyl)amino)-2-diazo-3-oxohexanoate (A-3) (2.0 g, 6.26 mmol) in toluene (50 mL) was added diacetoxyrhodium (0.138 g, 0.313 mmol) under N.sub.2 at rt. The reaction mixture was degassed for 10 min, then was stirred at 80° C. for 2 h. LC-MS showed reaction completed. The reaction mixture was concentrated and chromatographed over silica gel (0-100% EtOAc in hexanes) to give the title compound 1-benzyl 2-methyl (5R)-5-methyl-3-oxopyrrolidine-1,2-dicarboxylate. LC-MS 292.28 (M+1).

INTERMEDIATE B

Benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide

(5) ##STR00020##

Step 1: methyl (R)-5-(((benzyloxy)carbonyl)amino)-3-oxohexanoate (B-1)7

(6) To a solution of 1-benzyl 2-methyl (5R)-5-methyl-3-oxopyrrolidine-1,2-dicarboxylate (A) (5000 mg, 17.16 mmol) in DCM (100 mL) was added 4-methoxybenzylamine (2.467 mL, 18.88 mmol) and catalytic amount of acetic acid (0.049 mL, 0.858 mmol). The mixture was stirred at rt for 30 mins, then sodium triacetoxyborohydride (4.37 g, 20.6 mmol) was added to the mixture. The reaction was stirred at rt overnight. LC-MS showed completion of the reaction. The reaction was quenched with sat. aq. NaHCO.sub.3 (50 mL), extracted with DCM (3×50 mL). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in Hexane 0-100%) to afford the title compound 1-benzyl 2-methyl (5R)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1,2-dicarboxylate. LC-MS 413 (M+1).

Step 2: benzyl (2R,3S,5R)-2-(hydromethyl)-3-((4-methoxybenzyl)amino-5-methylpyrrolidine-1-carboxylate (B-2)

(7) To a solution of 1-benzyl 2-methyl (5R)-3-((4-methoxybenzyl)amino)-5-methyl-pyrrolidine-1,2-dicarboxylate (B-1) (2000 mg, 4.85 mmol) in THF (50 mL) at −15° C. was added LiAlH.sub.4 (5.82 mL, 5.82 mmol, 1M in THF) under N.sub.2. The reaction was stirred at −15° C. for 15 min. LC-MS showed completion of the reaction. The reaction was quenched by sequential addition of 0.5 mL of H.sub.2O, 0.5 mL of 1N NaOH and 1.5 mL of H.sub.2O. After stirring for 0.5 h, the reaction mixture was filtered and the organic phase was collected, dried (MgSO.sub.4), concentrated in vacuo and chromatographed over silica gel with 0-100% EtOAc in hexanes as eluent to give the title product benzyl (5R)-2-(hydroxymethyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate.

(8) LC-MS 385 (M+1).

Step 3: benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2-oxide (B-3)

(9) To a solution of benzyl (5R)-2-(hydroxymethyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (B-2) (2320 mg, 6.03 mmol) in DCM (50 mL) was added pyridine (1432 mg, 18.10 mmol), followed by addition of sulfurous dichloride (861 mg, 7.24 mmol) in 10 mL of DCM via a syringe pump over 30 min at −78° C. (acetone in dry ice) under N.sub.2. The reaction mixture was allowed to gradually rise to rt and stirred for 2 h. Then 50 mL MTBE were added and the mixture was filtered. The filtrate was dried over K2CO.sub.3, filtered and concentrated. The crude was purification by column chromatography (silica gel with EtOAc in hexanes, 0-100%) to give the title compound benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2-oxide. LC-MS 431 (M+1).

Step 4: benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide (B)

(10) To a solution of RuCl.sub.3 (121 mg, 0.465 mmol) in 10 mL of H.sub.2O was added sodium periodate (1292 mg, 6.04 mmol) little by little until a yellow solution formed. Then 5 g of silica gel, as well as the rest of NaIO.sub.4 were added sequentially to the reaction mixture, followed by addition of 20 mL of EtOAc. The resulting suspension was cooled to 0° C. and a solution of benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2-oxide (B-3) (2000 mg, 4.65 mmol) in 10 mL of EtOAc was added dropwise. After the reaction mixture was stirred for 1 h at 0° C., LC-MS showed that the reaction was completed. The mixture was filtered using a 2-layered diatomaceous earth and silica gel pad, and eluted with 50 mL of EtOAc. The filtrate was concentrated in vacuo to give the title compound benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide. LC-MS 469 (M+1).

INTERMEDIATE C

(2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine

(11) ##STR00021##

Step 1: benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (C-1)

(12) To a solution of benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide (B) (2000 mg, 4.48 mmol) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (2189 mg, 6.72 mmol) and 4-isopropylphenol (732 mg, 5.37 mmol) at rt under N.sub.2. The reaction mixture was stirred at 40° C. for overnight. LC-MS showed reaction completed. The reaction mixture was filtered through a pad of diatomaceous earth. The organic phase was collected, concentrated and dissolved in 30 mL of THF, then was cooled to 0° C. 5 mL of 2N HCl was added. After stirring for 20 min, LC-MS showed only the desired product. The reaction mixture was diluted with 50 mL of EtOAc, then to the reaction mixture was added K2CO.sub.3 to neutralized the reaction mixture. The organic phase was collected, dried (K2CO.sub.3), concentrated and chromatographed over silica gel with 0-40% EtOAC in hexanes as eluent to give the title compound benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate. LC-MS 503 (M+1).

Step 2: (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine

(13) To a solution of benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (C-1) (2500 mg, 4.97 mmol) in THF (30.00 mL) was added palladium on carbon (5%, 1059 mg, 0.497 mmol). The reaction mixture was degassed and refilled with H2 three times. The reaction mixture was stirred at rt for 1 h. LC-MS showed reaction completed. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated to give the title compound (2R,3S,5R)-2-((4-isopropylphenoxy)-methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine. LC-MS 369 (M+1).

INTERMEDIATE D

(2R,3S,5R)-2-((4-(trifluoromethyl)phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine

(14) ##STR00022##

Step 1: benzyl (2R,3S,5R)-2-((4-(trifluoromethyl)phenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (D-1)

(15) To a solution of benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide (B) (200 mg, 0.448 mmol) in DMF (12 mL) was added Cs.sub.2CO.sub.3 (219 mg, 0.672 mmol) and 4-(trifluoromethyl)phenol (87 mg, 0.537 mmol) at rt under N.sub.2. The reaction mixture was stirred at 40° C. overnight. LC-MS showed no starting material left. The reaction mixture was filtered through a pad of diatomaceous earth. The organic phase was collected, concentrated and dissolved in 30 mL of THF, then was cooled to 0° C. 5 mL of 2N HCl was added and the reaction mixture was stirred for 20 min, LC-MS showed only the desired product. The reaction mixture was diluted with 50 mL of EtOAc, then to the reaction mixture was added K2CO.sub.3 to neutralized the reaction mixture. The organic phase was collected, dried (K2CO.sub.3), concentrated and chromatographed over silica gel with 0-40% EtOAC in hexanes to give the title compound benzyl (2R,3S,5R)-2-((4-(trifluoromethyl)phenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate. LC-MS 529 (M+1).

Step 2: (2R,3S,5R)-2-((4-(trifluoromethyl)phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine

(16) To a solution of benzyl (2R,3S,5R)-2-((4-(trifluoromethyl)phenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (D-1) (150 mg, 0.284 mmol) in THF (4 mL) was added palladium on carbon (5%, 30 mg, 0.028 mmol). The reaction mixture was degassed and refilled with H2 from a balloon three times. The reaction mixture was stirred at rt for 3 h. LC-MS showed reaction completed. The reaction mixture was then filtered through a pad of diatomaceous earth. The filtrate was concentrated to give the title compound (2R,3S,5R)-2-((4-(trifluoromethyl)-phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine. LC-MS 395 (M+1).

INTERMEDIATE E

(2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine

(17) ##STR00023##

Step 1: benzyl (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)phenoxy)methyl)-3-((4-methoxybenzyl)-amino)-5-methylpyrrolidine-1-carboxylate (E-1)

(18) To a solution of benzyl (4aR,6R,7aS)-1-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrrolo[3,2-d][1,2,3]oxathiazine-5-carboxylate 2,2-dioxide (B) (400 mg, 0.896 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (438 mg, 1.344 mmol) and 4-(2,2,2-trifluoroethyl)phenol (189 mg, 1.075 mmol) at rt under N.sub.2. The reaction mixture was stirred at 40° C. for overnight. LC-MS showed no starting material left. The reaction mixture was filtered through a pad of diatomaceous earth. The organic phase was collected, concentrated and dissolved in 30 mL of THF, then was cooled to 0° C. 5 mL of 2N HCl was added and the reaction mixture, then the reaction was stirred for 20 min, LC-MS showed only the desired product. The reaction mixture was diluted with 50 mL of EtOAc, then to the reaction mixture was added K2CO.sub.3 to neutralized the reaction mixture. The organic phase was collected, dried (K2CO.sub.3), concentrated and chromatographed over silica gel with 0-40% EtOAC in hexanes to give the title compound benzyl (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)phenoxy)-methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate. LC-MS 543 (M+1).

Step 2: (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl))phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine (E)

(19) To a solution of benzyl (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)phenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (E-1) (220 mg, 0.405 mmol) in THF (4 mL) was added palladium on carbon (5%, 43 mg, 0.041 mmol). The reaction mixture was degassed and refilled with H2 three times. The reaction mixture was stirred at rt for 1 h. LC-MS showed SM disappeared. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated to give the title compound (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)-phenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine. LC-MS 409 (M+1).

INTERMEDIATE F

1-benzyl 2-methyl (5R)-3-(benzyloxy)-5-methylpyrrolidine-1,2-dicarboxylate

(20) ##STR00024##

Step 1: 1-benzyl 2-methyl (5R)-3-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (F-1)

(21) To a solution of 1-benzyl 2-methyl (5R)-5-methyl-3-oxopyrrolidine-1,2-dicarboxylate (A) (9.7 g, 33.3 mmol) in MeOH (20 mL) and THF (50 mL) was slowly added NaBH.sub.4 (1.0 g, 26.4 mmol) under N.sub.2 at 0° C. over a period of 15 min. The reaction mixture was stirred for 0.5 h. LC-MS showed reaction completed. The reaction was quenched by dropwise addition of 2N KHSO.sub.4 at 0° C. until pH<2. The mixture was extracted by 2 portions of 50 mL of EtOAc. The organic phases were combined, dried (MgSO.sub.4), concentrated and chromatographed over silica gel with 0-50% EtOAc in hexanes as eluent to give product 1-benzyl 2-methyl (5R)-3-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate. LC-MS 294 (M+1).

Step 2: 1-benzyl 2-methyl (5R)-3-(benzyloxy)-5-methylpyrrolidine-1,2-dicarboxylate (F-2)

(22) To a solution of 1-benzyl 2-methyl (5R)-3-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (F-1) (2000 mg, 6.82 mmol) and benzyl bromide (0.892 mL, 7.50 mmol) in DMF (30 mL) was added NaH (355 mg, 8.86 mmol) at 0° C. under N.sub.2. After stirring for 10 min, LC-MS showed reaction completed. The reaction mixture was quenched by addition of sat. aq. NH.sub.4Cl, then to the suspension was added 10 mL of EtOAc. After stirring for 30 min, the organic phase was separated, dried (MgSO.sub.4), concentrated and chromatographed over silica gel with 0-100% EtOAc in hexanes as eluent to give product 1-benzyl 2-methyl (5R)-3-(benzyloxy)-5-methylpyrrolidine-1,2-dicarboxylate (F-2). LC-MS 384 (M+1).

Step 3: benzyl (5R)-3-(benzyloxy)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (F-3)

(23) To a solution of 1-benzyl 2-methyl (5R)-3-(benzyloxy)-5-methylpyrrolidine-1,2-dicarboxylate (F-2) (2000 mg, 5.22 mmol) in THF (30 mL) was added LiAlH.sub.4 (5.22 mL, 5.22 mmol) dropwise at −15° C. under N.sub.2. The reaction mixture was stirred for 5 min. LC-MS showed formation of the desired product. The reaction was quenched by adding 2 mL of H.sub.2O, 2 mL of 1N NaOH and 6 mL of H.sub.2O. After stirring for 0.5 h, the reaction mixture was filtered and the filtrate was collected, dried (MgSO.sub.4), concentrated and purified by chromatography on silica gel with 0-50% ethyl acetate in hexanes as eluent to give the desired product benzyl (5R)-3-(benzyloxy)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (F-3). LC-MS 356 (M+1).

Step 4: benzyl (5R)-3-(benzyloxy)-2-formyl-5-methylpyrrolidine-1-carboxylate (F)

(24) To a solution of oxalyl chloride (0.394 mL, 4.50 mmol) in DCM (30 mL) was added DMSO (0.639 mL, 9.00 mmol) in DCM (5 mL) at −78° C. under N.sub.2. After addition finished, the reaction mixture was stirred for 5 min before addition of benzyl (5R)-3-(benzyloxy)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (F-3) (800 mg, 2.251 mmol) in 2 mL of DCM. The reaction was stirred for 30 min until no starting material left. A solution of Et.sub.3N (1.255 mL, 9.00 mmol) in 2 mL of DCM was added, then the reaction mixture was allowed to raise to rt, then the reaction was quenched by 2 mL of sat. aq. NaHCO.sub.3. The organic phase was collected and dried (MgSO.sub.4), filtered and the filtrate was concentrated to give the title compound benzyl (5R)-3-(benzyloxy)-2-formyl-5-methylpyrrolidine-1-carboxylate (F). LC-MS 354 (M+1).

INTERMEDIATE G

(CIS)-4-phenylcyclohexanol

(25) ##STR00025##

(26) To a mixture of 4-phenylcyclohexanone (10.50 g, 60.3 mmol) in THF (201 mL) at −78° C. was added L-Selectride (102 mL, 102 mmol) in THF over 20 min. The mixture stirred at −78° C. for 3 hours before warming to 0° C. and stirring for an additional 2 hours. The reaction was quenched with a saturated solution of NH.sub.4Cl (200 mL), extracted with EtOAc (250 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (2% to 60% EtOAc/hexanes) to afford the title compound. MS: 199.9 (M+23).

INTERMEDIATE H

((CIS)-4-(chloromethoxy)cyclohexyl)benzene

(27) ##STR00026##

(28) To a mixture of (CIS)-4-phenylcyclohexanol (INTERMEDIATE G) (5.00 g, 28.4 mmol) in DCM (28.4 mL) at ambient temperature was added paraformaldehyde (0.937 g, 31.2 mmol) followed by the dropwise addition of TMS-Cl (10.88 mL, 85 mmol). The mixture was stirred for 2 hours before concentrating down, taking up in DCM (50 mL), drying over Na.sub.2SO4, and reconcentrating, and then placed under vacuum. The resulting residue was used directly without any further purification.

INTERMEDIATE I

2-(1-(4-fluorobenzamido)cyclopropyl)-7,8-dihydroquinolin-5-yl trifluoromethanesulfonate

(29) ##STR00027##

Step 1: 1-benzyl 3-ethyl 4-oxo-5-((((1s,4s)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1,3-dicarboxylate (C-2)

(30) To a mixture of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (I-1) (7.50 g, 25.7 mmol) in THF (129 mL)/DMPU (12.42 mL, 103 mmol) at −78° C. was added LDA (28.3 mL, 56.6 mmol) in THF dropwise. The mixture stirred for 15 min before adding ((CIS)-4-(chloromethoxy)cyclohexyl)benzene (INTERMEDIATE H) (6.36 g, 28.3 mmol) in THF (15 mL). The mixture stirred for another 20 min before quenching with a saturated solution of NH.sub.4Cl (100 mL). The mixture was warmed to ambient temperature, extracted with EtOAc (3× @ 200 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (2% to 100% EtOAc/hexanes) to afford the title compound. MS: 480.5 (M+1).

Step 2: benzyl 3-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (I-3)

(31) To a mixture of 1-benzyl 3-ethyl 4-oxo-5-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1,3-dicarboxylate (I-2) (4.00 g, 8.34 mmol) in DMSO (25.3 mL) was added NaCl (0.975 g, 16.68 mmol) and H.sub.2O (3.01 mL, 167 mmol). The mixture was heated to 130° C. and stirred for 2 hours before cooling to ambient temperature. The mixture was purified directly by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 408.5 (M+1).

Step 3: benzyl (CIS)-3-amino-2-((((CIS)-4-phenylcyclohexyloxy)methyl)pyrrolidine-1-carboxylate (INTERMEDIATE I)

(32) To a mixture of benzyl 3-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (I-3) (6.00 g, 14.72 mmol) in Methanol (294 mL) at ambient temperature was added ammonium acetate (34.0 g, 442 mmol). The mixture stirred for 1 hour. NaCNBH.sub.4 (0.925 g, 14.72 mmol) was added to the mixture for 16 more hours before it was concentrated. Take up in DCM (250 mL) and basify with a saturated solution of NaHCO.sub.3 (250 mL). Extract with DCM (3×250 mL), dry over Na.sub.2SO.sub.4, and concentrate. The resulting residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 409.5 (M+1).

INTERMEDIATE J

N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide

(33) ##STR00028##

Step 1: benzyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (J-1)

(34) To a mixture of benzyl 3-amino-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (INTERMEDIATE I) (1.00 g, 2.448 mmol) in DCM (12.24 mL) at ambient temperature was added TRIETHYLAMINE (0.682 mL, 4.90 mmol) and METHANESULFONYL CHLORIDE (0.229 mL, 2.94 mmol). The mixture stirred for 2 hours before quenching with a saturated solution of NaHCO.sub.3 (25 mL). The mixture was extracted with EtOAc (3×25 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (5% to 70% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 487.4 (M+1).

Step 2: N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (INTERMEDIATE J)

(35) To a mixture benzyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (J-1) (756 mg, 1.554 mmol) in MeOH (10.400 mL) at ambient temperature was added Pd/C (165 mg, 0.155 mmol). A balloon of H2 was added (vacuum purge 3×) and the mixture stirred for 2 hours. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to afford the title compound. MS: 353.3 (M+1).

INTERMEDIATE K

N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide

(36) ##STR00029##

Step 1: N-((CIS)-1-benzyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (K-1)

(37) To a mixture of N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (INTERMEDIATE J) (325 mg, 0.922 mmol) in DMF (2794 μl) at ambient temperature was added TRIETHYLAMINE (257 μl, 1.844 mmol) and BENZYL BROMIDE (132 μl, 1.106 mmol). The mixture was stirred for 2 hours before it was acidified with a few drops of AcOH. The mixture was purified directly by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 443.5 (M+1).

Step 2: N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (INTERMEDIATE K)

(38) To a mixture of N-((CIS)-1-benzyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (K-1) (400 mg, 0.719 mmol) in THF (20.5 mL) was added sodium bicarbonate (604 mg, 7.19 mmol) dissolved in water (8.20 mL) and 12 (1368 mg, 5.39 mmol). The mixture was stirred for 6 hours before it was diluted with DCM (50 mL) and quenched with a saturated solution of NaS.sub.2O.sub.3 (25 mL), extracted with DCM (3×50 mL), dried over Na.sub.2SO.sub.4, and concentrated. The resulting residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 457.5 (M+1).

INTERMEDIATE L

(1s,4s)-4-(3-fluorophenyl)cyclohexan-1-ol

(39) ##STR00030##

Step 1: 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (L-1)

(40) A suspension of 1-bromo-3-fluorobenzene (2.4 g, 13.71 mmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(ii)dichloride dichloromethane complex (2.240 g, 2.74 mmol), sodium carbonate (4.36 g, 41.1 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (4.38 g, 16.46 mmol) in DME (54 ml) and H.sub.2O (18 ml) was degassed for 10 mins. The reaction mixture was sealed and heated at 100° C. for overnight. LC-MS indicated reaction was completed. The reaction mixture was cooled down to rt, then was diluted with 70 mL of EtOAc. The organic phase was collected and the aqueous layer was extracted with 2×20 ml of EtOAc. The combined organic phase was dried over MgSO.sub.4, concentrated, and the residue was purified by ISCO (silica gel, 120 g, eluent with 0˜10% EtOAc in hexane) to give the title compound 8-(3-fluoro-phenyl)-1,4-dioxaspiro[4.5]dec-7-ene. (L-1). LC-MS 235 (M+1).

Step 2: 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane (L-2)

(41) To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (L-1) (3.17 g, 13.53 mmol) in MeOH (60 ml) was added 10% Pd on C (1.152 g, 1.083 mmol). The reaction mixture was stirred under a H.sub.2 balloon for overnight. LC-MS indicated reaction completion. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the title compound 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane. (L-2). LC-MS 237 (M+1).

Step 3: 4-(3-fluorophenyl)cyclohexan-1-one (L-3)

(42) To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane (L-2) (3.18 g, 13.46 mmol) in acetone (35 ml) was added 2M HCl in water (16.82 ml, 33.6 mmol). The reaction mixture was heated at 70° C. for 3 hrs. LC-MS indicated reaction completed. The reaction was concentrated to remove acetone. The residue was extracted with 3 portions of 30 ml of EtOAc, dried over MgSO.sub.4, concentrated to give a yellow oil. The residue was purified by ISCO (silica gel, 80 g, eluent with 0˜12% EtOAc in hexane) to give the title compound 4-(3-fluorophenyl)cyclohexan-1-one. (L-3). LC-MS 193 (M+1).

Step 4: (1s,4s)-4-(3-fluorophenyl)cyclohexan-1-ol (L)

(43) To a solution of 4-(3-fluorophenyl)cyclohexan-1-one (L-3) (1.99 g, 10.35 mmol) in THF (35 ml) at −78° C. under nitrogen was added L-Selectride (1.0 M in THF, 15.53 ml, 15.53 mmol) dropwise. The mixture was stirred at −78° C. for 20 mins. LC-MS indicated completion. The reaction mixture was quenched with water followed by MeOH, 1N NaOH and H2O2 solution. It was stirred at rt for 10 mins, then it was extracted with EtOAc (30 mL×3), dried over MgSO.sub.4, and concentrated to leave colorless oil. The residue was purified by Isco (Loaded onto a 80 g column, eluent with 0˜20% EtOAc in hexane, the peak was collected at 16% EtOAc in hexane) to give the title compound (1s,4s)-4-(3-fluorophenyl)cyclohexan-1-ol ((L). LC-MS 236 (M+1).

INTERMEDIATE M, N, O

(1s,4s)-4-(2,5-difluorophenyl)cyclohexan-1-ol (M), (1s,4s)-4-(2,3,6-trifluorophenyl)-cyclohexan-1-ol (N), (1s,4s)-4-(2-(trifluoromethyl)phenyl)cyclohexan-1-ol (O) and (1s,4s)-4-(2-fluorophenyl)cyclohexan-1-ol (P)

(44) ##STR00031##

(45) Each the intermediate compounds were prepared by following the same procedure as intermediate H using commercially available 2-bromo-1,4-difluorobenzene, 1-bromo-2,3,5-trifluorobenzene and 1-bromo-2-(trifluoromethyl)benzene and 1-bromo-2-fluorobenzene.

INTERMEDIATE Q

(4S)-2-fluoro-4-(3-fluorophenyl)cyclohexan-1-one (Q)

(46) ##STR00032##

(47) To a solution of 4-(3-fluorophenyl)cyclohexan-1-one (L-3) (400 mg, 2.081 mmol) in acetonitrile (10 ml) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (737 mg, 2.081 mmol) and the reaction mixture was heated under reflux for 6 h until KI starch paper showed consumption of the fluorinating reagent. The reaction was stopped and the solvent removed under reduced pressure. The crude reaction mixture was dissolved in CH.sub.2Cl.sub.2 (10 ml) and the insoluble material was filtered off. The solution was washed with saturated aqueous NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and the solvent was concentrated in vacuo. The crude was chromatographed over silica gel (ISCO, 24 g, EtOAc in hexanes 0-80%) to give the desired product 2-fluoro-4-(3-fluorophenyl)cyclohexan-1-one (Q). LC-MS 211 (M+H+).

INTERMEDIATE R

benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (R)

(48) ##STR00033##

Step 1: 1-benzyl 2-methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1,2-dicarboxylate (R-1

(49) Into a 2000-mL 4-necked round-bottom flask, was placed DCM (450 ml), 1-benzyl 2-methyl (5R)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1,2-dicarboxylate (150 g, 1 eq) and 1-(N,N-dimethylsulfamoyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (370 g, 3 equiv), The resulting solution was stirred for 3 d at 80° C. in an oil bath. The reaction progress was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5-1/4) to give the desired product benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (R).

Step 2: benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (R-2)

(50) Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-benzyl 2-methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1,2-dicarboxylate (R-1) (40 g, 80 mmol) in THF (400 ml). This was followed by the addition of LiBH4 (7 g, 315 mmol) with stirring at 0° C. The resulting solution was stirred at 40° C. for 16 h. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3×500 ml of EA and the organic layers combined and dried over Na.sub.2SO.sub.4 and concentrated to give the desired product benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate. (ESI, m/z): (M+Na).sup.+: 514

Step 3: benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (R)

(51) Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (34 g, 69 mmol) in DMF (340 ml) was added TEA (8.36 g, 83 mmol) at r.t under N.sub.2. Then add DMAP (1.68 g, 14 mmol) to the system. This was followed by the addition of TESCl (12.5 g, 83 mmol) dropwise with stirring at 0° C. The resulting solution was stirred at 25° C. for 3 h. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 2×300 mL of EA. The organic layer was washed with 200 mL of brine and the organic layers combined and dried over Na.sub.2SO.sub.4 and concentrated. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (15/1) to give the desired product benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate. (ESI, m/z): (M+Na).sup.+: 606.

INTERMEDIATE S AND T

(52) ##STR00034##

(53) Benzyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (S) and benzyl (2R,3S,5R)-5-methyl-2-(((triethyl silyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (T) were prepared according to the same procedure provided in Intermediate R by substituting the appropriate methylsulfonyl chloride or trifluoroacetic anhydride.

INTERMEDIATE U

tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(54) ##STR00035## ##STR00036##

Step 1: benzyl (CIS)-3-((4-methoxybenzyl)amino)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (U-1)

(55) To a mixture of benzyl 3-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (I-3) (10.00 g, 24.54 mmol) in DCM (100 ml) at ambient temperature was added 4-METHOXYBENZYLAMINE (4.81 ml, 36.8 mmol), ACETIC ACID (0.070 ml, 1.227 mmol), and MgSO.sub.4 (5.91 g, 49.1 mmol). The mixture stirred for 3 hours before adding SODIUM TRIACETOXYBOROHYDRIDE (5.72 g, 27.0 mmol) and continuing stirring overnight. The reaction was quenched with a saturated solution of NaHCO.sub.3 (100 mL), extracted with DCM (3× @100 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (2% to 90% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 529.4 (M+1).

Step 2: benzyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (U-2)

(56) To a mixture of 1-METHYLIMIDAZOLE (226 μl, 2.84 mmol) in DMF (1433 μl) at 0° C. was added METHANESULFONYL CHLORIDE (221 μl, 2.84 mmol) dropwise. The mixture stirred for 20 min before adding benzyl (CIS)-3-((4-methoxybenzyl)amino)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (U-1) (250 mg, 0.473 mmol) and TRIETHYLAMINE (395 μl, 2.84 mmol) in DMF (1433 μl) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was quenched with a saturated solution of NaHCO.sub.3 (10 mL), extracted with DCM (3× @ 10 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (2% to 90% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 607.4 (M+1).

Step 3: N-(4-methoxybenzyl)-N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (U-3)

(57) To a mixture of benzyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (U-2) (130 mg, 0.214 mmol) in MeOH (2142 μl) at ambient temperature was added Pd/C (22.80 mg, 0.021 mmol). A hydrogen balloon was added (vacuum purge 3×) and the reaction was allowed to stir overnight. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give the title compound. MS: 473.4 (M+1).

Step 4: tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (U-4)

(58) To a mixture of N-(4-methoxybenzyl)-N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (U-3) (1.90 g, 4.02 mmol) in DCM (20.10 ml) at ambient temperature was added BOC2O (1.120 ml, 4.82 mmol) and TRIETHYLAMINE (1.121 ml, 8.04 mmol). The mixture was stirred for 2 hours before quenching with a saturated solution of NaHCO.sub.3 (20 mL), extracting with DCM (3× @ 30 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica (2% to 70% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 573.4 (M+1).

Step 5: tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (INTERMEDIATE U)

(59) To a solution of tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (U-4) (100 mg, 0.175 mmol) in MeCN (2000 μl) and Water (200 μl) was added KETOABNO (16.15 mg, 0.105 mmol) under ambient atmosphere and a constant Potential of 2.5 V was applied resulting in an initial current of 12.2 mA. The working electrode is RVC and the cathode was the IKA platinum plated electrode. Amount of LiClO4 was adjusted to be approximately 0.1M. Reaction stopped after 7 hours, Reaction worked up by partitioning between EtOAc and sat NaHCO.sub.3, phases separated, organic phase dried with MgSO.sub.4 and concentrated under vacuum. The residue was purified by column chromatography on silica (20% to 70% MTBE/hexanes) to afford the title compound.

INTERMEDIATE V

tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(60) ##STR00037## ##STR00038##

Step 1: tert-butyl (S)-3-amino-4-((tert-butyldiphenylsilyl)oxy)butanoate (V-2)

(61) To a mixture of tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-hydroxybutanoate (V-1) (5.00 g, 12.58 mmol) in DCM (15.72 ml) at ambient temperature was added TBDPS-Cl (3.55 ml, 13.84 mmol), TRIETHYLAMINE (2.279 ml, 16.35 mmol), and DMAP (0.154 g, 1.258 mmol). The mixture was heated to 40° C. for 3 hours before cooling back to ambient temperature and adding PIPERIDINE (3.74 ml, 37.7 mmol). The mixture stirred for another 1 hour before quenching with a saturated solution of NaHCO.sub.3 (50 mL), extracting with DCM (3× @ 50 mL), drying over Na.sub.2SO.sub.4, and concentrating. The residue was purified by column chromatography on silica (2% to 60% EtOAc/hexanes) to afford the title compound. MS: 414.5 (M+1).

Step 2: tert-butyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methoxycarbonyl)amino)butanoate (V-3)

(62) To a mixture of tert-butyl (S)-3-amino-4-((tert-butyldiphenylsilyl)oxy)butanoate (V-2) (5.15 g, 12.45 mmol) in DCM (37.7 ml) at ambient temperature was added TRIETHYLAMINE (3.47 ml, 24.90 mmol) and METHYL CHLOROFORMATE (1.157 ml, 14.94 mmol). The mixture stirred for 16 hour before quenching with a saturated solution of NaHCO.sub.3 (50 mL), extracting with DCM (3×@ 50 mL), drying over Na.sub.2SO.sub.4, and concentrating. The residue was purified by column chromatography on silica (1% to 40% EtOAc/hexanes) to afford the title compound. MS: 472.5 (M+1).

Step 3: (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methoxycarbonyl)amino)butanoic acid (V-4)

(63) To a mixture of tert-butyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methoxycarbonyl)amino)butanoate (V-3) (5.50 g, 11.66 mmol) in DCM (23.32 ml) at ambient temperature was added TFA (8.98 ml, 117 mmol). The mixture stirred for 4 hours before diluting with EtOAc (150 mL) and quenching with a saturated solution on NaHCO.sub.3 (150 mL), extract with EtOAc (3× @ 150 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 416.4 (M+1).

Step 4: methyl (S)-6-((tert-butyldiphenylsilyl)oxy)-5-((methoxycarbonyl)amino)-3-oxohexanoate (V-5)

(64) To a mixture of (S)-4-((tert-butyldiphenylsilyl)oxy)-3-((methoxycarbonyl)amino)butanoic acid (V-4) (2.50 g, 6.02 mmol) in THF (20.05 ml) at ambient temperature was added CDI (1.463 g, 9.02 mmol). The mixture stirred for 1 hour before adding potassium 3-methoxy-3-oxopropanoate (1.879 g, 12.03 mmol) and magnesium chloride (1.145 g, 12.03 mmol). The mixture was allowed to stir for 20 hours before quenching with a saturated solution of NaHCO.sub.3 (50 mL), extracting with EtOAc (3× @ 50 mL), drying over Na.sub.2SO.sub.4 and concentrating. The residue was purified by column chromatography on silica (2% to 75% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 472.4 (M+1).

Step 5: methyl (S)-6-((tert-butyldiphenylsilyl)oxy)-2-diazo-5-((methoxycarbonyl)amino)-3-oxohexanoate (V-6)

(65) To a mixture of methyl (S)-6-((tert-butyldiphenylsilyl)oxy)-5-((methoxycarbonyl)amino)-3-oxohexanoate (V-5) (1.75 g, 3.71 mmol) in DCM (18.55 ml) at ambient temperature was added 4-acetamidobenzenesulfonyl azide (0.891 g, 3.71 mmol) and TRIETHYLAMINE (1.552 ml, 11.13 mmol). The mixture stirred for 2 hours before diluting with water (20 mL), extracting with DCM (3× @ 20 mL), drying over Na.sub.2SO.sub.4 and concentrating. The residue was purified by column chromatography on silica (2% to 50% EtOAc/hexanes) to afford the title compound. MS: 498.4 (M+1).

Step 6: dimethyl (5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-oxopyrrolidine-1,2-dicarboxylate (V-7)

(66) To a mixture of methyl (S)-6-((tert-butyldiphenylsilyl)oxy)-2-diazo-5-((methoxycarbonyl)amino)-3-oxohexanoate (V-6) (1.80 g, 3.62 mmol) in Toluene (18.09 ml) at ambient temperature was added RHODIUM(II) ACETATE DIMER (0.080 g, 0.181 mmol) and the mixture was heated to 80° C. and stirred for 20 min. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica (2% to 80% EtOAc/hexanes) to afford the title compound. MS: 470.4 (M+1).

Step 7: dimethyl (2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (V-8)

(67) To a mixture of dimethyl (5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-oxopyrrolidine-1,2-dicarboxylate (V-7) (1.55 g, 3.30 mmol) in Tetrahydrofuran (22.00 ml) at 0° C. was added (4-methoxyphenyl)methanamine (0.517 ml, 3.96 mmol) followed by TITANIUM(IV) ISOPROPOXIDE (0.967 ml, 3.30 mmol) dropwise. The mixture was warmed to ambient temperature and stirred for 5 hours. To the mixture was added SODIUM TRIACETOXYBOROHYDRIDE (2.099 g, 9.90 mmol) and stirred for 20 hours. Add SODIUM TRIACETOXYBOROHYDRIDE (2.099 g, 9.90 mmol) and stir for another 24 hours. The reaction was diluted with EtOAc (100 mL) and quenched with a saturated solution of NaHCO.sub.3 (100 mL). Extract with EtOAc (3× @ 100 mL), dry over Na.sub.2SO.sub.4, and concentrate. The residue was purified by column chromatography on silica (2% to 75% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 591.6 (M+1).

Step 8: dimethyl (2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (INTERMEDIATE V)

(68) To a mixture of dimethyl (2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (V-8) (1650 mg, 2.79 mmol) in MeCN (3990 μl) at ambient temperature was added 1-(N,N-dimethylsulfamoyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (2843 mg, 8.38 mmol). The mixture was warmed to 80° C. and stirred for 3 days. The mixture was cooled and purified directly by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 698.6 (M+1).

INTERMEDIATE W

methyl (2R,3S,5R)-3-amino-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (W)

(69) ##STR00039## ##STR00040##

Step 1: benzyl (2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (W-1)

(70) To a stirred solution of benzyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (T) (400 mg, 0.673 mmol) and 4-(3-fluorophenyl)cyclohexan-1-one (L-3) (155 mg, 0.807 mmol) in acetonitrile (8000 μl) cooled in a acetonitrile/dry ice bath (−30° C.) was added triisopropylsilane (276 μl, 1.345 mmol). Trimethylsilyl trifluoromethanesulfonate (TMS-OTf) (122 μl, 0.673 mmol) as a solution in CH.sub.2Cl.sub.2 (1000 μl) was then added to above mixture dropwise under N.sub.2 at −30° C. The resulting mixture was stirred at −30° C. for 30 min. The cold bath was then replaced with an ice bath. After stirring for 1 hr at −0° C., the reaction was quenched with aqueous sodium hydrogen carbonate (saturated, 30 mL) and brine (10 ml) to facilitate layer separation. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried (Na.sub.2SO.sub.4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on 40 g ISCO silica gel column, eluting with 0 to 30% EtOAc/isohexane. The desired fractions were combined and concentrated under reduced pressure to afford the title compound. MS: 656.0 (M+1).

Step 2: 2,2,2-trifluoro-N-((2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-yl)-N-(4-methoxybenzyl)acetamide (W-2)

(71) To a stirred solution of benzyl (2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (547 mg, 0.833 mmol) (W-1) and palladium on carbon (17.73 mg, 0.167 mmol) in MeOH (10 ml) under a Hydrogen balloon. After 1 hr, the reaction was completed with formation of the desired product. The mixture was filtered through a diatomaceous earth cake, washing with methanol. The combined filtrates were concentrated under reduced pressure to the title compound. MS: 522.0 (M+1).

Step 3: methyl (2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (W-3)

(72) Methyl chloroformate (0.116 ml, 1.498 mmol) was added to a stirred and cooled in an ice bath mixture of 2,2,2-trifluoro-N-((2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-yl)-N-(4-methoxybenzyl)acetamide (435 mg, 0.832 mmol) (W-2) and triethylamine (0.348 ml, 2.497 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was directly purified by column chromatography on 80 g ISCO silica gel column, eluting with 0 to 50% EtOAc/isohexane. The desired fractions were combined and concentrated under reduced pressure to give the title compound. MS: 580.1 (M+1)

Step 4: methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (W-4)

(73) To a stirred solution of methyl (2R,3S,5R)-2-(((4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (W-3) (353 mg, 0.608 mmol) in THF (4000 μl)/MeOH (2000 Cl)/H2O (2000 μl) was added LiOH (87 mg, 3.65 mmol). The mixture was heated to 50° C. After 1 hr, the SM was fully consumed. Removed most of solvent under reduce pressure. The residue was added water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried (Na.sub.2SO.sub.4), filtered and the solvent was evaporated under reduced pressure. The residue was purified on a reverse preparative HPLC using C18 column and eluting with 5 to 75% water in acetonitrile+0.05% TFA in 15 min method. Two isomers were mostly separated. The desired fractions were combined and concentrated under reduced pressure to give title compound W-4a and W-4b. MS: 484.0 (M+H)

Step 5: methyl (2R,3S,5R)-3-amino-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (INTERMEDIATE W)

(74) To a stirred solution of methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)-methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (W-4a) (228 mg, 0.470 mmol) in MeOH (10 ml) was added acetic acid (0.027 ml, 0.470 mmol) followed by Pd(OH).sub.2 (66.1 mg, 0.094 mmol). The mixture was stirred at 25° C. under a hydrogen balloon. After 3 hr, the mixture was filtered, washing with methanol. The combined filtrates were concentrated under reduced pressure. The residue was purified by ISCO preparative reverse phase HPLC (40 g C18 column), eluting with 10 to 100% water in acetonitrile with 0.05% TFA. The desired fractions of cis isomer were combined and concentrated to the title compound. MS: 364.0 (M+H).

INTERMEDIATE X

Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate

(75) ##STR00041##

Step 1: Methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (X-1)

(76) A solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (R) (2.44 g, 4.61 mmol), 4-(benzyloxy)cyclohexan-1-one (1.223 g, 5.99 mmol) and TRIISOPROPYLSILANE (1.887 ml, 9.21 mmol) at −35° C. in DCM (4.61 ml)/Acetonitrile (41.5 ml) under N.sub.2 was treated with trimethylsilyl trifluoromethanesulfonate (0.834 ml, 4.61 mmol) via a syringe (glass) and needle and the mixture stirred at −35° C. for 3 h (temp up to −20 C). The reaction was quenched with Sat. Aq NaHCO.sub.3 and diluted with EtOAc. After warming to rt the layers were separated (need some brine) and the aq layer washed EtOAc. The combined organics was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel chromatography, on the Combiflash NextGEn 300+ with ELDS on an 80 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexanes—0:100 to 20:80 to afford the title compound (cis/trans). MS: m/z=604.4 (M+1).

Step 2: Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (X-2)

(77) In a round bottom flask containing a solution of methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (Intermediate X-1), 2.58 g, 4.27 mmol in MeOH (85 ml) was added PdOH2 (0.600 g, 0.855 mmol) and the flask sealed. The flask was purged, and the mixture stirred under a Hydrogen atmosphere (Balloon) for 10 h. The mixture was diluted with MeOH and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford the crude as a blackish solid. The crude was purified on the CombiFlash NextGEn 300+ with ELDS on a silica gel 80 g column, eluting with a gradient of ethyl acetate; ethanol (3:1)/hexane 0:100% to 60:40% to give the title compound (mixture of diastereomers). MS: m/z=514.3 (M+1).

Step 3: Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-oxocyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (X-3)

(78) A solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (Intermediate X-2) 1000 mg, 1.947 mmol, in DCM (9734 μl) at 0° C. was treated with Dess-Martin Periodinane (1651 mg, 3.89 mmol) in 3 portions and the mixture stirred at 0° C. for 15 min then at 25° C. for another 4.5 h. At 0° C. the mixture was quenched with Sat. Aq. NaHCO.sub.3 and diluted with DCM. The layers were separated and the aq layer washed with DCM. The combined organics was washed with brine, filtered and concentrated under reduced pressure to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ with ELSD on a silica gel 40 g column, eluting with a gradient of ethyl acetate; ethanol (3:1)/hexane 0:100% to 50:50% to give the title compound as a white sticky solid. MS: m/z=512.3 (M+1).

Step 3: Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate X)

(79) A suspension of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-oxocyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate X-3) 844 mg, 1.650 mmol in THF (8248 μl) at 25° C. was treated with 2-[N,N-BIS(TRIFLUOROMETHANESULFONYL)AMINO]-5-CHLOROPYRIDINE (713 mg, 1.815 mmol) and the mixture cool to −78° C. POTASSIUM BIS(TRIMETHYLSILYL)AMIDE (2145 μl, 2.145 mmol) (1 M in THF) was then added via a Hamilton syringe and needle dropwise and the mixture stirred at −78° C. for 2 h. At −78° C. the reaction was quenched with Sat. Aq. NaHCO.sub.3. The mixture was diluted with EtOAc and the layers separated. The aq layer was washed with EtOAc and the combined organics washed with brine, dried, filtered and concentrated under reduced pressure to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ with ELSD on a silica gel 24 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexane 0:100% to 60:45% to give the title compound (Intermediate X). LC-MS: m/z=644.3 (M+1).

EXAMPLE 1

(2R,3S,5R)—N-ethyl-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxamide

(80) ##STR00042##

Step 1: benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-(N-(4-methoxybenzyl)-methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (1-1)

(81) To a solution of benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxy-benzyl)-amino)-5-methylpyrrolidine-1-carboxylate (C-1) (500 mg, 0.995 mmol) in 30 mL of THF was added Et.sub.3N (0.416 mL, 2.98 mmol) followed by addition of MsCl (0.093 mL, 1.194 mmol) at 0° C. under N.sub.2. The resulting mixture was stirred at 0° C. for 1 hr, then warmed up to rt and stirred for 2 hr. LC-MS showed completion of the reaction. The reaction mixture was filtered and the filtrate was washed with 5 mL of H.sub.2O, extracted with DCM (2×20 mL). The combined organic phases were dried over MgSO.sub.4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with 0-30% EtOAc in hexanes as eluent to afford the title compound benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)-methyl)-3-(N-(4-methoxybenzyl)-methyl sulfonamido)-5-methylpyrrolidine-1-carboxylate. LC-MS 581 (M+1).

Step 2: N-((2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidin-3-yl)methanesulfonamide (1-2)

(82) A solution of benzyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-(N-(4-methoxybenzyl)-methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (30 mg, 0.052 mmol) was dissolved in 4 mL of 4N HCl in dioxane. The reaction mixture was sealed in a microwave tube and stirred to 80° C. for 8 h. The reaction mixture was concentrated and the crude was purified by column chromatography (C18, 10-100% acetonitrile in H.sub.2O) to give the title compound N-((2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidin-3-yl)methanesulfonamide. LC-MS 327 (M+1).

Step 3: (2R,3S,5R)—N-ethyl-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxamide (1)

(83) To a solution of N-((2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidin-3-yl)methanesulfonamide (1-2) (8 mg, 0.025 mmol) dissolved in MeOH (5 mL) was added rhodium on alumina (5%, 5.04 mg, 2.451 μmol), followed by a few drops of acetic acid. The reaction mixture was degassed and refilled with H2 from balloon for 3 times, then was stirred at rt for 2 h. LC-MS showed reaction completed. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated and dissolved in DCM (5 mL). To the reaction mixture was added TEA (0.019 mL, 0.138 mmol), followed by addition of isocyanatoethane (7.84 mg, 0.110 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred at rt for 30 min. LC-MS showed reaction completed. The reaction was quenched by addition of a few drops of methanol and the reaction mixture was filtered through a silica gel pad. The filtrate was concentrated in vacuo, followed by column chromatography (C18, 10-100% acetonitrile in H.sub.2O) to give the title compound. LC-MS 404 (M+1).

EXAMPLE 2

(2R,3S,5R)—N-ethyl-5-methyl-3-(methylsulfonamido)-2-(((4-(trifluoromethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide

(84) ##STR00043##

Step 1: (2R,3S,5R)—N-ethyl-3-((4-methoxybenzyl)amino)-5-methyl-2-((4-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxamide (2-1)

(85) To a solution of (2R,3S,5R)—N-(4-methoxybenzyl)-5-methyl-2-((4-(trifluoromethyl)-phenoxy)methyl)pyrrolidin-3-amine (D) (34 mg, 0.086 mmol) in DCM (1.0 mL) at 0° C. was added Et.sub.3N (0.036 mL, 0.259 mmol), followed by ethyl isocyanate (7.85 μl, 0.099 mmol). The reaction mixture was stirred at 0° C. under N.sub.2 for 30 mins. LC-MS showed no starting material left. The reaction mixture was concentrated in vacuo and the residue was purified by prep TLC on on silica gel with 5% MeOH/DCM as eluent to give the title compound (2R,3S,5R)—N-ethyl-3-((4-methoxybenzyl)amino)-5-methyl-2-((4-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxamide. LC-MS: 466.3 (M+1).

Step 2: (2R,3S,5R)-3-amino-N-ethyl-5-methyl-2-((4-(trifluoromethyl)phenoxy)methyl)-pyrrolidine-1-carboxamide (2-2)

(86) To a solution of (2R,3S,5R)—N-ethyl-3-((4-methoxybenzyl)amino)-5-methyl-2-((4-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxamide (2-1) (39 mg, 0.084 mmol) in 1 mL of MeOH was added dihydroxypalladium on carbon (5%, 23.53 mg, 0.034 mmol) followed by addition of 3 drops of conc. aq. HCl. The reaction mixture was degassed and refilled with H.sub.2, 3 times, then was stirred under H2 at rt for overnight. LC-MS showed the reaction was completed. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was neutralized with TEA, then was concentrated in vacuo and the residue was purified by prep silica gel TLC with 5% 7N NH.sub.3 in MeOH/DCM to provide the title compound (2R,3S,5R)-3-amino-N-ethyl-5-methyl-2-((4-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxamide (2-2). LC-MS: 346.2 (M+1).

Step 3: (2R,3S,5R)—N-ethyl-5-methyl-3-(methylsulfonamido)-2-((4-(trifluoromethyl)phenoxy)-methyl)pyrrolidine-1-carboxamide (2-3)

(87) To a solution of (2R,3S,5R)-3-amino-N-ethyl-5-methyl-2-((4-(trifluoromethyl)phenoxy)-methyl)pyrrolidine-1-carboxamide (2-2) (29 mg, 0.084 mmol) in 1 mL of DCM was added TEA (0.035 mL, 0.252 mmol) followed by addition of Ms-Cl (8.51 μl, 0.109 mmol) at 0° C. under N.sub.2.

(88) After stirring for 20 mins, LC-MS showed reaction completed. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on C18 with 10-100% acetonitrile in H.sub.2O as eluent to provide the title compound (2R,3S,5R)—N-ethyl-5-methyl-3-(methyl sulfonamido)-2-((4-(trifluoromethyl)phenoxy)-methyl)pyrrolidine-1-carboxamide (2-3). MS: 424.6 (M+1).

Step 4: (2R,3S,5R)—N-ethyl-5-methyl-3-(methylsulfonamido)-2-(((4-(trifluoromethyl)cyclohexyl)-oxy)methyl)pyrrolidine-1-carboxamide (2)

(89) To a solution of (2R,3S,5R)—N-ethyl-5-methyl-3-(methylsulfonamido)-2-((4-(trifluoro-methyl)phenoxy)methyl)pyrrolidine-1-carboxamide (2-3) (33 mg, 0.078 mmol) in 1.2 mL of MeOH was added rhodium on alumina (5%, 48.1 mg, 0.023 mmol) followed by 3 drops of acetic acid. The reaction mixture was degassed and refilled with H2 three times, then stirred under hydrogen balloon at rt for overnight. LC-MS indicated reaction was completed. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to afford the title compound (2R,3S,5R)—N-ethyl-5-methyl-3-(methyl sulfonamido)-2-(((4-(trifluoromethyl)-cyclohexyl)oxy)methyl)pyrrolidine-1-carboxamide (2). MS: 430.2 (M+1).

EXAMPLES 3 AND 4

methyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)-pyrrolidine-1-carboxylate and methyl (2R,3S,5R)-2-((((1s,4S)-4-isopropylcyclohexyl)oxy)-methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate

(90) ##STR00044## ##STR00045##

Step 1: methyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (3-1)

(91) To a solution of (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-N-(4-methoxybenzyl)-5-methylpyrrolidin-3-amine (C) (1.2 g, 3.26 mmol) dissolved in DCM (50 mL) was added Et.sub.3N (0.908 mL, 6.51 mmol), followed by addition of methyl carbonochloridate (369 mg, 3.91 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred at rt for 30 min. LC-MS showed no starting material remained. The reaction mixture was quenched by addition of a few drops of methanol, and the reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography on silica gel with 0-50% EtOAc in hexanes as eluent to give the title compound methyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (3-1). LC-MS 427 (M+1).

Step 2: methyl (2R,3S,5R)-3-amino-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidine-1-carboxylate (3-2)

(92) To a solution of methyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxy-benzyl)amino)-5-methylpyrrolidine-1-carboxylate (3-1) (1.3 g, 3.05 mmol) in MeOH (50 mL) was added dihydroxypalladium on carbon (5%, 856 mg, 0.305 mmol) and a few drops of aq. HCl. The reaction mixture was degassed and refilled with H2 with balloon for 3 times. The reaction mixture was stirred at rt for 2 h. LC-MS showed no starting material remained. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was neutralized by Et.sub.3N, then concentrated and chromatographed via column chromatography on C18 with 10-100% acetonitrile in H.sub.2O as eluent to give the title compound methyl (2R,3S,5R)-3-amino-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidine-1-carboxylate. LC-MS 307 (M+1).

Step 3: methyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxylate (3-3)

(93) To a solution of methyl (2R,3S,5R)-3-amino-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidine-1-carboxylate (3-2) (450 mg, 1.469 mmol) in DCM (5 mL) was added Et.sub.3N (0.614 mL, 4.41 mmol), followed by addition of Ms-Cl (0.137 mL, 1.762 mmol) at 0° C. under N.sub.2. After stirring for 30 min. LC-MS showed reaction completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography on C18 with 10-100% acetonitrile in H.sub.2O as eluent to give the tittle compound methyl (2R,3S,5R)-2-((4-isopropylphenoxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (3-3). LC-MS 385 (M+1).

Step 4: EXAMPLE 3: methyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate and EXAMPLE 4: methyl (2R,3S,5R)-2-((((1s,4S)-4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate

(94) To a solution of methyl (5R)-2-((4-isopropylphenoxy)methyl)-5-methyl-3-(methyl-sulfonamido)pyrrolidine-1-carboxylate (3-3) (250 mg, 0.650 mmol) in MeOH (5 mL) was added rhodium on alumia (5%, 134 mg, 0.065 mmol) and a few drops of acetic acid. The reaction mixture was degassed three times, then hydrogenated with balloon. After stirring for overnight, LC-MS showed reaction was completed. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give the title product methyl (2R,3S,5R)-2-(((4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (3).

(95) The crude material was further purified by column chromatography to title compound methyl (2R,3S,5R)-2-((((1s,4S)-4-isopropylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxylate (4). LC-MS 391 (M+1).

(96) The following compounds were prepared according to the general procedure provided in Examples 1-4, and procedures herein, by substituting the appropriate alkyl carbonochloridate and sulfamoyl chloride. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

(97) TABLE-US-00001 Exact Example Mass Number Structure Name [M + H].sup.+ 5 isopropyl (2R,3S,5R)-2-(((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1-carboxylate 419.0 6 isopropyl (2R,3S,5R)-2-(((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3-((N- methylsulfamoyl)amino) pyrrolidine-1-carboxylate 434.1 7 ethyl (2R,3S,5R)-2-(((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1-carboxylate 405.0 8 ethyl (2R,3S,5R)-3-((N,N- dimethylsulfamoyl)amino)-2- (((4- isopropylcyclohexyl)oxy)meth- yl)-5-methylpyrrolidine-1- carboxylate 434.2 9 0 2,2-difluoroethyl (2R,3S,5R)- 2-(((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1-carboxylate 441.1 10 2-fluoroethyl (2R,3S,5R)-2- (((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1-carboxylate 423.2 11 methyl (2R,3S,5R)-3-((N,N- dimethylsulfamoyl)amino)-5- methyl-2-(((4- (trifluoromethyl)cyclohexyl)oxy) methyl)pyrrolidine-1- carboxylate 446.1 12 methyl (2R,3S,5R)-5-methyl- 3-(methylsulfonamido)-2- (((4-(2,2,2- trifluoroethyl)cyclohexyl)oxy) methyl)pyrrolidine-1- carboxylate 431.2 13 2,2-difluoroethyl (2R,3S,5R)- 2-(((4- isopropylcyclohexyl)oxy)meth- yl)-5-methyl-3-((N- methylsulfamoyl)amino)pyrro- lidine-1-carboxylate 456.2 14 2,2-difluoroethyl (2R,3S,5R)- 3-((N,N- dimethylsulfamoyl)amino)-2- (((4- isopropylcyclohexyl)oxy)meth- yl)-5-methylpyrrolidine-1- carboxylate 470.3

EXAMPLE 15

methyl (2R,3S,5R)-5-methyl-3-(methyl sulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate

(98) ##STR00056##

1: benzyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-1)

(99) To a solution of benzyl (5R)-3-(benzyloxy)-2-formyl-5-methylpyrrolidine-1-carboxylate (F) (400 mg, 1.132 mmol) and (1s,4s)-4-phenylcyclohexan-1-ol (299 mg, 1.698 mmol) in 2 mL of acetonitrile was added chlorodimethylsilane (161 mg, 1.698 mmol) at 0° C. under N.sub.2. The reaction mixture was raised to rt and stirred for 8 h. LC-MS showed formation of the desired product. The reaction was quenched by sat. aq. NaHCO.sub.3, and the mixture was diluted with 5 mL of DCM, derived by MgSO.sub.4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on C18 with 10-100% acetonitrile in H.sub.2O as eluent to give the title compound benzyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-1). LC-MS 514 (M+1).

Step 2: methyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-2)

(100) To a solution of benzyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-1) (210 mg, 0.409 mmol) in THF (10 mL) was added palladium on carbon (5%, 87 mg, 0.041 mmol). The reaction mixture was degassed and refilled with H2 three times from a balloon. The reaction mixture was stirred at rt for 30 min.

(101) LC-MS showed reaction completed. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give the crude product (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine. LC-MS 380 (M+1). The crude product was dissolved in DCM (5 mL), followed by addition of Et.sub.3N (0.044 mL, 0.316 mmol) and chloromethylformate (17.93 mg, 0.190 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred for 20 min. LC-MS showed reaction completed. The reaction mixture was quenched by methanol, then was concentrated in vacuo. The crude was chromatographed over silica gel with 0-50% EtOAc in hexanes as eluent to give the title compound methyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-2). LC-MS 438 (M+1).

Step 3: methyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-3)

(102) A solution of methyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1S,4R)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (15-2) (45 mg, 0.103 mmol) was dissolved in methanol (5 mL), followed by addition of dihydroxypalladium on carbon (5%, 28.9 mg, 10.28 μmol). The reaction mixture was degassed and refilled with H2 for 3 times, then stirred at rt for 2 h. LC-MS showed reaction was complete. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The crude was chromatographed over silica gel on C18 with 10-100% acetonitrile in H.sub.2O to give the title compound methyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-3). LC-MS 348 (M+1).

Step 4: methyl (2S,5R)-5-methyl-3-oxo-2-(((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-4)

(103) A solution of methyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (15-3) (30 mg, 0.086 mmol) was dissolved in DCM (5 mL), followed by addition of Dess-MartinPeriodinane (36.6 mg, 0.086 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred for 2 h. LC-MS showed reaction was complete. The reaction mixture was washed with sat. aq. NaHCO.sub.3, then was dried (MgSO.sub.4) and concentrated in vacuo. The crude material was chromatographed over silica gel and eluted with 10-100% acetonitrile in H.sub.2O to give the title compound methyl (2S,5R)-5-methyl-3-oxo-2-((((1s,4R)-4-phenylcyclohexyl)-oxy)-methyl)pyrrolidine-1-carboxylate (15-4). LC-MS 346 (M+1).

Step 5: methyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-5)

(104) To a solution of methyl (2S,5R)-5-methyl-3-oxo-2-(((((1S,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (15-4) (20 mg, 0.058 mmol) in DCM (10 mL) was added (4-methoxyphenyl)methanamine (8.74 mg, 0.064 mmol) and catalytic amount of acetic acid (0.166 μl, 2.89 μmol). The mixture was stirred at rt for 30 mins, then sodium triacetoxyborohydride (14.72 mg, 0.069 mmol) was added to the mixture. The reaction was stirred at rt for overnight. LCMS showed completion of the reaction. The reaction was quenched with saturated NaHCO.sub.3 solution (10 mL), extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel with 0-100% EtOAc in hexanes as eluent to afford the title compound methyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (15-5). LCMS 467 (M+1).

Step 6: methyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (15-6)

(105) A solution of methyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-5) (18 mg, 0.039 mmol) was dissolved in MeOH (10 mL), followed by addition of dihydroxypalladium on carbon (5%, 10.83 mg, 3.86 mol). The reaction mixture was degassed and refilled with H2 for 3 times with balloon. The reaction mixture was stirred at rt for 30 min. LC-MS showed reaction was completed. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated and chromatographed over over C18 with 10-100% acetonitrile in H.sub.2O) to give the title compound methyl (2R,3S,5R)-3-amino-5-methyl-2-(((4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15-6). LC-MS 347 (M+1).

Step 7: methyl (2R,3S,5R)-5-methyl-3-(methyl sulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (15)

(106) To a solution of methyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (15-6) (10 mg, 0.029 mmol) in DCM (5 mL) was added Et.sub.3N (0.012 mL, 0.087 mmol), followed by addition of Ms-Cl (2.70 μl, 0.035 mmol) at 0° C. under N.sub.2.

(107) After stirring for 30 min. LC-MS showed reaction was completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude was purified by column chromatography over C18 with 10-100% acetonitrile in H.sub.2O to give the title compound methyl (2R,3S,5R)-5-methyl-3-(methyl sulfonamido)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (15). LC-MS 425 (M+1); .sup.1H NMR (500 MHz, Methanol-d4) δ 7.26 (m, 4H), 7.15 (m, 1H), 4.14 (s, 1H), 3.99 (dt, J=12.0, 7.7 Hz, 1H), 3.95-3.82 (m, 1H), 3.79-3.65 (m, 5H), 3.03 (s, 3H), 2.58 (ddd, J=12.2, 8.9, 3.3 Hz, 1H), 2.45 (dt, J=12.1, 7.3 Hz, 1H), 2.20-2.04 (m, 2H), 2.04-1.75 (m, 3H), 1.72-1.51 (m, 4H), 1.41 (d, J=6.0 Hz, 3H).

EXAMPLE 16

2,2-difluoroethyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(108) ##STR00057## ##STR00058##

Step 1: 2,2-difluoroethyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-1)

(109) To a solution of benzyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)-oxy)-methyl)pyrrolidine-1-carboxylate (15-1) (160 mg, 0.311 mmol) in THF (10 ml) was added palladium on carbon (5%, 66 mg, 0.031 mmol). The reaction mixture was degassed and refilled with H2 from a balloon. The reaction mixture was stirred at rt for 30 min. LC-MS shown reaction completed. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the crude product (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine. LC-MS 380 (M+1).

(110) The crude product (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine was dissolved in CH.sub.2Cl.sub.2 (5 ml), followed by addition of Et.sub.3N (0.081 ml, 0.58 mmol) and 2,2-difluoroethyl carbonochloridate (50.3 mg, 0.348 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred for 20 min. LC-MS shown reaction completed. The reaction mixture was quenched by methanol, then was concentrated in vacuo. The crude was chromatographed over silic gel with 0-50% EtOAc in hexanes as eluent to give the title compound 2,2-difluoroethyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-1). LC-MS 488 (M+1).

Step 2: 2,2-difluoroethyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-2)

(111) A solution of 2,2-difluoroethyl (2S,5R)-3-(benzyloxy)-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-1) (120 mg, 0.246 mmol) was dissolved in methanol (10 ml), followed by addition of dihydroxypalladium on carbon (5%, 69.1 mg, 0.025 mmol). The reaction mixture was degassed and refilled with H2 for 3 times, then stirred at rt for 2 h. LC-MS shown reaction completed. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The crude was chromatographed over silic gel on C18 with 10-100% acetonitrile in H.sub.2O to give the title compound 2,2-difluoroethyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-2). LC-MS 398 (M+1).

Step 3: 2,2-difluoroethyl (2S,5R)-5-methyl-3-oxo-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (16-3)

(112) A solution of 2,2-difluoroethyl (2S,5R)-3-hydroxy-5-methyl-2-((((1s,4R)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-2) (80 mg, 0.201 mmol) was dissolved in CH.sub.2Cl.sub.2 (5 ml), followed by addition of Dess-MartinPeriodinane (85 mg, 0.201 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred for 2 h. LC-MS shown reaction completed. The reaction mixture was washed with sat. aq. NaHCO.sub.3, then was dried (MgSO.sub.4) and concentrated in vacuo. The crude was chromatographed over silic gel and eluted with 10-100% acetonitrile in H.sub.2O to give the title compound 2,2-difluoroethyl (2S,5R)-5-methyl-3-oxo-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (16-3). LC-MS 396 (M+1).

Step 4: 2,2-difluoroethyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (16-4)

(113) To a solution of 2,2-difluoroethyl (2S,5R)-5-methyl-3-oxo-2-((((1s,4R)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (16-3) (55 mg, 0.139 mmol) in DCM (10 ml) was added (4-methoxyphenyl)methanamine (20.99 mg, 0.153 mmol) and catalytic amount of acetic acid (0.398 μl, 6.95 μmol). The mixture was stirred at rt for 30 mins, then sodium triacetoxyborohydride (35.4 mg, 0.167 mmol) was added to the mixture. The reaction was stirred at rt for overnight. LCMS shown completion of the reaction. The reaction was quenched with saturated NaHCO.sub.3 solution (10 ml), extracted with CH.sub.2Cl.sub.2 (3×5 ml). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel with 0-100% EtOAc in hexanes as eluent to afford the title compound 2,2-difluoroethyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (16-4). LCMS 517 (M+1).

Step 5: 2,2-difluoroethyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-5)

(114) A solution of 2,2-difluoroethyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (16-4) (18 mg, 0.035 mmol) was dissolved in MeOH (10 ml), followed by addition of dihydroxypalladium on carbon (5%, 9.8 mg, 3.48 μmol). The reaction mixture was degassed and refilled with H2 for with balloon. The reaction mixture was stirred at rt for 30 min. LC-MS shown reaction completed. The reaction mixture was filtered through a syringe filter and the filtrate was concentrated and chromatographed over over C18 with 10-100% acetonitrile in H.sub.2O) to give the title compound 2,2-difluoroethyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-5). LC-MS 397 (M+1).

Step 6: 2,2-difluoroethyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (16)

(115) To a solution of 2,2-difluoroethyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-5) (10 mg, 0.025 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added Et.sub.3N (0.011 ml, 0.076 mmol), followed by addition of methylsulfamoyl chloride (3.92 mg, 0.030 mmol) at 0° C. under N.sub.2. After stirring for 30 min. LC-MS shown reaction completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude was purified by column chromatography over C18 with 10-100% acetonitrile in H.sub.2O to give the title compound 2,2-difluoroethyl (2R,3S,5R)-5-methyl-3-((N-methyl sulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (16). LC-MS 490.1 (M+1); .sup.1H NMR (500 MHz, Methanol-d4) δ 7.30 (dt, J=11.8, 7.3 Hz, 4H), 7.08 (tt, J=6.4, 1.7 Hz, 1H), 6.07 (t, J=55.0 Hz, 1H), 4.33 (dt, J=30.0, 15.6 Hz, 2H), 4.23 (dt, J=7.2, 3.3 Hz, 1H), 4.11 (m, 1H), 3.87 (dt, J=11.9, 7.7 Hz, 2H), 3.75-3.60 (m, 3H), 3.39 (s, 1H), 3.17 (p, J=1.6 Hz, 19H), 2.80 (s, 3H), 2.59 (tt, J=12.2, 3.3 Hz, 1H), 2.48 (dd, J=10.2, 4.1 Hz, 1H), 2.12 (ddt, J=19.8, 14.0, 2.8 Hz, 2H), 1.98-1.74 (m, 3H), 1.69-1.55 (m, 4H), 1.43 (d, J=6.0 Hz, 3H).

EXAMPLE 17

2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(116) ##STR00059##

(117) To a solution of 2,2-difluoroethyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (16-5) (9 mg, 0.023 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added Et.sub.3N (0.010 ml, 0.068 mmol), followed by addition of dimethylsulfamoyl chloride (3.66 μl, 0.034 mmol) at 0° C. under N.sub.2. After stirring for 48 h, LC-MS shown reaction completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude was purified by column chromatography over C18 with 10-100% acetonitrile in H.sub.2O to give the title compound 2,2-difluoroethyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (17). LC-MS 504.2 (M+1); .sup.1H NMR (500 MHz, Chloroform-d) δ 7.25 (dt, J=11.8, 7.3 Hz, 4H), 7.15 (tt, J=6.4, 1.7 Hz, 1H), 6.08 (t, J=55.0 Hz, 1H), 4.33 (dt, J=30.0, 15.6 Hz, 2H), 4.17 (dt, J=7.2, 3.3 Hz, 1H), 3.95 (dt, J=11.9, 7.7 Hz, 2H), 3.82-3.67 (m, 3H), 3.61 (s, 1H), 3.33 (p, J=1.6 Hz, 19H), 2.81 (s, 6H), 2.58 (tt, J=12.2, 3.3 Hz, 1H), 2.46 (dd, J=10.2, 4.1 Hz, 1H), 2.12 (ddt, J=19.8, 14.0, 2.8 Hz, 2H), 1.96 (s, 1H), 1.93-1.74 (m, 3H), 1.71-1.56 (m, 4H), 1.43 (d, J=6.0 Hz, 3H).

EXAMPLE 18

methyl (2R,3S, R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate

(118) ##STR00060##

methyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (18)

(119) To a solution of methyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (15-6) (12 mg, 0.035 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added Et.sub.3N (0.014 ml, 0.104 mmol), followed by addition of methylsulfamoyl chloride (6.73 mg, 0.052 mmol) at 0° C. under N.sub.2. After stirring for 30 min. LC-MS shown reaction completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude was purified by column chromatography over C18 with 10-100% acetonitrile in H.sub.2O to give the title compound methyl (2R,3S,5R)-5-methyl-3-((N-methyl-sulfamoyl)amino)-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (18). LC-MS 440.1 (M+1); .sup.1H NMR (500 MHz, Chloroform-d) δ 7.29-7.21 (m, 4H), 7.15 (t, J=6.8 Hz, 1H), 4.17 (s, 1H), 3.84 (ddd, J=12.3, 8.9, 6.6 Hz, 2H), 3.70 (d, J=15.8 Hz, 6H), 3.60-3.48 (m, 1H), 3.36-3.29 (m, 4H), 2.65 (s, 3H), 2.58 (ddd, J=15.4, 7.8, 3.2 Hz, 1H), 2.46 (dt, J=14.2, 7.0 Hz, 1H), 2.11 (dd, J=25.5, 14.0 Hz, 2H), 1.96-1.75 (m, 3H), 1.63 (q, J=14.5, 13.5 Hz, 4H), 1.40 (d, J=5.9 Hz, 3H), 1.31 (s, 1H).

EXAMPLE 19

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate

(120) ##STR00061##

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (19)

(121) To a solution of methyl (2R,3S,5R)-3-amino-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (15-6) (12 mg, 0.029 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added Et.sub.3N (0.014 ml, 0.104 mmol), followed by addition of dimethylsulfamoyl chloride (5.58 μl, 0.052 mmol) at 0° C. under N.sub.2. After stirring for 48 h, LC-MS shown reaction completed. To the reaction mixture was added a few drops of methanol, then the reaction mixture was concentrated in vacuo. The crude was purified by column chromatography over C18 with 10-100% acetonitrile in H.sub.2O to give the title methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (19). LC-MS 454.2 (M+1); .sup.1H NMR (500 MHz, Chloroform-d) δ 7.31-7.20 (m, 4H), 7.15 (t, J=6.9 Hz, 1H), 4.87 (s, 8H), 4.22-4.11 (m, 1H), 3.88 (ddt, J=35.1, 9.2, 7.2 Hz, 2H), 3.70 (d, J=15.3 Hz, 6H), 3.33 (s, 6H), 2.81 (s, 6H), 2.58 (tt, J=12.2, 3.1 Hz, 1H), 2.45 (dt, J=12.3, 7.4 Hz, 1H), 2.10 (ddt, J=25.4, 14.0, 6.9 Hz, 2H), 1.97-1.74 (m, 3H), 1.63 (q, J=15.4, 12.5 Hz, 4H), 1.40 (d, J=6.0 Hz, 3H), 1.31 (s, 1H).

(122) The following compounds were prepared according to the general procedure provided in Examples 1-15, and procedures herein, by substituting the appropriate alkyl carbonochloridate, methylsulfamoyl chloride and dimethylsulfamoyl chloride. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

(123) TABLE-US-00002 Exact Example Mass Number Structure Name [M + H].sup.+ 20 methyl (2R,3S,5R)-2- ((((1r,4R)-4-(2,5- difluorophenyl)cyclo- hexyl)oxy)methyl)-5- methyl-3-(methylsulfona- mido)pyrrolidine-1- carboxylate 461.2 21 methyl (2R,3S,5R)-2- ((((1R,4R)-4-(2,5- difluorophenyl) cyclohexyl)oxy)methyl)-3- ((N,N-dimethylsulfa- moyl)amino)-5- methylpyrrolidine-1- carboxylate 490.1 22 2,2-difluoroethyl (2R,3S,5R)-2-((((1r,4R)-4- (2,5-difluorophenyl)- cyclohexyl)oxy)methyl)-3- ((N,N- dimethylsulfamoyl)amino)- 5-methylpyrrolidine-1- carboxylate 540.2 23 methyl (2R,3S,5R)-3-((N,N- dimethylsulfamoyl)amino)- 2- ((((1s,4S)-4-(2- fluorophenyl)cyclohexyl)oxy) methyl-5- methylpyrrolidine-1- carboxylate 472.2 24 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohexyl)oxy) methyl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1-carboxylate 443.2 25 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohexyl)oxy) methyl)-5-methyl-3-((N- methylsulfamoyl)amino)pyrro- lidine-1-carboxylate 458.2 26 methyl (2R,3S,5R)-3- ((fluoromethyl)sulfonamido)- 2-((((1s,4S)-4-(3- fluorophenyl)cyclohexyl)oxy) methyl)-5- methylpyrrolidine-1- carboxylate 461.2 27 methyl (2R,3S,5R)-5- methyl-3- (methylsulfonamido)-2- ((((1r,4R)-4-(2-(trifluorometh- yl)phenyl)cyclohexyl)oxy) methyl)pyrrolidine-1- carboxylate 493.2 28 0 methyl (2R,3S,5R)-5- methyl-3- (methylsulfonamido)-2- ((((1r,4R)-4-(2,3,6- trifluorophenyl)- cyclohexyl)oxy)methyl)pyrro- lidine-1-carboxylate 479.1 29 methyl (2R,3S,5R)-3- ((fluoromethyl)sulfonamido)- 5-methyl-2-((((1r,4R)-4- phenylcyclohexyl)oxy)meth- yl)pyrrolidine-1-carboxylate 443.3

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (30)

(124) ##STR00072##

Step 1: benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (30-1)

(125) To a solution of benzyl (5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (R) (300 mg, 0.495 mmol), 2-fluoro-4-phenylcyclohexan-1-one (143 mg, 0.743 mmol) in acetonitrile (20 ml) was added triisopropylsilane (157 mg, 0.99 mmol) and trimethylsilyl trifluoromethanesulfonate (132 mg, 0.594 mmol) at −20° C. under N.sub.2. The reaction mixture was raised to 0° C. and stirred for overnight. LC-MS shown formation of desired product. The reaction was quenched by addition of 1 ml of sat. aq. NaHCO3, and the mixture was diluted with 10 ml of EtOAc, dried by MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Gilson, C18, 10-100% acetonitrile in H.sub.2O) to give the product benzyl (5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (30-1). LC-MS is 548.2 (M+H+).

Step 2: (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine (30-2)

(126) To a solution of benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (30-1) (130 mg, 0.237 mmol) dissolved in THF (2.00 ml) was added palladium on carbon (25.3 mg, 0.237 mmol), degassed and refilled with H2 from a balloon. The reaction mixture was stirred for 1 h. LC-MS shown Cbz removed. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the desired product (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine (30-2). The crude was pure enough for direct use in the following step. LC-MS is 414.2 (M+H+).

Step 3: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (30)

(127) To a solution of (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidine (91 mg, 0.22 mmol) dissolved in CH.sub.2Cl.sub.2 (10 ml), was added TEA (0.066 ml, 0.475 mmol) and methyl carbonochloridate (33.6 mg, 0.356 mmol). After stirring for 1 h, LC-MS shown formation of the desired product. To the reaction mixture was added a few drops of MeOH, then the reaction mixture was concentrated and chromatographed over Gilson (10-100% EtOAc Acetonitrile in H.sub.2O) to give the desired products methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1R,4S)-2-fluoro-4-phenylcyclo-hexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate and diastereomers (30). LC-MS 472.2.

(128) The following compounds were prepared according to the general procedure provided in Examples 30, and procedures herein, by using different arylcyclohexanones. The starting materials are either prepared as described in the intermediates section (intermediate Q), or commercially available 4-(3,5-difluorophenyl)cyclohexan-1-one as described in Example 32.

(129) TABLE-US-00003 31 methyl (2R,3S,5R)-3-((N,N- dimethylsulfamoyl)amino)-2- ((((1R,4S)-2-fluoro-4-(3- fluorophenyl)cyclohexyl)oxy)methyl)- 5-methylpyrrolidine-1-carboxylate 490.2 32 methyl (2R,3S,5R)-2-((((1s,4S)-4- (3,5-difluorophenyl)cyclohexyl)oxy) methyl)-3-((N,N- dimethylsulfamoyl)amino)-5- methylpyrrolidine- 1-carboxylate 490.4

EXAMPLE 33

methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (33)

(130) ##STR00075##

Step 1: benzyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-1)

(131) To a solution of benzyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (S) (150 mg, 0.260 mmol) in acetonitrile (3.0 ml) at 0° C. was added 2-methoxy-4-phenylcyclohexan-1-one (69.1 mg, 0.338 mmol) followed by triisopropylsilane (0.107 ml, 0.520 mmol) under N.sub.2. Then the reaction mixture was cooled to −30° C. DCM (0.35 ml) was added followed by trimethylsilyl trifluoromethanesulfonate (0.047 ml, 0.260 mmol). The reaction mixture was allowed warm up to 0° C. slowly. After 5 mins stirring at 0° C., LC-MS showed completion. The reaction mixture was quenched with sat. aq. NH.sub.4Cl. The reaction mixture was extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave colorless oil. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM to give the title compound benzyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-1). LC-MS 651 (M+1).

Step 2: N-((2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (33-2)

(132) To a solution of benzyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-1) (125 mg, 0.192 mmol) in THF (2.5 ml) was added 10% palladium on carbon (20.44 mg, 0.019 mmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon for 55 mins, LC-MS showed completion. The reaction mixture was filtered through a celite pad. The filtrate was concentrated to leave yellow oil. The residue was purified by prep silica gel TLC eluent with 4% 7N NH.sub.3 in MeOH/DCM to give the title compound N-((2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (33-2). LC-MS 517 (M+1).

Step 3: methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-3)

(133) To a solution of N-((2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (33-2) (59 mg, 0.114 mmol) in DCM (1.5 ml) at 0° C. was added Et.sub.3N (0.048 ml, 0.343 mmol) followed by methyl carbonochloridate (11 μl, 0.148 mmol) under N.sub.2. The reaction mixture was stirred at 0° C. for 20 mins. LC-MS showed completion. The reaction mixture was concentrated to leave colorless film. The residue was purified by prep silica gel TLC eluent with 4% MeOH/DCM to give the title compound methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-3). LC-MS 575 (M+1).

Step 4: methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (33)

(134) To a solution of methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (33-3) (55 mg, 0.096 mmol) in DCM (1.5 ml) was added MsOH (37 μl, 0.574 mmol) at rt under N2. The reaction mixture was stirred at rt for 20 mins, LC-MS showed completion. The reaction mixture was concentrated to leave colorless film. The residue was purified by Gilson to give the title compound methyl (2R,3S,5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)-pyrrolidine-1-carboxylate (33). LC-MS 455 (M+1).

EXAMPLE 34

methyl (2R,3S,5R)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (34)

(135) ##STR00076##

Step 1: N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (34-1)

(136) To a solution of benzyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (S) (620 mg, 1.075 mmol) in THF (12 ml) was added 10% palladium on carbon (114 mg, 0.107 mmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon for 1 hr, LC-MS showed completion. The reaction mixture was filtered through a celite pad. The filtrate was concentrated to give the title compound N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (34-1). LC-MS 444 (M+1).

Step 2: methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2 (((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (34-2)

(137) To a solution of N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)-methyl)pyrrolidin-3-yl)methanesulfonamide (34-1) (450 mg, 1.017 mmol) in DCM (10 ml) at 0° C. was added Et3N (0.425 ml, 3.05 mmol) followed by methyl chloroformate (0.102 ml, 1.321 mmol) under N.sub.2. The reaction mixture was stirred at 0° C. for 50 mins. LC-MS showed completion. The reaction mixture was concentrated to leave yellow oil. The residue was purified by prep silica gel TLC eluent with 1% MeOH/DCM to give the title compound methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethyl silyl)oxy)-methyl)pyrrolidine-1-carboxylate (34-2). LC-MS 501 (M+1).

Step 3: methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (34-3)

(138) To a solution of methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (34-2) (110 mg, 0.220 mmol) in Acetonitrile (1.5 ml) and DCM (1.5 ml) at 0° C. was added 2-methyl-4-phenylcyclohexan-1-one (62.0 mg, 0.330 mmol) followed by triisopropylsilane (0.090 ml, 0.439 mmol) under N.sub.2. Then the reaction mixture was cooled to −30° C. Trimethylsilyl trifluoromethanesulfonate (0.040 ml, 0.220 mmol) was added. The reaction mixture was allowed warm up to 0° C. slowly. After 1.5 hrs stirring at 0° C., LC-MS showed the major was desired product formation. The reaction mixture was quenched with sat. aq. NaHCO.sub.3. The reaction mixture was extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave colorless oil. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM to give the title compound methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (34-3). LC-MS 559 (M+1).

Step 4: methyl (2R,3S,5R)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (34)

(139) To a solution of methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (34-3) (108 mg, 0.193 mmol) in DCM (2.0 ml) was added MsOH (75 μl, 1.160 mmol) at rt under N.sub.2. The reaction mixture was stirred at rt started for 25 mins, LC-MS showed completion. The reaction mixture was concentrated to leave light brown film. The residue was purified by Gilson to give the title compound methyl (2R,3S,5R)-5-methyl-2-(((2-methyl-4-phenylcyclohexyl)oxy)methyl)-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (34). LC-MS 439 (M+1).

EXAMPLE 35 AND 36

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (35) methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36)

(140) ##STR00077## ##STR00078## ##STR00079##

Step 1: N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidin-3-yl)-N,N-dimethylsulfonamide (36-1)

(141) To a solution of benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (C) (2.0 g, 3.30 mmol) in THF (30 ml) was added 10% palladium on carbon (351 mg, 0.330 mmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon for 100 mins. LC-MS showed completion. The reaction mixture was filtered through a celite pad. The filtrate was concentrated to give the title compound N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidin-3-yl)-N,N-dimethylsulfonamide (36-1). LC-MS 473 (M+1).

Step 2: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (36-2)

(142) To a solution of N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2 (((triethylsilyl)oxy)methyl)pyrrolidin-3-yl)-N,N-dimethylsulfonamide (36-1) (1.55 g, 3.29 mmol) in DCM (24 ml) at 0° C. was added Et.sub.3N (1.374 ml, 9.86 mmol) followed by methyl chloroformate (0.331 ml, 4.27 mmol) under N.sub.2. The reaction mixture was stirred at 0° C. for 20 mins and then warmed up to rt and stirred at rt for 2 hrs. LC-MS showed completion. The reaction mixture was quenched with water. Separated the organic layer, dried with MgSO.sub.4, concentrated to leave yellow oil. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM t to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (36-2). LC-MS 530 (M+1).

Step 3: methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethyl-sulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (36-3)

(143) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (36-2) (3.32 g, 6.27 mmol) in Acetonitrile (48 ml) at 0° C. was added 4-(benzyloxy)cyclohexan-1-one (1.92 g, 9.40 mmol) followed by triisopropylsilane (2.57 ml, 12.53 mmol) under N2. Then the reaction mixture was cooled to −30° C., trimethylsilyl trifluoromethanesulfonate (1.134 ml, 6.27 mmol) was added. It was continued to stir at −30° C. for 4 hrs. LC-MS showed almost completion. The reaction mixture was quenched with sat. aq. NaHCO.sub.3. The reaction mixture was extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave yellow oil. The residue was purified by ISCO (Loaded onto a 80 g column, eluent with 0˜55% EtOAc/hexane, the peak was collected at 50% EtOAc/hexane) to give the title compound methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (36-3). LC-MS 604 (M+1).

Step 4: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-4)

(144) To a solution of methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (36-3) (3.65 g, 6.05 mmol) in MeOH (45 ml) was added PALLADIUM HYDROXIDE ON CARBON (20%, 1.486 g, 2.116 mmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon overnight. LC-MS showed completion. The reaction mixture was filtered through a celite pad. The filtrate was concentrated) to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate & methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-4). LC-MS 514 (M+1).

Step 5: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-oxocyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (36-5)

(145) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate and methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((4-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-4) (3.08 g, 6.00 mmol) in DCM (50 ml) at 0° C. was added DESS-MARTIN PERIODINANE (5.09 g, 11.99 mmol). The reaction mixture was stirred at 0° C. for 30 mins and then let it warm up to rt slowly and stirred at rt overnight. LC-MS showed completion. The reaction mixture was washed with sat. NaHCO.sub.3. The organic layer was dried with MgSO.sub.4, concentrated to leave yellow oil. The residue was purified by ISCO (Loaded onto a 80 g column, eluent with 0˜6% MeOH/DCM, the peak was collected at 6% MeOH/DCM) to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-oxocyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (36-5). LC-MS 512 (M+1).

Step 6: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-((((S)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (36-6)

(146) To a mixture of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-methyl-2-(((4-oxocyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (36-5) (2.94 g, 5.75 mmol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (2.93 g, 7.47 mmol) in 55 ml of THF at −78° C. was added POTASSIUM BIS(TRIMETHYLSILYL)AMIDE (1.0 M in THF, 8.62 ml, 8.62 mmol). The reaction mixture was stirred at −78° C. under nitrogen for 4 hrs. LC-MS showed the major was desired product. The reaction was quenched with sat. NaHCO.sub.3 at −78° C. Let it stirring at rt for 30 mins. Extracted with EtOAc (×3). The organic layer was dried with MgSO.sub.4, concentrated to leave brown oil. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-methyl-2-((((S)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)-pyrrolidine 1-carboxylate (36-6). LC-MS 644 (M+1).

Step 7: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-7)

(147) A suspension of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxy-benzyl)amino)-5-methyl-2-((((S)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (36-6) (53 mg, 0.082 mmol), 1,1′-BIS(DIPHENYL-PHOSPHINO)FERROCENE-PALLADIUM(II)DICHLORIDE DICHLOROMETHANE COMPLEX (13.45 mg, 0.016 mmol), SODIUM CARBONATE (26.2 mg, 0.247 mmol) and (3-fluorophenyl)boronic acid (13.82 mg, 0.099 mmol) in Dioxane (1 ml) and Water (0.5 ml) was bubbled with nitrogen for 5 min. The reaction mixture was sealed in the reaction vial and heated at 100° C. overnight. LC-MS showed completion. The reaction mixture was purified by prep silica gel TLC eluent with 2% MeOH/DCM to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-7). LC-MS 590 (M+1).

Step 8: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (35)

(148) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxy-benzyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-7) (7 mg, 0.012 mmol) in DCM (0.5 ml) was added MsOH (3.85 μl, 0.059 mmol) at rt under N2. The reaction mixture was stirred at rt for 1.5 hrs, LC-MS showed ˜70% desired product was formed. The reaction mixture was concentrated to leave colorless film. The residue was purified by Gilson to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (35). LC-MS 470 (M+1).

Step 9: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-8)

(149) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((S)-3′-fluoro-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-7) (35 mg, 0.059 mmol) in THF (1.5 ml) at 0° C. was added BORANE-THF COMPLEX (1.0 M in THF, 0.237 ml, 0.237 mmol). The reaction mixture was warmed up to rt and stirred at rt under nitrogen for 3 days. LC-MS showed the major was desired product. The reaction was cooled down in the ice bath again, and then water (21.38 μl, 1.186 mmol) was added followed by 3N NaOH (0.064 ml, 0.192 mmol) and H.sub.2O.sub.2 solution (30% in water, 0.064 ml, 0.734 mmol). The resulting reaction mixture was warmed up to rt and stirred at rt for another 2.5 hrs. Then the reaction mixture was quenched with brine, extracted with EtOAc twice. The organic layer was washed with water, dried with MgSO.sub.4, concentrated to leave colorless film. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-8). LC-MS 608 (M+1).

Step 10: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36)

(150) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxy-benzyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36-8) (10 mg, 0.016 mmol) in DCM (0.5 ml) was added MsOH (7.48 μl, 0.115 mmol) at rt under N2. The reaction mixture was stirred at rt for 5 mins, LC-MS showed completion. The reaction mixture was concentrated to leave colorless film. The residue was purified by Gilson to give the title compound methyl (2R,3S,5R)-3-((N,N-dimethyl-sulfamoyl)amino)-2-((((1S)-4-(3-fluorophenyl)-3-hydroxycyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (36). LC-MS 488 (M+1).

EXAMPLE 37

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)-oxy)methyl)-5-methylpyrrolidine-1-carboxylate

(151) ##STR00080## ##STR00081##

Step 1: benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37-1)

(152) To a solution of benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate R, 175 mg, 0.289 mmol) in acetonitrile (4.0 ml) at 0° C. was added 4-(3-fluorophenyl)cyclohexan-1-one (Intermediate L-3, 72.2 mg, 0.375 mmol) followed by triisopropylsilane (0.118 ml, 0.578 mmol) under N.sub.2. The reaction mixture was then cooled to −30° C. A solution of trimethylsilyl trifluoromethanesulfonate (0.052 ml, 0.289 mmol) in 0.5 ml of DCM was added. The reaction mixture was allowed to warm up to 0° C. slowly. After stirring for another 1 h, the reaction mixture was quenched with sat. aq. NH4Cl. The reaction mixture was extracted with 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to give a colorless oil. The residue was purified by prep silica gel TLC eluent with 2% MeOH/DCM to provide the desired product. LC-MS 668.4 (M+1).

Step 2: (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine (37-2)

(153) To a solution of benzyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37-1, 1.23 g, 1.842 mmol) in THF (25 ml) was added 10% palladium on carbon (196 mg, 0.184 mmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon for 1 h, and the reaction mixture was filtered through a celite pad. The filtrate was concentrated to afford crude desired product. LC-MS 534.4 (M+1).

Step 3: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37-3)

(154) To a solution of (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine (37-2, 972 mg, 1.821 mmol) in CH.sub.2Cl.sub.2 (15 ml) at 0° C. was added Et.sub.3N (0.762 ml, 5.46 mmol) followed by methyl carbonochloridate (0.183 ml, 2.368 mmol) under N.sub.2. The reaction mixture was stirred at 0° C. for 1 h, then stopped and concentrated. The residue was purified by prep silica gel TLC eluent with 4% MeOH/DCM to provide the title compound (37-3). LC-MS 592.3 (M+1).

Step 4: methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)-cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37)

(155) To a solution of methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37-3, 950 mg, 1.605 mmol) in CH.sub.2Cl.sub.2 (16 ml) was added MsOH (1.251 ml, 19.27 mmol) at rt under N.sub.2. The reaction mixture was stirred at rt 15 min, then the reaction was stopped and concentrated. The residue was purified by Gilson (C18, 10-100% acetonitrile in H.sub.2O) to provide the title compound methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (37). LC-MS 472.4 (M+1). .sup.1H NMR (500 MHz, Methanol-d4) δ 7.27 (q, J=7.9 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 6.97 (d, J=10.5 Hz, 1H), 6.93-6.85 (m, 1H), 4.16 (s, 1H), 3.87 (m, 1H), 3.82 (m, 1H), 3.72 (m. 3H), 3.69 (s, 3H), 2.81 (s, 6H), 2.63 (m, 1H), 2.45 (dt, J=12.2, 7.4 Hz, 1H), 2.12 (m, 2H), 1.82 (m, 3H), 1.68 (m, 2H), 1.62 (m, 2H), 1.39 (d, J=5.9 Hz, 3H).

EXAMPLE 38

isopropyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38)

(156) ##STR00082## ##STR00083##

Step 1: 2,2,2-trifluoro-N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidin-3-yl)acetamide (38-1)

(157) To a solution of benzyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (T) (400 mg, 0.673 mmol) in THF (10 ml) was added Pd on C (71.6 mg, 0.067 mmol) at rt under N.sub.2. The reaction mixture was degassed and refilled with H2 (1.356 mg, 0.673 mmol) for 3 times. The reaction mixture was left stirring at rt for 30 min. LC-MS shown starting material disappeared and desired product formed. The reaction mixture was filtered through a celite pad. The crude product was concentrated to give 2,2,2-trifluoro-N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-pyrrolidin-3-yl)acetamide (38-1). Since LC-MS shown it to be sufficiently pure, it was used in the next step without further purification. LC-MS 462.

Step 2: isopropyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-2)

(158) To a solution of 2,2,2-trifluoro-N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidin-3-yl)acetamide (38-1) (260 mg, 0.564 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added TEA (0.157 ml, 1.129 mmol) and isopropyl carbonochloridate (83 mg, 0.677 mmol) at 0° C. under N.sub.2. The reaction mixture was stirred at rt for 30 min. LC-MS shown starting material disappeared. To the reaction mixture was added a few drops of methanol, then the reaction mixture was washed with 2 ml of sat. aq. NaHCO.sub.3. The organic phase was collected, dried (MgSO.sub.4) and concentrated and the crude product was chromatographed over silica gel (ISCO 12 g, 0-40% EtOAc in hexanes) to give the desired product isopropyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-2). LC-MS 548.

Step 3: benzyl 4-(((2R,3S,5R)-1-(isopropoxycarbonyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidin-2-yl)methoxy)piperidine-1-carboxylate (38-3)

(159) To a solution of isopropyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-2) (240 mg, 0.439 mmol) in acetonitrile (5 ml) was added benzyl 4-oxopiperidine-1-carboxylate (133 mg, 0.571 mmol) and triisopropylsilane (139 mg, 0.878 mmol) at 0° C. under N.sub.2. When cooling to −20° C., the reaction mixture turned cloudy. Up to 0.5 ml of DCM was added and the solution turned clear. A solution of trimethylsilyl trifluoromethanesulfonate (98 mg, 0.439 mmol) in 0.2 ml of DCM was added dropwise. The reaction mixture was allowed to slowly raise to rt. After 10 min, LCMS shown formation of the desired product. The reaction mixture was allowed to stir for 30 min, then to the reaction was added 0.5 ml of sat. aq. NaHCO.sub.3. The reaction mixture was extracted by 2 portions of 10 ml of EtOAc. The combined organic phase was collected and concentrated. The crude was chromatographed over silic gel (ISCO, 12 g, EtOAc in hexanes 0-60%) to give the desired product benzyl 4-(((2R,3S,5R)-1-(isopropoxycarbonyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidin-2-yl)methoxy)piperidine-1-carboxylate (38-3). LC-MS 650.

Step 4: isopropyl (2R,3S,5R)-5-methyl-2-((piperidin-4-yloxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-4)

(160) A solution of benzyl 4-(((2R,3S,5R)-1-(isopropoxycarbonyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidin-2-yl)methoxy)piperidine-1-carboxylate (38-3) (230 mg, 0.354 mmol) in THF (10 ml) was added Pd on Carbon (0.354 mg, 0.354 mmol), then was degassed and refilled with H2 three times with a balloon. The reaction mixture was stirred at rt for 30 min. LC-MS shown starting material disappeared. The reaction mixture was filtered through a celite pad and the filtrate was concentrated directly to give the crude product isopropyl (2R,3S,5R)-5-methyl-2-((piperidin-4-yloxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)-acetamido)pyrrolidine-1-carboxylate (38-4). LC-MS 516. It is pure enough and used directly in the next step.

Step 5: isopropyl (2R,3S,5R)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-5)

(161) A solution of isopropyl (2R,3S,5R)-5-methyl-2-((piperidin-4-yloxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-4) (50 mg, 0.097 mmol) in Dioxane (5 ml) was added 2-bromopyrimidine (30.8 mg, 0.194 mmol) and N-ethyl-N-isopropylpropan-2-amine (62.7 mg, 0.485 mmol) was heated to 100° C. for 8 h. LC-MS shown formation of the desired product. The reaction mixture was concentrated and chromatographed over C18 (10-100% Acetonitrile in H.sub.2O) to give the desired product isopropyl (2R,3S,5R)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)-pyrrolidine-1-carboxylate (38-5). LC-MS 594.

Step 6: isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-6)

(162) To solution of isopropyl (2R,3S,5R)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrolidine-1-carboxylate (38-5) (35 mg, 0.059 mmol) in THF (5 ml) was added 2M LiOH solution 1 ml, and another 1 ml of MeOH was added to get a clear solution. The reaction mixture was heated at 50° C. for 2 h. LC-MS shown SM disappeared. The reaction mixture was extracted by 2 portions of 10 ml of EtOAc. The combined organic phases were dried (MgSO.sub.4), concentrated and chromatographed over C18 (10-100% acetonitrile in H.sub.2O) to give the desired product isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-6). LC-MS 498.

Step 7: isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)(N-methyl sulfamoyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-7)

(163) A solution of isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-6) (25 mg, 0.050 mmol) was dissolved in CH.sub.2Cl.sub.2 (10 ml), followed by addition of methylsulfamoyl chloride (19.53 mg, 0.151 mmol) at rt under N.sub.2. The reaction mixture was stirred at 0° C. for 10 min, followed by addition of N-ethyl-N-isopropylpropan-2-amine (26.0 mg, 0.201 mmol). LC-MS shown SM disappeared and the desired product formed. The reaction completed after 30 min. To the reaction mixture was added sat. aq. NaHCO.sub.3, then the organic phase was collected, dried (MgSO.sub.4), concentrated and chromatographed over silica gel (ISCO, 12 g, 0-80% EtOAc in hexanes) to give the desired product isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)(N-methylsulfamoyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-7). LC-MS 591.

Step 8: isopropyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38)

(164) To a solution of isopropyl (2R,3S,5R)-3-((4-methoxybenzyl)(N-methylsulfamoyl)amino)-5-methyl-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38-7) (21 mg, 0.036 mmol) in CH.sub.2Cl.sub.2 (2 ml) was added MsOH (0.012 ml, 0.178 mmol) at rt under N.sub.2. The reaction mixture was stirred for 0.5 h. LC-MS shown no SM left. The reaction mixture was diluted with 5 ml of DCM, washed with sat. aq. NaHCO.sub.3, dried (MgSO.sub.4), concentrated, then was dissolved in 2 ml of DMF, chromatographed via Gilson (C18, 10-100% acetonitrile in H.sub.2O) to give the desired product isopropyl (2R,3S,5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate (38). LC-MS 471.

EXAMPLE 39

(165) isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (39)

(166) ##STR00084## ##STR00085##

Step 1: isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (39-1)

(167) To a solution of (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine (36-1) (600 mg, 1.272 mmol) in CH.sub.2Cl.sub.2 (12 ml) at 0° C. was added Et.sub.3N (0.532 ml, 3.82 mmol) followed by isopropyl carbonochloridate (1.0 M in toluene, 1.653 ml, 1.653 mmol) under N.sub.2. The reaction mixture was stirred at 0° C. for 70 mins. LC-MS indicated almost completion. The reaction mixture was concentrated to leave yellow oil. The residue was purified by prep silica gel TLC eluent with 1% MeOH/DCM to give the title compound isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate. (39-2). LC-MS 558 (M+1).

Step 2: benzyl 4-(((2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-1-(isopropoxycarbonyl)-5-methylpyrrolidin-2-yl)methoxy)piperidine-1-carboxylate (39-3)

(168) To a solution of isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-methyl-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (39-2) (65 mg, 0.117 mmol) in acetonitrile (0.8 ml) and DCM (0.8 ml) at 0° C. was added benzyl 4-oxopiperidine-1-carboxylate (43.5 mg, 0.186 mmol) followed by triisopropylsilane (0.048 ml, 0.233 mmol) under N.sub.2. After 5 mins stirring at 0° C., trimethylsilyl trifluoromethanesulfonate (0.021 ml, 0.117 mmol) was added. After 6 hrs stirring at 0° C., LC-MS indicated almost completion. The reaction mixture was quenched with sat. aq. NaHCO.sub.3, extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave colorless oil. The residue was purified by prep silica gel TLC eluent with 3% MeOH/DCM to give the title compound benzyl 4-(((2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-1-(isopropoxycarbonyl)-5-methylpyrrolidin-2-yl)methoxy)piperidine-1-carboxylate. (39-3). LC-MS 661 (M+1).

Step 3: isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-((piperidin-4-yloxy)methyl)pyrrolidine-1-carboxylate (39-4)

(169) To a solution of benzyl 4-(((2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-1-(isopropoxy-carbonyl)-5-methylpyrrolidin-2-yl)methoxy)piperidine-1-carboxylate (39-3) (13 mg, 0.024 mmol) in THF (1.0 ml) was added 10% palladium on carbon (3.84 mg, 3.61 μmol). The reaction mixture was degassed and refilled with H2 from balloon for three times. The reaction mixture was stirred at rt under hydrogen balloon for 1.5 hrs. LC-MS indicated completion. The reaction mixture was filtered through a celite pad. The filtrate was concentrated to give the title compound isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((piperidin-4-yloxy)methyl)pyrrolidine-1-carboxylate. (39-4). LC-MS 527 (M+1).

Step 4: isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (39)

(170) To a solution of isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-5-methyl-2-((piperidin-4-yloxy)methyl)pyrrolidine-1-carboxylate (39-4) (10 mg, 0.025 mmol) and 2-bromo-5-fluoropyrimidine (6.97 mg, 0.039 mmol) in 1,4-dioxane (0.5 ml) was added DIPEA (13 μl, 0.074 mmol). The reaction mixture was sealed in the reaction vial and heated at 100° C. overnight. LC-MS indicated completion. The reaction mixture was concentrated to leave brown oil. The residue was dissolved in DCM (0.25 ml). MsOH (0.024 ml, 0.369 mmol) was added. The reaction mixture was stirred at rt for 10 mins. LC-MS indicated completion. The reaction mixture was concentrated to leave brown oil. The residue was purified by Gilson (the peak was collected at −13.5 mins) to give the title compound isopropyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate. (39). LC-MS 503 (M+1).

EXAMPLES 40 AND 41

methyl (CIS)-5-ethyl-3-(methyl sulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate and methyl (CIS)-6-(methyl sulfonamido)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-4-azaspiro[2.4]heptane-4-carboxylate

(171) ##STR00086## ##STR00087##

Step 1: N-((CIS)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (40-1) and N-((CIS)-4-benzyl-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-4-azaspiro[2.4]heptan-6-yl)methanesulfonamide (41-1)

(172) To a mixture of N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)methanesulfonamide (INTERMEDIATE K) (150 mg, 0.329 mmol) in Tetrahydrofuran (2190 μl) at −78° C. was added titanium(IV) isopropoxide (289 μl, 0.986 mmol). After stirring for 10 min, add ethylmagnesium bromide (657 μl, 1.971 mmol). The mixture was stirred for 30 min before warming to ambient temperature. After 1 hour at ambient temperature was added titanium(IV) isopropoxide (289 μl, 0.986 mmol) followed by ethylmagnesium bromide (657 μl, 1.971 mmol). After another 2 hours added ethylmagnesium bromide (657 μl, 1.971 mmol). After another 2 hours the mixture was quenched with a sat'd solution of NH.sub.4Cl (15 mL), taken up in EtOAc (15 mL), filtered through a pad of diatomaceous earth, extracted with EtOAc (3× @ 15 mL), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford a mixture of both the title compounds. 40-1 MS: 471.4 (M+1). 41-1 MS: 469.5 (M+1).

Step 2: N-((CIS)-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (40-2) and N-((CIS)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-4-azaspiro[2.4]heptan-6-yl)methanesulfonamide (41-2)

(173) To a mixture of N-((CIS)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)methanesulfonamide (40-1) and N-((CIS)-4-benzyl-5-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)-4-azaspiro[2.4]heptan-6-yl)methanesulfonamide (41-1) (60 mg, 0.128 mmol) in Methanol (1216 μl)/AcOH (64.0 μl) was added Pd/C (13.62 mg, 0.013 mmol). A H2 balloon was added (vacuum purge 3×) and the mixture was stirred for 2 hours. The resulting solution was filtered through a pad of diatomaceous earth and the filtrate was concentrated. The mixture was purified by mass triggered reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford both title compounds separately. 40-2 MS: 381.4 (M+1). 41-2 MS: 379.4 (M+1).

Step 3: methyl (CIS)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (40)

(174) To a mixture of N-((CIS)-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)methanesulfonamide (40-2) (4 mg, 10.51 μmol) in DCM (105 μl) at ambient temperature was added triethylamine (5.86 μl, 0.042 mmol) and methyl chloroformate (1.628 μl, 0.021 mmol). The mixture was stirred for 30 min before being quenched with a few drops of H.sub.2O.

(175) The mixture was concentrated. The residue was purified by mass triggered reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford the title compound. MS: 439.2 (M+1).

Step 4: methyl (CIS)-6-(methylsulfonamido)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-4-azaspiro[2.4]heptane-4-carboxylate (41)

(176) To a mixture of N-((CIS)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-4-azaspiro[2.4]heptan-6-yl)methanesulfonamide (41-2) (5 mg, 0.013 mmol) in DCM (132 μl) at ambient temperature was added triethylamine (7.36 μl, 0.053 mmol) and methyl chloroformate (2.046 μl, 0.026 mmol). The mixture was stirred for 30 min before being quenched with a few drops of H.sub.2O. The mixture was concentrated, and the residue was purified by mass triggered reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford the title compound. MS: 437.1 (M+1).

EXAMPLE 42

methyl (CIS)-2,2-diethyl-4-(methyl sulfonamido)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate

(177) ##STR00088## ##STR00089##

Step 1: N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-1)

(178) To a mixture of N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidin-3-yl)methanesulfonamide (INTERMEDIATE K) (250 mg, 0.548 mmol) in DMF (2738 μl) at 0° C. was added NaH (26.3 mg, 0.657 mmol). The mixture stirred for 10 min before adding SEM-Cl (107 μl, 0.602 mmol) and warming to ambient temperature. After 2 hours the reaction was quenched with H.sub.2O (10 mL), extract with EtOAc (3× @ 10 mL), dry over Na.sub.2SO.sub.4, and concentrate. The residue was purified by column chromatography on silica (2% to 50% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 587.5 (M+1).

Step 2: N-((CIS)-1-benzyl-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-2)

(179) To a mixture N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-1) (50 mg, 0.085 mmol) in DCM (501 μl) at −78° C. was added 2,6-di-tert-butyl-4-methylpyridine (20.99 mg, 0.102 mmol) followed by TriflicAnhydride (102 μl, 0.102 mmol) in DCM. The reaction was stirred for 45 min before adding ethylmagnesium bromide (28.4 μl, 0.085 mmol) in Et.sub.2O before slowly warming to ambient temperature over 1 hour. Next, NaBH.sub.4 (9.67 mg, 0.256 mmol) was added along 1.0 mL DCM and 0.5 mL MeOH and the mixture stirred for 2 hours. The resulting mixture was concentrated, and the residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 629.4 (M+1).

Step 3: N-((CIS)-1-benzyl-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (42-3)

(180) To a mixture of N-((CIS)-1-benzyl-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-2) (35 mg, 0.056 mmol) in DCM (556 μl) was added TFA (86 μl, 1.113 mmol). The mixture was stirred for 16 hours. The mixture was concentrated and placed under vacuum. The residue was taken up in Dioxane (185 μl) at ambient temperature and added 4.0 M HCl (278 μl, 1.113 mmol) in Dioxane. The mixture was heated to 50° C. and stirred for 4 hours. The resulting mixture was concentrated and placed under vacuum to afford the title compound. MS: 499.4 (M+1).

Step 4: N-((CIS)-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (42-4)

(181) To a mixture of N-((CIS)-1-benzyl-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidin-3-yl)methanesulfonamide (42-3) (25 mg, 0.050 mmol) in MeOH (501 μl) was added Pd/C (5.33 mg, 5.01 μmol). A hydrogen balloon was added (vacuum purge 3×) and the reaction was stirred overnight. The resulting residue was filtered through a pad of diatomaceous earth and the resulting filtrate was concentrated to the title compound. MS: 409.4 (M+1).

Step 5: methyl (CIS)-2,2-diethyl-4-(methylsulfonamido)-5-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (22)

(182) To a mixture of N-((CIS)-5,5-diethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)methanesulfonamide (42-4) (15 mg, 0.037 mmol) in DCM (367 μl) at ambient temperature was added triethylamine (10.23 μl, 0.073 mmol) and methyl chloroformate (4.27 μl, 0.055 mmol). The reaction was stirred for 24 hours. Methyl chloroformate (4.27 μl, 0.055 mmol), triethylamine (10.23 μl, 0.073 mmol), and DMAP (0.224 mg, 1.836 μmol) were added. The mixture was stirred for another 24 hours, and the reaction was concentrated. The residue was purified by mass triggered reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford the title compound. MS: 467.3 (M+1).

EXAMPLE 43

(183) ##STR00090##

methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate

Step 1: N-((2R,3S)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-1)

(184) To a mixture of N-((CIS)-1-benzyl-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-1) (250 mg, 0.426 mmol) in DCM (4260 μl) at −78° C. was added 2,6-di-tert-butyl-4-methylpyridine (105 mg, 0.511 mmol) followed by Triflic Anhydride (511 μl, 0.511 mmol) in DCM. The reaction mixture was warmed to 0° C. and stirred for one hour. The reaction was cooled back to −78° C. and ethylmagnesium bromide (142 μl, 0.426 mmol) in Et.sub.2O was added before slowly warming to ambient temperature over 1 hour. Next, NaBH.sub.4 (48.3 mg, 1.278 mmol) was added with 1.0 mL DCM and 0.5 mL MeOH and the mixture was stirred for 2 hours. The resulting mixture was concentrated, and the residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 601.5 (M+1).

Step 2: N-((2R,3S,5R)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-2)

(185) To a mixture of N-((2R,3S)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-1) (115 mg, 0.183 mmol) in Dioxane (609 μl) at ambient temperature was added 4.0 M HCl (914 μl, 3.66 mmol) in dioxanes. The mixture was heated to 50° C. and stirred for 8 hours. The resulting mixture was concentrated and placed under vacuum. The residue was purified by reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford the title compound. MS: 471.3 (M+1).

Step 3: N-((2R,3S,5R)-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (racemic) (43-3)

(186) To a mixture of N-((2R,3S,5R)-1-benzyl-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-2) (50.0 mg, 0.106 mmol) in MeOH (1062 μl) was added Pd/C (11.31 mg, 10.62 μmol). A hydrogen balloon was added (vacuum purge 3×) and the reaction was stirred 8 h. The resulting residue was filtered through a pad of diatomaceous earth and the resulting filtrate was concentrated to the title compound. MS: 381.2 (M+1).

Step 4: methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)-oxy)methyl)pyrrolidine-1-carboxylate (racemic) (43)

(187) To a mixture of N-((2R,3S,5R)-5-ethyl-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidin-3-yl)methanesulfonamide (racemic) (43-3) (40 mg, 0.098 mmol) in DCM (979 μl) at ambient temperature was added triethylamine (40.9 μl, 0.294 mmol) and methyl chloroformate (11.37 μl, 0.147 mmol). The reaction was stirred for 2 hours before being concentrated. The residue was purified by reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to afford the title compound. MS: 439.4 (M+1). .sup.1H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=7.5 Hz, 2H), 7.28-7.15 (m, 3H), 5.52 (d, J=78.8 Hz, 1H), 4.96 (brs, 1H), 4.24 (d, J=42.4 Hz, 1H), 4.05 (brs, 1H), 3.81-3.59 (m, 6H), 3.02 (s, 3H), 2.62-2.50 (m, 2H), 2.25 (brs, 1H), 2.11-2.01 (m, 2H), 1.85 (brs, 1H), 1.81-1.69 (m, 4H), 1.69-1.53 (m, 2H), 1.47 (brs, 1H), 0.90 (t, J=7.5 Hz, 3H).

(188) The following compound was prepared according to the general procedure provided in Examples 1-21, and procedures herein, by substituting the appropriate alkyl carbonochloridate and sulfamoyl chloride. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

(189) TABLE-US-00004 Exact Example Mass Number Structure Name [M + H].sup.+ 44 methyl (CIS)-5- cyclopropyl-3- (methylsulfonamido)- 2-((((CIS)-4- phenylcyclohexyl)oxy) methyl)pyrrolidine-1- carboxylate 451.0

EXAMPLE 45 and EXAMPLE 46

methyl (2S,3R,5S)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate and methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(190) ##STR00092##

(191) A mixture of methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (racemic) (23) was subjected to SFC purification, OJ-H, 21×250 mm, 15% (MeOH) to obtain two chiral isomers: methyl (2S,3R,5S)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (25, peak 1): MS: 439.2. .sup.1H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=7.6 Hz, 2H), 7.27-7.18 (m, 3H), 5.54 (d, J=77.8 Hz, 1H), 4.23 (d, J=44.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.72 (d, J=10.6 Hz, 6H), 3.01 (s, 3H), 2.62-2.48 (m, 2H), 2.27 (brs, 1H), 2.07 (d, J=14.5 Hz, 2H), 1.84 (brs, 1H), 1.81-1.69 (m, 4H), 1.69-1.55 (m, 2H), 1.55-1.39 (m, 1H), 0.91 (q, J=7.9, 7.5 Hz, 3H). methyl (2R,3S,5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (26, peak 2): MS: 439.2. .sup.1H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=7.5 Hz, 1H), 7.27-7.18 (m, 3H), 5.55 (d, J=77.3 Hz, 1H), 4.23 (d, J=40.7 Hz, 1H), 4.09=4.00 (m, 1H), 3.72 (d, J=10.6 Hz, 6H), 3.01 (s, 3H), 2.63-2.49 (m, 2H), 2.27 (brs, 1H), 2.07 (d, J=14.3 Hz, 2H), 1.84 (brs, 1H), 1.80-1.69 (m, 4H), 1.69-1.53 (m, 2H), 1.53-1.40 (m, 1H), 0.90 (t, J=7.4 Hz, 3H).

EXAMPLE 47

methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate

(192) ##STR00093## ##STR00094##

Step 1: tert-butyl ((CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-1-(((CIS)-4-phenylcyclohexyl)oxy)-7-(trimethylsilyl)hept-6-yn-2-yl)carbamate (47-1)

(193) To a mixture of ethynyltrimethylsilane (803 μl, 5.79 mmol) in THF (7243 μl) at 0° C. was added 2.0 M octylmagnesium chloride in THF (2173 μl, 4.35 mmol). The reaction stirred for 1 hour. In a separate flask combine tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (INTERMEDIATE U) (850 mg, 1.449 mmol) with THF (7243 μl) and cool to −10° C. Add 1 equiv. Grignard reagent to the flask containing the lactam. After 1 hour, add another 1 equiv. of Grignard reagent and stir for another 30 min. Quench the reaction with a saturated solution of NH4Cl (5 mL) and warm to ambient temperature. The reaction mixture was extracted with EtOAc (3× @ 5 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica (2% to 70% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 685.5 (M+1).

Step 2: tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-((trimethyl silyl)ethynyl)pyrrolidine-1-carboxylate (47-2)

(194) To a mixture of tert-butyl ((CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-1-(((CIS)-4-phenylcyclohexyl)oxy)-7-(trimethylsilyl)hept-6-yn-2-yl)carbamate (47-1) (560 mg, 0.818 mmol) in EtOAc (5450 μl) at 0° C. was added SODIUM TRIACETOXYBOROHYDRIDE (260 mg, 1.226 mmol) followed by TFA (252 μl, 3.27 mmol) dropwise. After 4 hours, add SODIUM TRIACETOXYBOROHYDRIDE (260 mg, 1.226 mmol) and TFA (252 μl, 3.27 mmol). The mixture stirred overnight before adding SODIUM TRIACETOXYBOROHYDRIDE (260 mg, 1.226 mmol) and TFA (252 μl, 3.27 mmol) reaction was stirred overnight. The mixture was quenched with a saturated solution of NaHCO.sub.3 (10 mL), extracted with EtOAc (3× @ 10 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica (2% to 70% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 691.3 (M+23).

Step 3: N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-((trimethylsilyl)ethynyl)pyrrolidin-3-yl)methanesulfonamide (47-3)

(195) To a mixture of tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (27-2) (422 mg, 0.631 mmol) in DCM (4206 μl) at ambient temperature was added METHANESULFONIC ACID (410 μl, 6.31 mmol) dropwise. The mixture stirred for 2 hours before quenching with a saturated solution of NaHCO.sub.3 (5 mL), extracting with EtOAc (3× @ 5 mL), dried over Na.sub.2SO.sub.4, and concentrated to afford the title compound. MS: 449.2 (M+1).

Step 4: N-((CIS)-5-ethynyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (47-4)

(196) To a mixture of N-((CIS)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-((trimethylsilyl)-ethynyl)pyrrolidin-3-yl)methanesulfonamide (47-3) (283 mg, 0.631 mmol) in MeOH (4205 μl) at ambient temperature was added K2CO.sub.3 (174 mg, 1.261 mmol). The mixture stirred for 2 hours before filtering off the solids and concentrating to afford the title compound. MS: 377.4 (M+1).

Step 5: methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-pyrrolidine-1-carboxylate (47)

(197) To a mixture of N-((CIS)-5-ethynyl-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide (47-4) (237.0 mg, 0.629 mmol) in DCM (4196 μl) was added METHYL CHLOROFORMATE (63.4 μl, 0.818 mmol) and TRIETHYLAMINE (175 μl, 1.259 mmol). The mixture stirred for 1 hour before concentrating. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 435.3 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.33-7.29 (m, 2H), 7.28-7.24 (m, 2H), 7.20 (t, J=7.1 Hz, 1H), 5.80-5.48 (m, 1H), 4.45 (s, 1H), 4.26-4.03 (m, 2H), 3.78 (d, J=6.3 Hz, 3H), 3.73 (s, 1H), 3.02 (s, 3H), 2.70 (dt, J=12.4, 7.6 Hz, 1H), 2.63-2.51 (m, 2H), 2.46-2.34 (m, 1H), 2.26 (s, 1H), 2.19-2.00 (m, 2H), 1.89-1.68 (m, 4H), 1.60 (dt, J=27.0, 12.9 Hz, 2H).

EXAMPLE 48

methyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-vinylpyrrolidine-1-carboxylate (48)

(198) ##STR00095##

(199) To a mixture of methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (47) (25 mg, 0.058 mmol) in Methanol (575 μl) at ambient temperature was added QUINOLINE (13.63 μl, 0.115 mmol) and Lindlar Catalyst (6.12 mg, 2.88 μmol). A balloon of H2 was added (vacuum purge 3×) and the mixture stirred for 3 hours. The mixture was filtered through a pad of celite and concentrated. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 437.4 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=7.5 Hz, 2H), 7.25 (d, J=7.1 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 5.91-5.81 (m, 1H), 5.57-5.02 (m, 4H), 4.31-4.15 (m, 2H), 4.14-4.01 (m, 1H), 3.88-3.76 (m, 2H), 3.72 (s, 3H), 3.02 (s, 3H), 2.59 (dt, J=15.2, 7.9 Hz, 2H), 2.07 (d, J=14.8 Hz, 2H), 2.01 (d, J=10.2 Hz, 1H), 1.83-1.68 (m, 3H), 1.68-1.52 (m, 2H).

EXAMPLE 49

methyl (CIS)-5-(2-hydroxyethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate

(200) ##STR00096##

(201) To a mixture of methyl (CIS)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)-5-vinylpyrrolidine-1-carboxylate (48) (10 mg, 0.023 mmol) in THF (229 μl) at ambient temperature was added 9-BBNDimer (8.32 mg, 0.034 mmol). The mixture was heated to 50° C. for one hour before cooling to 0° C. To the mixture was added SODIUM CARBONATE (45.8 μl, 0.092 mmol) and 30% H2O2 (8.02 μl, 0.092 mmol). The mixture stirred for 2 hours before purifying directly using column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 455.4 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=7.6 Hz, 2H), 7.22 (dd, J=16.2, 7.6 Hz, 3H), 5.38 (s, 1H), 4.27 (s, 1H), 4.14-4.01 (m, 2H), 3.75 (s, 3H), 3.72 (d, J=13.9 Hz, 4H), 3.01 (s, 3H), 2.61 (dt, J=15.7, 8.0 Hz, 2H), 2.07 (s, 3H), 1.88 (s, 2H), 1.82-1.55 (m, 8H).

EXAMPLE 50

methyl (CIS)-5-(hydroxymethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate

(202) ##STR00097##

Step 1: methyl (CIS)-5-formyl-3-(methyl sulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)pyrrolidine-1-carboxylate (50-1)

(203) To a mixture of methyl (CIS)-3-(methyl sulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)-methyl)-5-vinylpyrrolidine-1-carboxylate (48) (110 mg, 0.252 mmol) in THF (13.4 mL)/Water (3.35 mL) at ambient temperature was added SODIUM PERIODATE (269 mg, 1.260 mmol) and 2.5% OSMIUM TETROXIDE (0.051 mL, 5.04 μmol) in water. The mixture was allowed to stir overnight before quenching with a saturated solution of sodium thiosulfate (15 mL), NaHCO.sub.3 (15 mL), extracting with DCM (3× @ 15 mL), drying over Na2SO4, and concentrating to afford the title compound. MS: 439.2 (M+1).

Step 2: methyl (CIS)-5-(hydroxymethyl)-3-(methylsulfonamido)-2-((((CIS)-4-phenylcyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (50)

(204) To a mixture of methyl (CIS)-5-formyl-3-(methyl sulfonamido)-2-((((CIS)-4-phenylcyclo-hexyl)oxy)methyl)pyrrolidine-1-carboxylate (50-1) (110.0 mg, 0.251 mmol) in MeOH (2508 μl) at ambient temperature was added NaBH4 (9.49 mg, 0.251 mmol). The mixture stirred for overnight before adding a few drops of 2.0 M HCl. The resulting mixture was purified directly by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 441.4 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.33 (t, J=7.6 Hz, 2H), 7.27-7.19 (m, 3H), 5.64-5.50 (m, 1H), 5.27 (s, 1H), 4.78-4.63 (m, 1H), 4.46 (s, 1H), 4.30-3.97 (m, 3H), 3.89 (d, J=10.3 Hz, 1H), 3.85-3.64 (m, 5H), 3.02 (s, 3H), 2.60 (t, J=11.2 Hz, 1H), 2.48 (s, 1H), 2.14-1.96 (m, 3H), 1.85-1.55 (m, 6H).

EXAMPLE 51

methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)-oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51)

(205) ##STR00098## ##STR00099##

Step 1: dimethyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (51-1)

(206) To a mixture of dimethyl (2R,3S,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (INTERMEDIATE V) (175 mg, 0.251 mmol) in THF (501 μl) at ambient temperature was added 1.0 MTBAF (501 μl, 0.501 mmol) in THF. The mixture stirred for 4 hours before concentrating. The residue was purified by column chromatography on silica (1% to 80% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 460.4 (M+1).

Step 2: dimethyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (51-2)

(207) To a mixture of dimethyl (2R,3S,5S)-3-((N,N-dimethyl sulfamoyl)(4-methoxybenzyl)amino)-5-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (51-1) (100 mg, 0.218 mmol) in DCM (1088 μl) at 0° C. was added IODOMETHANE (21.77 μl, 0.348 mmol), 2,6-di-tert-butyl-4-methylpyridine (89 mg, 0.435 mmol), and SILVER TRIFLUOROMETHANESULFONATE (89 mg, 0.348 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The resulting mixture was filtered through a pad of celite and concentrated. The residue was purified by column chromatography on silica (2% to 75% EtOAc/hexanes) to afford the title compound. MS: 474.3 (M+1).

Step 3: methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51-3)

(208) To a mixture of dimethyl (2R,3S,5S)-3-((N,N-dimethyl sulfamoyl)(4-methoxybenzyl)-amino)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (51-2) (70 mg, 0.148 mmol) in THF (2956 μl) at −20° C. was added 1.0 M LAH (148 μl, 0.148 mmol) in THF. The mixture stirred for 20 min before quenching with solid Na2SO4-10H2O. After stirring for 20 min, the mixture was filtered through a pad of celite and concentrated to afford the title compound. MS: 446.4 (M+1).

Step 4: methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-(methoxymethyl)-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (51-4)

(209) To a mixture of methyl (2R,3S,5S)-3-((N,N-dimethyl sulfamoyl)(4-methoxybenzyl)-amino)-2-(hydroxymethyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51-3) (65 mg, 0.146 mmol) in DCM (729 μl) at ambient temperature was added TRIETHYLAMINE (30.5 μl, 0.219 mmol), DMAP (1.782 mg, 0.015 mmol), and chlorotriethylsilane (29.4 μl, 0.175 mmol). The mixture stirred overnight before concentrating. The residue was purified by column chromatography on silica (1% to 50% EtOAc/hexanes) to afford the title compound.

Step 5: methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51-5)

(210) To a mixture of methyl (2R,3S,5S)-3-((N,N-dimethyl sulfamoyl)(4-methoxybenzyl)amino)-5-(methoxymethyl)-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (51-4) (45 mg, 0.080 mmol) in Acetonitrile (2412 μl)/DCM (268 μl) at ambient temperature was added 4-(3-fluorophenyl)cyclohexan-1-one (INTERMEDIATE L-3) (30.9 mg, 0.161 mmol) and triisopropylsilane (32.9 μl, 0.161 mmol). The mixture was cooled to −30° C. and TRIMETHYLSILYL TRIFLUOROMETHANESULFONATE (14.53 μl, 0.080 mmol) was added dropwise. The mixture was warmed to 0° C. and stirred for 10 min before quenching with a saturated solution of NaHCO.sub.3 (10 mL), extract with DCM (3× @ 10 mL), dry over Na2SO4, and concentrate.

(211) The residue was purified by column chromatography on silica (0% to 50% EtOAc/hexanes) to afford the title compound. MS: 622.5 (M+1).

Step 6: methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51)

(212) To a mixture of methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-(methoxymethyl)pyrrolidine-1-carboxylate (51-5) (30 mg, 0.048 mmol) in DCM (241 μl) at ambient temperature was added TFA (37.2 μl, 0.482 mmol). The mixture stirred for 2 hours before concentrating. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 502.5 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.27-7.22 (m, 1H), 7.04 (d, J=7.7 Hz, 1H), 6.97 (d, J=10.3 Hz, 1H), 6.94-6.85 (m, 1H), 5.50 (s, 1H), 4.24 (s, 1H), 4.04-3.95 (m, 1H), 3.92 (s, 1H), 3.79-72 (m, 5H), 3.70 (s, 1H), 3.47 (s, 1H), 3.35 (s, 3H), 2.83 (s, 6H), 2.62-2.48 (m, 2H), 2.12-1.94 (m, 5H), 1.79-1.69 (m, 3H), 1.66-1.53 (m, 2H).

EXAMPLE 52

methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (52)

(213) ##STR00100## ##STR00101##

Step 1: dimethyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-((((4-(trifluoromethyl)phenyl)sulfonyl)oxy)methyl)pyrrolidine-1,2-dicarboxylate (52-1)

(214) To a mixture of dimethyl (2R,3S,5S)-3-((N,N-dimethyl sulfamoyl)(4-methoxybenzyl)amino)-5-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (51-1) (125 mg, 0.272 mmol) in DCM (1360 μl) at ambient temperature was added 4-(trifluoromethyl)benzenesulfonyl chloride (87 mg, 0.354 mmol), Et.sub.3N (56.9 μl, 0.408 mmol), and DMAP (3.32 mg, 0.027 mmol). The mixture stirred for 4 hours before concentrating. The residue was purified by column chromatography on silica (1% to 60% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 668.5 (M+1).

Step 2: dimethyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (52-2)

(215) To a mixture of dimethyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)-amino)-5-((((4-(trifluoromethyl)phenyl)sulfonyl)oxy)methyl)pyrrolidine-1,2-dicarboxylate (52-1) (160 mg, 0.240 mmol) in DMSO (479 μl) at ambient temperature was added POTASSIUM CYANIDE (23.41 mg, 0.359 mmol). The reaction was heated to 60° C. and stirred for 16 hours. After cooling the reaction mixture was purified directly by column chromatography on silica (2% to 80% 3:1 EtOAc:EtOH/hexanes) to afford the title compound. MS: 469.4 (M+1).

Step 3: methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (52-3)

(216) To a mixture of dimethyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (52-2) (60.0 mg, 0.128 mmol) in THF (1281 μl) at ambient temperature was added LiBH4 (5.58 mg, 0.256 mmol). The mixture was heated to 50° C. and stirred for 5 hours before cooling, quenching with H2O (5 mL), extracting with DCM (4× @10 mL), dried over Na.sub.2SO.sub.4, and concentrated to afford the title compound. MS: 463.4 (M+23).

Step 4: methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((triethyl silyl)oxy)methyl)pyrrolidine-1-carboxylate (52-4)

(217) To a mixture of methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (52-3) (56 mg, 0.127 mmol) in DCM (636 μl) at ambient temperature was added TRIETHYLAMINE (26.6 μl, 0.191 mmol), DMAP (1.553 mg, 0.013 mmol), and chlorotriethylsilane (25.6 μl, 0.153 mmol). The mixture stirred overnight before concentrating. The residue was purified by column chromatography on silica (1% to 50% EtOAc/hexanes) to afford the title compound.

Step 5: methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (52-5)

(218) To a mixture of methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (52-4) (50 mg, 0.090 mmol) in Acetonitrile (2704 μl)/DCM (300 μl) at ambient temperature was added 4-(3-fluorophenyl)cyclohexan-1-one (INTERMEDIATE L-3) (34.7 mg, 0.180 mmol) and triisopropylsilane (36.9 μl, 0.180 mmol). The mixture was cooled to −30° C. and TRIMETHYLSILYL TRIFLUOROMETHANESULFONATE (16.29 μl, 0.090 mmol) was added dropwise. The mixture was warmed to 0° C. and stirred for 10 min before quenching with a saturated solution of NaHCO.sub.3 (10 mL), extract with DCM (3× @ 10 mL), dry over Na.sub.2SO.sub.4, and concentrate. The residue was purified by column chromatography on silica (0% to 50% EtOAc/hexanes) to afford the title compound. MS: 617.6 (M+1).

Step 6: methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (52)

(219) To a mixture of methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((CIS)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (52-5) (43 mg, 0.070 mmol) in DCM (349 μl) at ambient temperature was added TFA (53.7 μl, 0.697 mmol). The mixture stirred for 2 hours before concentrating. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 497.4 (M+1). 1H NMR (500 MHz, Chloroform-d) δ 7.26 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.96 (d, J=10.3 Hz, 1H), 6.90 (t, J=8.2 Hz, 1H), 5.37 (d, J=8.6 Hz, 1H), 4.37-4.18 (m, 2H), 4.10-3.95 (m, 2H), 3.85 (dd, J=10.2, 2.1 Hz, 1H), 3.89-3.66 (m, 4H), 3.08 (d, J=16.9 Hz, 1H), 2.96 (d, J=12.1 Hz, 1H), 2.84 (s, 6H), 2.78-2.55 (m, 2H), 2.19-1.85 (m, 4H), 1.82-1.60 (m, 5H).

EXAMPLE 53

Methyl (2R,3S,5R)-3-((N-(cyanomethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (53)

(220) ##STR00102##

Step 1: methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((fluorosulfonyl)amino)-5-methylpyrrolidine-1-carboxylate (53-1)

(221) Methyl (2R,3S,5R)-3-amino-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (W) (176 mg, 0.381 mmol) in acetonitrile (5 ml) at 0° C. was added triethylamine (0.175 ml, 1.256 mmol) followed by 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium methanesulfonate (231 mg, 0.842 mmol) all at once. The reactions were stirred at 0° C. for 15 min, then slowly allowed to warm to rt. After 2 hrs, conversion to the desired product was completed. The reaction was concentrated under reduced pressure and used directly on next step. MS: 446.4 (M+H)

Step 2: methyl (2R,3S,5R)-3-((N-(cyanomethyl)-N-methylsulfamoyl)amino)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (53)

(222) To a solution of methyl (2R,3S,5R)-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((fluorosulfonyl)amino)-5-methylpyrrolidine-1-carboxylate (53-1) (24 mg, 0.054 mmol) in 700 ul of acetonitrile was added triethylamine (18 mg, 0.178 mmol) followed by 2-(methylamino)-acetonitrile (9.13 mg, 0.130 mmol). The mixture was stirred at room temperature overnight. After removing the solvent under reduced pressure, the residue was purified by ISCO preparative reverse phase HPLC, eluting with 10 to 100% water in acetonitrile with 0.05% TFA. The desired fractions were combined and concentrated to the title compound. MS: 497.37 (M+H). .sup.1H NMR (500 MHz, DMSO-d6): δ 7.32 (q, J=7.3 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.98 (t, J=8.1 Hz, 2H), 4.31 (s, 2H), 3.98 (s, 1H), 3.71 (dd, J=11.2, 6.6 Hz, 2H), 3.57 (d, J=13.4 Hz, 2H), 2.81 (s, 3H), 2.62-2.57 (m, 1H), 2.54 (m, 3H), 2.31-2.24 (m, J=12.2, 7.2 Hz, 1H), 2.01 (d, J=13.7 Hz, 1H), 1.93 (d, J=13.6 Hz, 1H), 1.85-1.61 (m, 3H), 1.51-1.45 (m, 5H), 1.26 (d, J=5.8 Hz, 4H).

(223) The following compounds were prepared according to the general procedure provided in Examples 1-53, and procedures herein, by substituting with the appropriate amine after conversion into the sulfamoyl fluoride. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

(224) TABLE-US-00005 Exact Example Mass Number Structure Name [M + H].sup.+ 54 03 methyl (2R,3S,5R)-3- ((N-(2-cyanoethyl)-N- methylsulfamoyl)amino)- 2-((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methylpyrrolidine-1- carboxylate 511.4 55 04 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-3-((N- (2-methoxyethyl)-N- methylsulfamoyl)amino)- 5-methylpyrrolidine- 1-carboxylate 516.4 56 05 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-3-((N- (2-hydroxyethyl)-N- methylsulfamoyl)amino)- 5-methylpyrrolidine- 1-carboxylate 502.4 57 06 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methyl-3-((N-methyl- N-(2-(methyslulfonyl)- ethyl)sulfamoyl)amino) pyrrolidine-1- carboxylate 564.4 58 07 methyl (2R,3S,5R)-3- ((N-((1,1- dioxidothietan-3- yl)methyl)-N- methylsulfamoyl)amino)- 2-((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methylpyrrolidine-1- carboxylate 576.3 59 08 methyl (2R,3S,5R)-2- ((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methyl-3-((N-methyl- N-(2- (trifluoromethoxy)ethyl) sulfamoyl)amino)pyrro- lidine-1-carboxylate 570.4

EXAMPLE 60

Methyl (2R,3S,5R)-3-((2,2-difluoroethyl)sulfonamido)-2-((((1s,4S)-4-(3-fluorophenyl)-cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (60)

(225) ##STR00109##

(226) A solution of methyl (2R,3S,5R)-3-amino-2-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)-oxy)-methyl)-5-methylpyrrolidine-1-carboxylate (W) (15 mg, 0.032 mmol) in dichloromethane (300 μl) was added to 2,2-difluoroethyane-1-sulfonyl chloride (10.67 mg, 0.065 mmol) followed by triethylamine (18.08 μl, 0.130 mmol). The mixture was stirred at RT overnight. After removing the solvent under reduced pressure, the residue was purified by preparative reverse phase HPLC, eluting with 10 to 100% water in acetonitrile with 0.05% TFA. The desired fractions were combined and concentrated to the title compound. MS: 492.0 (M+H). .sup.1H NMR (500 MHz, Methanol-d4): δ7.27 (q, J=7.9, 7.2 Hz, 1H), 6.96 (d, J=10.6 Hz, 1H), 6.88 (t, J=8.3 Hz, 1H), 6.26 (t, J=55.1 Hz, 1H), 4.13 (s, 1H), 4.02 (s, 1H), 3.83 (dd, J=16.3, 12.2 Hz, 3H), 3.70 (d, J=19.7 Hz, 6H), 2.61 (t, J=11.8 Hz, 1H), 2.48-2.40 (m, 1H), 2.19-2.04 (m, 2H), 1.97-1.73 (m, 3H), 1.63 (d, J=8.9 Hz, 4H), 1.40 (d, J=5.6 Hz, 3H).

(227) The following compounds were prepared according to the general procedure provided in Examples 1-60, and procedures herein, by substituting with the appropriate sulfonyl chloride. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

(228) TABLE-US-00006 Exact Example Mass Number Structure Name [M + H].sup.+ 61 0 methyl (2R,3S,5R)-3- ((N-(2-cyanoethyl)-N- methylsulfamoyl)amino)- 2-((((1s,4S)-4-(3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methylpyrrolidine-1- carboxylate 487.2 62 methyl (2R,3S,5R)-3- ((fluoromethyl)sulfona- mido)-2-((((1s,4S)-4- (3- fluorophenyl)cyclohex- yl)oxy)methyl)-5- methylpyrrolidine-1- carboxylate 461.2

EXAMPLES 63 AND 64

Methyl (2R,3S,5R)-2-((((1s,4S)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)methyl)-3-(N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate (63)

Methyl (2R,3S,5R)-2-(((1r,4R)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate (64)

(229) ##STR00112##

Step 1: Methyl (2R,3S,5R)-2-(((4′-cyano-3′-methyl-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (63-1)

(230) A vial containing methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-(((4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (Intermediate X) 100 mg (0.155 mmol), 4-CYANO-3-METHYLPHENYLBORONIC ACID (25.01 mg, 0.155 mmol), SODIUM CARBONATE (49.4 mg, 0.466 mmol) and 1,1′-BIS(DIPHENYLPHOSPHINO)FERROCENE-PALLADIUM(II)-DICHLORIDE DICHLOROMETHANE COMPLEX (19.62 mg, 0.023 mmol) under N.sub.2 was treated with Dioxane (518 μl) and the mixture purged. Water (259 μl) was then added and the mixture purged and stirred under N.sub.2 at 95° C. for 8 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried (MsSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ on a silica gel 12 g column, eluting with a gradient of ethyl acetate/hexane 0:100% to 60:40% to give the title compound. LC-MS: m/z=611.3 (M+1).

Step 2: Methyl (2R,3S,5R)-2-(((4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (63-2)

(231) A solution of methyl (2R,3S,5R)-2-(((4′-cyano-3′-methyl-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (63-1), 42 mg (0.069 mmol) in MeOH (688 μl) and Ethyl acetate (688 μl) was purged and then Pd—C (7.32 mg, 6.88 μmol) was added. The resulting suspension was purged again and backfilled with H2 from a balloon. The mixture was then stirred at 25° C. for 3 h. The mixture was filtered through celite and the filtrate concentrated to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ with ELSD on a silica gel 12 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexane 0:100% to 40:60% to give the title compound as thin film (mixture of Diastereomers). LC-MS: m/z=613.3 (M+1).

Step 3: Methyl (2R,3S,5R)-2-((((1s,4S)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate (63) and Methyl (2R,3S,5R)-2-((((1r,4R)-4-(4-cyano-3-methylphenyl)cyclohexyl)oxy)methyl)-3-((N,N-dimethylsulfamoyl)amino)-5-methylpyrrolidine-1-carboxylate (64)

(232) A solution of methyl (2R,3S,5R)-2-(((4-(4-cyano-3-methylphenyl)cyclohexyl)-oxy)methyl)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methylpyrrolidine-1-carboxylate (63-2) 26 mg (0.042 mmol) in DCM (424 μl) was treated with METHANESULFONIC ACID (27.6 μl, 0.424 mmol) and the mixture stirred at 25° C. for 2 h. The mixture was cool to 0° C. and the reaction quenched slowly with Sat. Aq. NaHCO.sub.3. The mixture was extracted with DCM (×2) and the organic layer washed with brine, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product. This was purified on the CombiFlash NextGEn 300+ with ELSD, on a silica gel 12 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexane 0:100% to 30:70% to give 18 mg of a mixture of a mixture of diastereomers. The mixture was separated by SFC on the AD-H column to afford Examples 63 and 64. LC-MS: m/z=494.1 (M+1).

EXAMPLES 65 AND 66

Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1s,4S)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (65)

methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1r,4R)-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (66)

(233) ##STR00113##

(234) The title compound of Example 65 and 66 were prepared by following the general procedure described for Examples 63 and 64, using commercially available (2-ethylphenyl)boronic acid in Step 1.

EXAMPLES 67 AND 68

Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3R,4R)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (67)

Methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-2-((((1S,3S,4S)-4-(3-fluorophenyl)cyclohexyl-3,4-d2)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (68)

(235) ##STR00114##

(236) The title compound of Example 67 and 68 were prepared by following the general procedure described for Examples 63 and 64, using commercially available 3-Fluorophenylboronic in Step 1 and D2 in Step 2.

EXAMPLES 69 AND 70

Methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (69)

Methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (70)

(237) ##STR00115##

Step 1: methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (69-1)

(238) A solution of methyl (2R,3S,5R)-2-(hydroxymethyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (S) 50 mg, (0.129 mmol), 4-(pyrimidin-2-yl)cyclohexan-1-one (29.6 mg, 0.168 mmol) and TRIISOPROPYLSILANE (53.0 μl, 0.259 mmol) at −35° C. under N2 was treated with TRIMETHYLSILYL TRIFLUOROMETHANESULFONATE (23.42 μl, 0.129 mmol) via a syringe and needle and the mixture stirred at −35° C. for 1 h and slowly warm to 0° C. and kept for 2 h. The reaction was quenched with Sat. Aq. NaHCO.sub.3 and diluted with EtOAc. After warming up to rt the layers were separated and the Aq layer washed EtOAc. The combined organics was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel chromatography, on the Combiflash NextGen 300+ with ELSD on a 12 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexanes—0:100 to 40:60 to afford the title compound (mixture of Diastereomers). MS (m/z)=547.4 (M+1).

Step 2: Methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1r,4R)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (69) Methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1s,4S)-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (70)

(239) A solution of methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate (69-1), in DCM (284 μl) was treated with METHANESULFONIC ACID (18.41 μl, 0.284 mmol) and the mixture stirred at 25° C. for 2 h. The reaction was diluted with DCM and quenched with Sat. Aq. NaHCO.sub.3.

(240) The layers were separated and the Aq layer washed with DMC. The combined organics was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel chromatography, on the Combiflash NextGen 300+ with ELSD on a 4 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexanes—0:100 to 80:20 to afford the title compounds as a mixture of diastereomers. The mixture of diastereomers were separated by SFC to afford 69 (MS=427.3 (M+1)) and 70 (MS=427.3 (M+1)).

EXAMPLES 71 AND 72

Methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (71)

Methyl (2R,3S,5R)-2-((((1r,4R)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (72)

(241) ##STR00116## ##STR00117##

Step 1: Methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-1)

(242) A solution of methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (S) 3.0 g (5.99 mmol), 4-(benzyloxy)cyclohexan-1-one (1.591 g, 7.79 mmol) and TRIISOPROPYLSILANE (2.455 ml, 11.98 mmol) at −40° C. under N2 was treated with TRIMETHYLSILYL TRIFLUORO-METHANESULFONATE (1.084 ml, 5.99 mmol) using a Hamilton syringe and needle and the mixture stirred at −40° C. for 2 h (temp rise to −10 C). The reaction was quenched with Sat. Aq NaHCO.sub.3 and diluted with EtOAc. After warming to rt the layers were separated and the aq layer washed EtOAc. The combined organics was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel chromatography, on the Combiflash NextGen 300+ with ELSD on an 80 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexanes—0:100 to 30:70 to afford the title compound (cis/trans). MS: m/z=575.4 (M+1).

Step 2: Methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-2)

(243) In a rb flask containing a solution of methyl (2R,3S,5R)-2-(((4-(benzyloxy)-cyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-1), 2.76 g (4.80 mmol) in MeOH (96 ml) was treated with 20% Pd(OH).sub.2 on carbon (0.674 g, 0.960 mmol) and the flask sealed. The flask was purged, and the mixture stirred under a HYDROGEN atmosphere (Balloon) for 10 h. The mixture was diluted with MeOH and filtered through celite. The filtrate was concentrated under reduced pressure to afford the crude as a blackish solid. The crude was purified on the CombiFlash NextGEn 300+ on a silica gel 80 g column, eluting with a gradient of ethyl acetate; ethanol (3:1)/hexane 0 to 100% to give the title compound (mixture of diastereomers). MS: m/z=485.4 (M+1).

Step 3: methyl (2R,3S,5R)-2-(((4-bromocyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-3)

(244) A solution of methyl (2R,3S,5R)-2-(((4-hydroxycyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-2) 1.5 g (3.10 mmol) and CARBON TETRABROMIDE (1.232 g, 3.71 mmol) at 0° C. under N.sub.2, was treated with TRIPHENYLPHOSPHINE (0.974 g, 3.71 mmol) slowly, and the mixture stirred at 0° C. 3 h then at 25° C. for 16. At 0° C., the reaction was quenched with NaHCO.sub.3 and then extracted with EtOAc (×2).

(245) The organic layer was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel chromatography, on the Combiflash Rf on an 80 g column, eluting with a gradient of ethyl acetate/hexanes—0:100 to 40:60 to afford the title compound as a white solid (mixture of diastereomers). MS: m/z=547.4, 549.4 (M, M+2).

Step 4: methyl (2R,3S,5R)-2-(((4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-4)

(246) To a vial containing methyl (2R,3S,5R)-2-(((4-bromocyclohexyl)oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-3), 75 mg (0.137 mmol), pyridine-2,6-bis(carboximidamide)dihydrochloride (3.23 mg, 0.014 mmol), 1-bromo-3,5-difluorobenzene, 52.9 mg (0.274 mmol) and Tetrabutylammonium Iodide (12.65 mg, 0.034 mmol) in a vial in the glove box was added ZINC (26.9 mg, 0.411 mmol) followed by Nickel (II) Chloride Ethylene Glycol Dimethyl Ether complex (3.01 mg, 0.014 mmol) dissolved in DMA (1370 μl) and the mixture stirred at 60° C. in the glove box for 18 h. Analysis showed lots of SM. Added more ZINC (26.9 mg, 0.411 mmol), NICKEL(II) CHLORIDE ETHYLENE GLYCOL DIMETHYL ETHER COMPLEX (3.01 mg, 0.014 mmol), pyridine-2,6-bis(carboximidamide)dihydrochloride (3.23 mg, 0.014 mmol) and TETRABUTYL-AMMONIUM IODIDE (12.65 mg, 0.034 mmol) and stirred in the Glove box for another 20 h. The mixture was quenched with water and extracted with EtOAc (×2). The organic layer was washed with brine, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ with ELSD on a silica gel 12 g column, eluting with a gradient of ethyl acetate/hexane 0:100% to 80:20% to give the title compound (as a mixture of diastereomers). LC-MS: m/z=581.4 (M+1).

Step 5: Methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate (71)

Methyl (2R,3S,5R)-2-((((1r,4R)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-1-carboxylate (72)

(247) A solution of methyl (2R,3S,5R)-2-(((4-(3,5-difluorophenyl)cyclohexyl)-oxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-1-carboxylate (71-4) 33 mg (0.057 mmol) in DCM (568 μl) at 25° C. was treated with Methanesulfonic acid (36.9 μl, 0.568 mmol) and the mixture stirred at 25° C. for 2 h. The reaction mixture was diluted DCM and quenched with Sat. Aq. NaHCO.sub.3. The layers were separated, and the organic layer washed with brine, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude. The crude was purified on the CombiFlash NextGEn 300+ with ELSD on a silica gel 12 g column, eluting with a gradient of ethyl acetate:ethanol (3:1)/hexane 0:100% to 65:35% to give the title compound as a clear sticky oil as a mixture of diastereomers. The Diastereomers were separated by SFC on an AD-H column to afford Examples 71 and 72. LC-MS: m/z=461.4 (M+1).

EXAMPLE 73

Methyl (2R,3S,5R)-2-((((1s,4S)-4-(3,4-difluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(methyl sulfonamido)pyrrolidine-1-carboxylate (73)

(248) ##STR00118##

(249) The title compound of Example 73 was provided by following the general procedure described for Examples 71, but using 4-bromo-1,2-difluorobenzene in Step 4.

(250) The following table shows representative data for the compounds of the Examples as orexin receptor agonists as determined by the assays described herein.

(251) TABLE-US-00007 hOX2R_IP Emax Example IC.sub.50 (nM) (%) 1 15.2 101 2 117 100 3 19.3 98 4 17.7 102 5 227 101 6 78.5 100 7 45.5 100 8 9.52 101 9 8.57 101 10 69.3 99 11 264 99 12 390 99 13 1.9 101 14 2.5 100 15 3.18 101 16 0.5 101 17 0.53 102 18 0.5 101 19 0.5 100 20 1.67 102 21 0.47 101 22 0.66 100 23 0.92 97 24 1.00 102 25 0.27 102 26 0.92 98 26 0.23 102 27 6.82 100 28 1.07 102 29 0.93 102 30 10.8 100 31 3.63 100 32 0.52 101 33 2150 92 34 37.5 99 35 12.5 102 36 0.76 99 37 0.23 102 37 1027 96 38 7.07 100 39 1.15 101 40 4.56 100 41 224 99 42 316 100 43 8.1 103 44 73.5 101 45 7331 62 46 3.0 101 47 34.8 101 48 9.4 102 49 5.5 102 50 17.7 101 51 0.7 101 52 7.8 102 53 0.6 102 54 0.7 98 55 1.2 100 56 0.8 101 57 1.6 100 58 1.8 101 59 1.0 99 60 5.2 99 61 4.6 105 62 1.4 98 63 1.1 100 64 12.5 99 65 2.2 101 66 111 100 67 0.46 101 68 8.3 102 69 10420 98 70 892 99 71 0.76 102 72 108 100 73 25.5 101

(252) With respect to other compounds such as those disclosed in US 2017/0226137, WO 2017/135306, WO 2018/164191, WO 2018/164192, WO 2019/027003, WO 2019/027058, U.S. Pat. No. 9,527,807, 10,287,305, 10,428,023, or 10,508,083 it would be desirable that the present compounds exhibit unexpected properties, such as improved Pgp transport properties and brain penetration for compounds wherein X is O, and equipotency among compounds wherein X is O and X is NH. For example, in contrast to compounds of US 2017/0226137, WO 2017/135306, WO 2018/164191, WO 2018/164192, WO 2019/027003, WO 2019/027058, U.S. Pat. No. 9,527,807, 10,287,305, 10,428,023, or 10,508,083, the compounds of the present examples may possess improved Pgp transport properties and brain penetration for the carbamate compounds wherein X is O, and possess essentially equipotency among the carbamate compounds wherein X is O and the urea compounds wherein X is NH.

(253) As indicated by the data herein, the compounds of the present examples provide unexpected potency as orexin receptor agonists. The distinction in potency as orexin receptor agonists provides greater functional activity and potential for enhanced in vivo efficacy and may provide benefits over other orexin receptor agonists that are known in the art.

(254) While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.