Necrosis Inhibitors

Abstract

The invention provides amides that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.

Claims

1. An amide compound that is an inhibitor of cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), of formula: ##STR00179## wherein: R.sub.1 is (a) substituted or unsubstituted phenyl; (b) substituted or unsubstituted 2-, 3- or 4-pyridine; (c) substituted or unsubstituted naphthyl or 3-azanaphthyl; (d) substituted or unsubstituted 0-3 heteroatom cyclohexyl, cyclopentyl; or (e) substituted or unsubstituted 0-3 heteroatom cyclopentene or cyclopentadiene; R.sub.2 is substituted or unsubstituted aziridine, azetidine, pyrrolidine, piperidine, oxazridine, oxazetidine, oxazolidine, oxazinane, thiaziridine, thiazetidine, thiazolidine, thiazinane, diaziridine, diazetidine, diazolidine (pyrazolidine), diazinane; or R.sub.2 is substituted or unsubstituted pyrrole, dihydropyrrole, pyridine, dihydropyridine, tetrahydropyridine, azole, pyrimidine, oxazine, thiazine, triazine, ozadiazine, thiadiazine; and R.sub.3 is substituted or unsubstituted, 0-3 heteroatom C1-C9 alkyl, alkenyl, or alkynyl; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

2. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole; R.sub.2 is substituted or unsubstituted: aziridine, azetidine, pyrrolidine, piperidine, oxazolidine, oxazinane; diazolidine, diazinane, pyrrole, dihydropyrrole, dihydropyridine, or tetrahydropyridine; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

3. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole; R.sub.2 is substituted or unsubstituted: azetidine, pyrrolidine, piperidine, oxazolidine, diazolidine, or diazinane; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

4. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole; R.sub.2 is substituted or unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

5. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl or cyclohexyl; and R.sub.2 is substituted or unsubstituted: azetidine, pyrrolidine, piperidine, oxazolidine, diazolidine, or diazinane; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

6. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl or cyclohexyl; R.sub.2 is substituted or unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1, 1-dimethylpropyl, 1,1-dimethylprop-2- enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

7. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted phenyl; R.sub.2 is substituted or unsubstituted: azetidine, pyrrolidine, piperidine, oxazolidine, diazolidine, diazinane; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

8. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted phenyl; R.sub.2 is substituted or unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

9. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted phenyl; R.sub.2 is unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl, 1,1-dimethylprop-2-enyl, or 1,1-dimethylprop-2-ynyl, each optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

10. The compound of claim 1, wherein: R.sub.1 is fluoro-substituted or unsubstituted phenyl; R.sub.2 is unsubstituted azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl, optionally fluorinated with 1-4 F atoms; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

11. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl, cyclohexyl, furan, thiophene or azole; R.sub.2 is substituted or unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

12. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl or cyclohexyl; and R.sub.2 is substituted or unsubstituted: azetidine, pyrrolidine, piperidine, oxazolidine, diazolidine, or diazinane; and R.sub.3 is 1,1-dimethylpropyl; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

13. The compound of claim 1, wherein: R.sub.1 is substituted or unsubstituted: phenyl or cyclohexyl; R.sub.2 is substituted or unsubstituted: azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

14. The compound of claim 1, wherein: R.sub.1 is fluoro-substituted or unsubstituted phenyl; R.sub.2 is unsubstituted azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl; or a corresponding sulfonamide of the amide compound, or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

15. The compound of claim 1, wherein: R.sub.1 is fluoro-substituted or unsubstituted phenyl; R.sub.2 is unsubstituted azetidine or pyrrolidine; and R.sub.3 is 1,1-dimethylpropyl; or a pharmaceutically acceptable salt, hydride or stereoisomer the compound or corresponding sulfonamide.

16. The compound of claim 1 having a formula of Table 1: TABLE-US-00004 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 S13 S14 S15 S16 S17

17. The compound of claim 1 having a formula: ##STR00270##

18. A pharmaceutical compositions comprising a compound of claim 1 and a pharmaceutically-acceptable excipient, in unit dosage.

19. A pharmaceutical compositions comprising a compound of claim 1 and a pharmaceutically-acceptable excipient, in unit dosage, and a different therapeutic agent for a necrosis-associated disease or condition.

20. A method of treating a necrosis-associated disease or condition, comprising administering an effective amount of a compound of claim 1 to a patient in need thereof, optionally further comprising the antecedent step of diagnosing the necrosis-associated disease or condition, and/or the subsequent step of detecting a resultant amelioration of the necrosis-associated disease or condition.

Description

EXAMPLES

[0112]

TABLE-US-00001 TABLE 1 Compound List [00004] 1 [00005] 2 [00006] 3 [00007] 4 [00008] 5 [00009] 6 [00010] 7 [00011] 8 [00012] 9 [00013] 10 [00014] 11 [00015] 12 [00016] 13 [00017] 14 [00018] 15 [00019] 16 [00020] 17 [00021] 18 [00022] 19 [00023] 20 [00024] 21 [00025] 22 [00026] 23 [00027] 24 [00028] 25 [00029] 26 [00030] 27 [00031] 28 [00032] 29 [00033] 30 [00034] 31 [00035] 32 [00036] 33 [00037] 34 [00038] 35 [00039] 36 [00040] 37 [00041] 38 [00042] 39 [00043] 40 [00044] 41 [00045] 42 [00046] 43 [00047] 44 [00048] 45 [00049] 46 [00050] 47 [00051] 48 [00052] 49 [00053] 50 [00054] 51 [00055] 52 [00056] 53 [00057] 54 [00058] 55 [00059] 56 [00060] 57 [00061] 58 [00062] 59 [00063] 60 [00064] 61 [00065] 62 [00066] 63 [00067] 64 [00068] 65 [00069] 66 [00070] 67 [00071] 68 [00072] 69 [00073] 70 [00074] 71 [00075] 72 [00076] 73 [00077] 74 [00078] 75 [00079] 76 [00080] 77 [00081] 78 [00082] S1 [00083] S2 [00084] S3 [00085] S4 [00086] S5 [00087] S6 [00088] S7 [00089] S8 [00090] S9 [00091] S10 [00092] S11 [00093] S12 [00094] S13 [00095] S14 [00096] S15 [00097] S16 [00098] S17

2. Compound Preparation

Compound 1: Preparation of 2,2-dimethyl-1-(2-phenylaziridin-1-yl)butan-1-one

[0113] ##STR00099##

[0114] 2-phenylaziridine (35 mg, 0.294 mmoL) and triethylamine (59.4 mg, 0.588 mmol) were dissolved in 1.5 mL of dry CH.sub.2Cl.sub.2. 2,2-dimethylbutanoyl chloride (43.3 mg, 0.323m mol) in 1 mL of CH.sub.2Cl.sub.2 was added slowly to the solution at 0° C. under nitrogen. The mixture was stirred at room temperature for 2 h, diluted with CH.sub.2Cl.sub.2 and water. The organic layer were washed with saturated NaHCO.sub.3, brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound 1 (20 mg, 31%) as an colorless oil .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.36-7.44 (m, 5H), 5.90 (dd, 1H, J=9.2, 4.0 Hz), 3.44 (dd, 1H, J=13.6, 9.2 Hz), 3.26 (dd, 1H, J=4.0, 13.6 Hz), 1.61 (qd, 2H, J=7.6, 2.4 Hz), 1.21 (s, 3H), 1.19 (s, 3H), 0.74 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.14H.sub.19NO, 218.1; found, 218.3.

Compound 2: Preparation of 2,2-dimethyl-1-(2-phenylazetidin-1-yl)butan-1-one

[0115] ##STR00100##

[0116] The titled compound 2 was prepared in 77% yield from 2-phenylazetidine (50 mg) and 2,2-dimethylbutanoyl chloride(55 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ 7.31-7.36 (m, 4H), 7.23-7.28 (m, 1H), 5.35-5.39 (m, 1H), 4.34-4.46 (m, 2H), 2.66-2.74 (m, 1H), 2.07-2.14 (m, 1H), 1.59 (q, 2H, J=7.6 Hz), 1.14 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.21NO, 232.2;found, 232.4.

Compound 3: Preparation of (S)-2,2-dimethyl-1-(2-phenylazetidin-1-yl)butan-1-one

[0117] ##STR00101##

[0118] The titled compound 3 was prepared in 77% yield from (S)-2-phenylazetidine(50 mg) and 2,2-dimethylbutanoyl chloride(55 mg) according to the procedure outlined for compound 1. .sup.1HNMR (CDCl.sub.3, 400 MHz): δ7.32-7.37 (m, 4H), 7.22-7.24 (m, 1H), 5.37 (dd, 1H, J=8.8, 6.4 Hz), 4.26-4.45 (m, 2H), 2.66-2.75 (m, 1H), 2.07-2.15 (m, 1H), 1.58 (q, 2H, J=7.6 Hz), 1.15 (s, 6H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.21NO, 232.2; found, 232.4.

Compound 4: Preparation of 2,2-dimethyl-1-(2-phenylpyrrolidin-1-yl)butan-1-one

[0119] ##STR00102##

[0120] The titled compound 4 was prepared in 46% yield from 2-phenylpyrrolidine (50 mg) and 2,2-dimethylbutanoyl chloride (55 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.28-7.30 (m, 1H), 7.15-7.20 (m, 3H), 5.25 (m, 1H), 3.82 (t, 2H, J=6.4 Hz), 2.17-2.26 (m, 1H), 1.78-2.01 (m, 3H), 1.59-1.67 (m, 2H), 1.23 (s, 6H), 0.85 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.23NO, 246.2; found 246.4.

Compound 5: Preparation of 1-(2-cyclohexylpyrrolidin-1-yl)-2,2-dimethylbutan- 1-one

[0121] ##STR00103##

[0122] The titled compound 5 was prepared in 46% yield from 2-cyclohexylpyrrolidine (70 mg) and 2,2-dimethylbutanoyl chloride(73 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ4.13-4.18 (m, 1H), 3.74-3.80 (m, 1H), 3.27-3.33 (m, 1H), 1.87-2.00 (m, 5H), 1.65-1.82 (m, 6H), 1.53-1.60 (m, 2H), 1.22 (s, 6H), 0.92-1.18 (m, 4H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.29NO, 252.2; found 252.4.

Compound 6: Preparation of 2,2-dimethyl-1-(2-phenyloxazolidin-3-yl)butan-1-one

[0123] ##STR00104##

[0124] The titled compound 6 was prepared in 46% yield from 2-phenyloxazolidine (80 mg) and 2,2-dimethylbutanoyl chloride(108 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.87-7.90 (m, 2H), 7.61-7.66 (m, 1H), 7.52-7.56 (m, 2H), 6.14 (brs, 1H), 3.72 (t, 2H, J=4.8 Hz), 3.43 (dd, 2H, J=10.0, 5.6 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.16 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.21NO.sub.2, 248.2; found, 248.4.

Compound 7: Preparation of (S)-2,2-dimethyl-1-(4-phenyloxazolidin-3-yl)butan-1-one

[0125] ##STR00105##

[0126] The titled compound 7 was prepared in 46% yield from(S)-4-phenyloxazolidine (57 mg) and 2,2-dimethylbutanoyl chloride (102 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.30-7.34 (m, 2H), 7.23-7.26 (m, 3H), 5.29 (dd, 2H, J=10.4, 4.4 Hz), 5.21 (dd, 1H, J=6.4, 4.4 Hz), 4.23 (dd, 1H, J=8.8, 6.4 Hz), 3.88 (dd, 1H, J=8.8, 4.4 Hz), 1.53-1.59 (m, 2H), 1.17 (s, 3 Hz), 1.16 (s, 3H), 0.81 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.21NO.sub.2, 248.2; found, 248.4.

Compound 8: Preparation of (R)-2,2-dimethyl-1-(4-phenyloxazolidin-3-yl)butan-1-one

[0127] ##STR00106##

[0128] The titled compound 8 was prepared in 46% yield from (R)-4-phenyloxazolidine (80 mg) and 2,2-dimethylbutanoyl chloride (86 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.40-7.42 (m, 2H), 7.30-7.33 (m, 3H), 5.29 (dd, 2H, J=4.4, 10.4 Hz), 5.21 (dd, 1H, J=4.0, 6.4 Hz), 4.23 (dd, 1H, J=8.4, 6.4 Hz), 3.87 (dd, 1H J=4.0, 8.4 Hz), 1.53-1.60 (m, 2H), 1.15 (s, 3H), 1.17 (s, 3H), 0.811 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.21NO.sub.2, 248.2; found 248.4.

Compound 9: Preparation of 1-(2-(3-fluorophenyl)pyrrolidin-1-yl)-2,2-dimethylbutan-1-one

[0129] ##STR00107##

[0130] The titled compound 9 was prepared in 66% yield from 2-(3-fluorophenyl)pyrrolidine (95 mg) and 2,2-dimethylbutanoyl chloride(93 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ 7.21-7.25 (m, 1H), 6.80-6.94 (m, 3H), 5.22 (m, 1H), 3.82 (t, 2H, J=6.8 Hz), 2.17-2.26 (m, 1H), 1.87-2.01 (m, 2H), 1.70-1.78 (m, 1H), 1.59-1.69 (m, 2H), 1.24 (s, 3H), 1.21 (s, 3H), 0.86 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.22FNO, 264.2; found, 264.4.

Compound 10: Preparation of 2,2-dimethyl-1-(2-(2,3,5-trifluorophenyl)pyrrolidin-1-yl)butan-1-one

[0131] ##STR00108##

[0132] The titled compound 10 was prepared in 66% yield from 2-(2,3,5-trifluorophenyl)pyrrolidine (50 mg) and 2,2-dimethylbutanoyl chloride (34 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ 6.66-6.71 (m, 1H), 6.44-6.46 (m, 1H), 5.43-5.46 (m, 1H), 3.79-3.86 (m, 2H), 2.21-2.26 (m, 1H), 1.90-1.98 (m, 2H), 1.69-1.77 (m, 1H), 1.61-1.68 (m, 2H), 1.26 (s, 3H), 1.23 (s, 3H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.20F.sub.3NO, 300.1; found, 300.4.

Compound 11: Preparation of 2,2-dimethyl-1-(2-phenylpiperidin-1-yl)butan-1-one

[0133] ##STR00109##

[0134] The titled compound 11 was prepared in 53% yield from 2-phenylpiperidine (50 mg) and 2,2-dimethylbutanoyl chloride(50 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.32-7.36 (m, 2H), 7.22-7.24 (m, 3H), 5.98 (m, 1H), 4.09 (m, 1H), 2.90 (m, 1H), 2.42 (d, 1H, J=14 Hz), 1.83-1.91 (m, 1H), 1.65-1.71 (m, 4H), 1.51-1.61 (m, 2H), 1.32 (s, 3H), 1.29 (s, 3H), 0.98 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.17H.sub.25NO, 260.2; found 260.4.

Compound 12: Preparation of 2,2-dimethyl-1-(3-phenylmorpholino)butan-1-one

[0135] ##STR00110##

[0136] The titled compound 12 was prepared 20% yield from 3-phenylmorpholine (25 mg) and 2,2-dimethylbutanoyl chloride(23 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ 7.47-7.52 (m, 2H), 7.32-7.36 (m, 2H), 7.25-7.28 (m, 1H), 5.54-5.76 (m, 1H), 4.50 (d, 1H, J=12.0 Hz), 3.83-3.91 (m, 3H), 3.56-3.62 (td, 1H, J=2.4, 12.0 Hz), 3.27-3.31 (m, 1H), 1.59 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.23NO.sub.2, 262.2; found, 262.4.

Compound 13: Preparation of 1- ((2S,4S)-4-hydroxy-2-phenylpyrrolidin-1-yl)-2,2-dimethylbutan-1-one

[0137] ##STR00111##

[0138] (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-phenylpyrrolidine(185 mg) and trimethylamine (0.18 ml) were dissolved in 2 mL of dry dichloromethane. The mixture was cooled to 0° C. and 2,2-dimethylbutanoyl chloride(134 mg) was added, then allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The organic layers were combined and concentrated. The residue was purified by column chromatography to give 1-((2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-phenylpyrrolidin-1-yl)-2,2-dimethylbutan-1-one(130 mg, 52%). .sup.1H-NMR (CDCl3): 7.11-7.29 (M, 5H), 5.10-5.20 (m, 1H), 4.31-4.37 (m, 1H), 4.12 (dd, J=6.0, 10.4 Hz), 3.62 (dd, J=6.4, 10.4 Hz), 2.46-2.52 (m, 1H), 1.80-1.84 (m, 1H), 1.57-1.72 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 0.84-0.87 (m, 12H), 0.09 (s, 3H), 0.01 (s, 3H).

[0139] The above intermediate (50 mg) was dissolved in THF (4 ml) and TBAF(42 mg) was added. The mixture was stirred at room temperature for 16 h, diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The organic layers were combined and concentrated. The residue was purified by column chromatography to give compound 13 (20 mg, 57%) as a white solid. .sup.1H-NMR (CDCl3): δ7.28-7.32 (m, 2H), 7.17-7.24 (m, 3H), 5.24-5.32 (m, 1H), 4.45-4.51 (m, 1H), 4.15 (dd, 1H, J=5.6, 11.2 Hz), 3.76 (dd, 1H, J=4.4, 11.2 Hz), 2.50-2.57 (m, 1H), 1.90-1.95 (m, 1H), 1.60-1.69 (m, 2H), 1.25 (s, 3H), 1.21 (s, 3H), 0.86 (t, 3H, J=7.6 Hz). MS(ES)[M+H].sup.+ calad for C.sub.16H.sub.23NO.sub.2, 262.2; found, 262.2.

Compound 14: Preparation of 1-(3,3-difluoro-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one

[0140] ##STR00112##

[0141] The titled compound 14 was prepared in 46% yield from 3,3-difluoro-2-phenylazetidine (25 mg) and 2,2-dimethylbutanoyl chloride (40 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3, 400 MHz): δ7.34-7.42 (m, 3H), 7.27-7.29 (m, 2H), 5.60-5.66 (m, 1H), 4.54-4.69 (m, 2H), 1.60 (q, 2H, J=7.6 Hz), 1.17 (s, 3 Hz), 1.15 (s, 3 Hz), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.19F.sub.2NO, 268.1; found, 268.1.

Compound 15: Preparation of 1-((2S,4R)-4-hydroxy-2-phenylpyrrolidin-1-yl)-2,2-dimethylbutan-1-one

[0142] ##STR00113##

[0143] To a solution of compound (30 mg) in dry DCM (4 Ml) was added 4-toluene sulfonyl chloride (27 mg) and the mixture was stirred at room temperature for 16 h and quenched with water (2 ml). The aqueous layers were extracted with DCM (15 mL×3) and the organic layers was combined, washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by column chromatography to give (3S,5S)-1-(2,2-dimethylbutanoyl)-5-phenylpyrrolidin-3-yl 4-methylbenzenesulfonate (38.1 mg, 80%) as a white solid. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): δ7.55 (d, 2H, J=8.0 Hz), 7.20-7.26 (m, 3H), 7.08-7.18 (m, 3H), 5.18-5.21 (m, 1H), 5.06-5.11 (m, 1H), 4.13-4.18 (m, 1H), 3.90-3.94 (m, 1H), 2.42 (s, 3H), 2.40-2.47 (m, 1H), 1.95-1.99 (m, 1H) 1.51-1.60 (m, 2H), 1.14 (s, 3H), 1.16 (s, 3H), 0.79 (t, 3H, J=7.6 Hz). The above intermediate was dissolved in dry DMSO (2 ml) and sodium acetate trihydrate (12 mg) was added. The mixture was stirred at 120° C. for 60 h and 4 ml of water was added. The aqueous layers were extracted with DCM (15 mL×3) and the organic layers was combined, washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by column chromatography to give (3R,5S)-1-(2,2-dimethylbutanoyl)-5-phenylpyrrolidin-3-ylacetate(13 mg, 47%). .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 87.27-7.31 (m, 2H), 7.16-7.22 (m, 3H), 5.27-5.32 (m, 2H), 5.12 (d, 2H, J=12.0 Hz), 3.91 (dd, 1H, J=4.0, 12.0 Hz), 2.42-2.49 (m, 1H), 2.06 (s, 3H), 1.52-1.61 (m, 2H), 1.22 (s, 3H), 1.19 (s, 3H), 0.84 (t, 3H, J=7.6 Hz).

[0144] The above intermediate (13 mg) was dissolved in THF(1 ml) and MeOH(0.2 ml) and 0.01 mL 1N NaOH was added. The mixture was stirred at 0° C. for 1 h and neutralized with 1N HCl. The aqueous layers were extracted with DCM and the organic layers was combined and evaporated to dryness. The residue was purified by Pre-HPLC to give the titled compound 15 (4 mg, 36%). .sup.1H NMR: (CDCl.sub.3, 400 M Hz): δ7.27-7.36 (m, 2H), 7.13-7.21 (m, 3H), 5.32 (t, 1H, J=7.6 Hz), 4.53-4.57 (m, 1H), 3.88-3.96 (m, 2H), 2.27-2.34 (m, 1H), 1.94-2.02 (m, 1H), 1.64-1.75 (m, 2H), 1.23 (s, 3H), 1.21 (s, 3H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.23 NO.sub.2, 262.2; found, 262.2.

Compound 16: Preparation of 1-(3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one

[0145] ##STR00114##

[0146] To a solution of 2-phenylazetidin-3-ol (27 mg) in THF (2 ml) and H.sub.2O(2 ml) was added sat. NaHCO.sub.3 (0.5 ml). The mixture was stirred at room temperature for 30 min, and cooled to 0° C., 2,2-dimethylbutanoyl chloride(37 mg) was added to the mixture and stirred for overnight. The mixture was extracted with DCM and the combined organic layers were washed with water and concentrated. The crude product was purified by Pre-HPLC to give compound 16 (5 mg, 12%) as a white solid. 1H NMR: (CDCl3, 400 M Hz): δ7.29-7.44 (m, 5H), 5.62-5.64 (m, 1H), 4.73-4.78 (m, 1H), 4.63-4.69 (m, 1H), 4.11-4.24 (m, 1H), 1.60 (q, 2H, J=7.6 Hz), 1.20 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H]+ calad for C15H21NO2, 248.2, found, 248.4.

Compound 17: Preparation of 2,2-dimethyl-1-(2-phenylpiperazin-1-yl)butan-1-one

[0147] ##STR00115##

[0148] tert-butyl 4-(2,2-dimethylbutanoyl)-3-phenylpiperazine-1-carboxylate (0.8 g) was dissolved in 3 ml of EtOAc, then 4N HCl in EtOAc (10 ml) was added. The mixture was stirred at room temperature for 3 h. After removing solvent, the residue was washed with petroleum ether to get compound 150 (0.45 g, 68%) as HCl salt, which was used for next step without further purification. .sup.1HNMR(CD3OD,400 MHz): δ7.43-7.47 (m, 2H), 7.29-7.36 (m, 3H), 5.93-5.99 (m, 1H), 4.54 (d, 1H, J=14.8 Hz), 4.14 (d, 1H, J=13.6 Hz), 3.41-3.48 (m, 2H), 3.26-3.29 (m, 1H), 3.13-3.21 (m, 1H), 1.69-1.79 (m, 2H), 1.32 (s, 3H), 1.29 (s, 3H), 0.96 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.24N.sub.2O, 261.2; found, 261.4.

Compound 18: Preparation of 1-(4-acetyl-2-phenylpiperazin-1-yl)-2,2-dimethylbutan-1-one

[0149] ##STR00116##

[0150] The titled compound 18 was prepared in 52% yield from compound 17 (20 mg) and acetyl chloride (6.4 mg) according to the procedure outlined for compound 1.

[0151] .sup.1HNMR(CDCl.sub.3, 400 MHz): δ1H-NMR (CDCl3) δ 7.27-7.35 (m, 5H), 5.75-5.77 (m, 1H), 4.27-4.30 (m, 1H), 4.11-4.21 (m, 2H), 3.58-3.64 (m, 2H), 3.23-3.30 (m, 1H), 2.03 (s, 3H), 1.61-1.66 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), 0.95 (t, 3H, J=8.0 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.18H.sub.26N.sub.2O.sub.2, 303.2; found, 303.4.

Compound 19: Preparation of tert-butyl 4-(2,2-dimethylbutanoyl)-3-phenylpiperazine-1-carboxylate

[0152] ##STR00117##

[0153] The titled compound 19 was prepared in 90% yield from tert-butyl3-phenylpiperazine-1-carboxylate (500 mg) and 2,2-dimethylbutanoyl chloride (282 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.31-7.34 (m, 4H), 7.22-7.25 (m, 1H), 5.76-5.86 (m, 1H), 4.55-4.70 (m, 1H), 3.75-4.15 (m, 2H), 2.80-3.30 (m, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.47 (s, 9H), 1.30 (s, 3H), 1.29 (s, 3H), 0.95 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.21H.sub.32N.sub.2O.sub.3, 361.2; found 361.4.

Compound 20: Preparation of 2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)butan-1-one

[0154] ##STR00118##

[0155] The titled compound 20 was prepared in 46% yield from 5-phenyl-4,5-dihydro-1H-pyrazole (60 mg) and 2,2-dimethylbutanoyl chloride (56 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.27-7.32 (m, 2H), 7.20-7.24 (m, 1H), 7.14-7.17 (m, 2H), 6.90 (t, 1H, J=1.6 Hz), 5.38 (dd, 1H, J=12.0, 4.8 Hz), 3.30 (ddd, 1H, J=18.0, 12.0, 1.6 Hz), 2.68 (ddd, 1H, J=18.0, 4.8, 1.6 Hz), 1.83 (qd, 2H, J=7.6, 3.2 Hz), 1.27 (s, 3H,), 1.25 (s, 3H,) 0.78 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.20N.sub.2O, 245.2; found, 245.2.

Compound 21: Preparation of 2,2-dimethyl-1-(5-phenylpyrazolidin-1-yl)butan-1-one

[0156] ##STR00119##

[0157] To a solution of compound 20 (40 mg) in dry tetrahydrofuran (5 ml) was added drop wise a solution of lithium triethylborohydride (1M in tetrahydrofuran) under nitrogen at 0° C. The mixture was stirred at 0° C. for 2 h and quenched with 2M sodium hydroxide (2 ml). The solvent was evaporated to dryness and the residue was extracted with dichloromethane. The extracts were washed with 2M sodium hydroxide solution and concentrated. The residue was purified by column chromatography to give compound 21 (23 mg, 56%). .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.27-7.35 (m, 4H), 7.22-7.26 (m, 1H), 5.39-5.43 (m, 1H), 3.34-3.38 (m, 1H), 2.71-2.77 (m, 1H), 2.01-2.10 (m, 1H), 1.72-1.80 (m, 1H), 1.50-1.55 (m, 2H), 1.22 (s, 3 Hz), 1.24 (s, 3 Hz), 0.84 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.22N.sub.2O, 247.1; found, 247.1.

Compound 22: Preparation of 2,2-dimethyl-1-(2-methyl-5-phenylpyrazolidin-1-yl)butan-1-one

[0158] ##STR00120##

[0159] Compound 21 (10 mg), cesium carbonate (26.5 mg) and iodomethane (11.5 mg) in N,N-dimethylformamide (1 ml) were carried out in a Biotage Initiator microwave synthesizer, which was programmed to heated up to 110° C. and stirred for 90 min. Then the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give compound 156 (4 mg, 38%). .sup.1HNMR(CDCl.sub.3, 400 M Hz): δ 7.25-7.32 (m, 4H), 7.18-7.22 (m, 1H), 5.38 (t, 1H, J=8.8 Hz), 2.94-3.05 (m, 2H), 2.58-2.65 (m, 1H), 2.56 (s, 3H), 2.32-2.38 (m, 1H), 1.76-1.89 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H), 0.92 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.24N.sub.2O, 261.2; found 261.2.

Compound 23: Preparation of (R)-3-(2,2-dimethylbutanoyl)-4-phenyloxazolidin-2-one

[0160] ##STR00121##

[0161] n-BuLi (2.4 M in THF, 0.214 mL, 0.51 mmol) was added slowly to a solution of (R)-4-phenyloxazolidin-2-one (80 mg, 0.49 mmoL) in 2 mL of THF at 0° C. under nitrogen, which was stirred at 0° C. for 50 min. Then 2,2-dimethylbutanoyl chloride (78.9 mg, 0.59 mmol) was added slowly to the solution at 0° C. The mixture was allowed to stir at room temperature for 3.5 h and quenched with saturated aqueous solution of NH.sub.4Cl. The aqueous layer were extracted with EtOAc (5 mL×3). The combined organic layers were washed with water and brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was crystallized with petroleum ether at −20° C. to give 31 mg of compound 23 as white solid (yield=24.2%). .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ (ppm) 7.29-7.40 (m, 5H), 5.48 (dd, 1H, J=4.8, 8.4 Hz), 4.67 (t, 1H, J=8.4 Hz), 4.23 (dd, 1H, J=4.8, 8.4 Hz), 1.77-1.95 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H), 0.70 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.19NO.sub.3, 262.1;found 262.2.

Compound 24: Preparation of (S)-1-(2,2-dimethylbutanoyl)-4-phenylazetidin-2-one

[0162] ##STR00122##

[0163] (S)-4-phenylazetidin-2-one (60 mg, 0.41 mmoL) and triethylamine (189.5 mg, 1.9 mmol) were dissolved in 2 mL of dry dichloromethane. The mixture was cooled to 0° C. and 2,2-dimethylbutanoyl chloride (60.1 mg, 0.448 mmol) was added, then allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The extracts were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography(ethyl acetate/petroleum ether=1/5) to give compound 24 (50 mg, 50%) as colorless oil. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ (ppm) 7.34-7.38 (m, 2H), 7.29-7.33 (m, 3H), 4.94 (dd, 1H, J=3.2 Hz, J=6.8 Hz), 3.38 (dd, 1H, J=6.8 Hz, J=16.4 Hz), 2.84 (dd, 1H, J=3.2 Hz, J=16.4 Hz), 1.84 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.80 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.19NO.sub.2, 246.1;found 246.2.

Compound 25: Preparation of 4-(3-azidophenyl)-1-(2,2-dimethylbutanoyl)azetidin-2-one

[0164] ##STR00123##

[0165] A solution of 1-azido-3-vinylbenzene (200 mg) in absolute toluene(3 ml) was added drop wise to a stirred solution of chlorosulfonyl isocyanate (119 ul) in absolute toluene (3 ml) at 0° C. The mixture was stirred at room temperature for 8 h and then left to stand overnight. The solution was added drop wise to a vigorously stirred solution of sodium sulfite (87 mg) and sodium carbonate (73 mg) in water (1 ml). The layer were separated and the aqueous was extracted with toluene. The combined organic layers were dried with Na.sub.2SO.sub.4, filtered and concentrated and the residue was washed with diethyl ether to give 4-(3-azidophenyl)azetidin-2-one (100 mg). .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.36 (t, J=7.76 Hz, 1H), 7.11-7.17 (m, 1H), 6.18-7.01 (m, 2H), 4.72 (dd, J=2.4, 5.2 Hz, 1H), 3.43-3.49 (m, 1H), 2.84-2.88 (m, 1H).

[0166] The above intermediate (30 mg) and triethylamine (27 uL) were dissolved in dichloromethane (4 mL). The mixture was cooled to 0° C. and 2,2-dimethylbutanoylchloride (26 mg) was added. The mixture was allowed to warm to room temperature and stirred for 2 h, and diluted with water. The aqueous layer was extracted with dichloromethane. The combined organic layers was washed with water and brine, dried with (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether=1/4) to give the desired product (35 mg, 48%) as an white solid. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.33-7.37 (m, 1H), 7.06-7.09 (m, 1H), 6.93-6.99 (m, 2H), 4.92 (dd, 1H, J=3.2, 6.4 Hz), 3.39 (dd, 1H, J=6.4, 16.4 Hz), 2.81 (dd, 1H, J=3.2, 16.4 Hz), 1.846 (qd, 2H, J=1.2, 7.6 Hz), 1.27 (s, 3H), 1.26 (s, 3H), 0.82 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.18N.sub.4O.sub.2, 287.1; found, 287.2.

Compound 26: Preparation of 4-(3-bromophenyl)-1-(2,2-dimethylbutanoyl)azetidin-2-one

[0167] ##STR00124##

[0168] Compound 26 was prepared in 51% from 4-(3-bromophenyl) azetidin-2-one (200 mg) and 2,2-dimethylbutanoyl chloride(147 mg) according to the procedure outlined for compound 25. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.41-7.47 (m, 2H), 7.23-7.24 (m, 2H), 4.89 (dd, 1H, J=3.6, 6.4 Hz), 3.39 (dd, 1H, J=6.4, 16.4 Hz), 2.81 (dd, 1H, J=3.6, 16.4 Hz), 1.84 (q, 2H, J=7.2 Hz), 1.26 (s, 6H), 0.82 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.18BrNO.sub.2, 324.1; found 324.2, 326.2.

Compound 172: Preparation of 1-(2,2-dimethylbutanoyl)-4-(3-ethynylphenyl)azetidin-2-one

[0169] ##STR00125##

[0170] To solution of compound 26 (165 mg) and triphenylphosphine (13 mg) in dry triethylamine (4 ml) was added ethynyltrimethylsilane (87 ul) and palladium acetate (6 mg) The mixture was heated to reflux for 4 h, cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (acetic ether/petroleum=1/10) to give 1-(2,2-dimethylbutanoyl)-4-(3-((trimethylsilyl)ethynyl)phenyl)azetidin-2-one (140 mg, 80%) as a yellow solid. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.38-7.42 (m, 2H), 7.22-7.31 (m, 2H), 4.90 (dd, J=3.2, 6.8 Hz, 1H), 3.37 (dd, J=6.8, 16.4 Hz, 1H), 2.82 (dd, J=3.2, 16.4 Hz, 1H), 1.95-1.73 (m, 2H), 1.26 (s, 6H), 0.81 (t, J=7.6 Hz, 3H), 0.24 (s, 9H).

[0171] The above intermediate (60 mg) was dissolved in tetrahydrofuran (3 ml), then tetrabutyl ammonium fluoride (51 mg) was added to the solution at 0° C. The mixture was stirred at 0° C. for 3 h. After completion of the reaction, H.sub.2O (3 ml) was added and extracted with CH.sub.2Cl.sub.2. The combined organic layers was washed with water and brine, dried with (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel column chromatography to give compound 27 (11 mg, 23%). .sup.1H NMR (CDCl.sub.3, 400 M Hz): 87.42-7.44 (m, 2H), 7.28-7.34 (m, 2H), 4.91 (dd, 1H, J=3.2, 6.4 Hz), 3.39 (dd, 1H, J=6.4, 16.4 Hz), 3.08 (s, 1H), 2.82 (dd, 1H, J=3.2, 16.4 Hz), 1.84 (q, 2H, J=7.2 Hz), 1.26 (s, 6H), 0.81 (t, 3H, J=7.2 Hz). MS(ES) [M+H].sup.+ calad for C.sub.17H.sub.19NO.sub.2, 270.1; found, 270.3.

Compound 28: Preparation of 1-(2,2-dimethylbutanoyl)-4-(3-nitrophenyl)azetidin-2-one

[0172] ##STR00126##

[0173] Compound 28 was prepared in 25% yield from 4-(3-nitrophenyl)azetidin-2-one (10 mg) (prepared form 1-nitro-3-vinylbenzene(200 mg) and chlorosulfonyl isocyanate (116 ul) according to the procedure outlined for compound 170) and 2,2-dimethylbutanoyl chloride(179 mg) according to the procedure outlined for compound 25. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ 8.18-8.20 (m, 2H), 7.64-7.66 (m, 1H), 7.55-7.59 (m, 1H), 5.04 (q, 1H, J=3.6, 6.4 Hz), 3.48 (dd, 1H, J=6.4, 16.4 Hz), 2.87 (dd, 1H, J=3.6, 16.4 Hz), 1.82-1.89 (m, 2H), 1.27 (s, 6H), 0.82 (t, 3H, J=7.6 Hz). MS(ES) [M+H].sup.+ calad for C.sub.15H.sub.18N.sub.2O.sub.4, 290; found, 291.

Compound 29: Preparation of 1-(2,2-dimethylbutanoyl)-5-phenylpyrrolidin-2-one

[0174] ##STR00127##

[0175] The titled compound 29 was prepared in 38% yield from 5-phenylpyrrolidin-2-one (50 mg) and 2,2-dimethylbutanoyl chloride(50 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.27-7.35 (m, 2H), 7.20-7.25 (m, 3H), 5.379 (dd, 1H, J=4.4 Hz, J=8.0 Hz), 2.70-2.79 (m, 1H), 2.42-2.60 (m, 2H), 1.87-2.00 (m, 2H), 1.64-1.73 (m, 1H), 1.30 (s, 3H), 1.24 (s, 3H), 0.68 (t, 3H, J=7.6 Hz). MS(ES)[M+H].sup.+ calad for C.sub.16H.sub.21NO.sub.2, 260.2; found, 260.3.

Compound 30: Preparation of (R)-3-(2,2-dimethylbutanoyl)-4-phenyl-1-(prop-2-yn-1-yl)imidazolidin-2-one

[0176] ##STR00128##

[0177] (R)-tert-butyl (2-oxo-1-phenyl-2-(prop-2-yn-1-ylamino)ethyl)carbamate was prepared from (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid and prop-2-yn-1-amine according to the procedure for compound 53. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.32-7.36 (m, 5H), 6.03 (brs, 1H), 5.73 (brs, 1H), 5.15 (brs, 1H), 3.93-4.12 (m, 2H), 2.20 (t, J=2.8 Hz), 1.41 (s, 9H).

[0178] The above compound (500 mg) was dissolved in CH.sub.2Cl.sub.2 (8 ml), TFA (2 ml) was added. The mixture was stirred for 4 h and concentrated. After standard work up, the resulting crude product:(R)-2-amino-2-phenyl-N-(prop-2-yn-1-yl) acetamide (240 mg) was added to a solution of lithium aluminum hydride(194 mg) in THF(5 ml) at 0° C. and stirred for 1 h, then the mixture was refluxed for 2 h, added 0.2 ml of water, 0.2 ml of 15% NaOH and 0.2 ml water in this order, filtered and evaporated. The resulting yellow liquid (130 mg) was used for next step without further purification.

[0179] The above compound: (R)-1-phenyl-N2-(prop-2-yn-1-yl)ethane-1,2-diamine(130 mg) and triethylamine (0.5 ml) were dissolved in dry THF(30 ml), phosgene(118 mg) was added at 0° C. and stirred for overnight. The mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers was washed with water and brine, dried(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography to give 150 mg of (R)-4-phenyl-1-(prop-2-yn-1-yl)imidazolidin-2-one

[0180] The above intermediate (150 mg) and triethylamine (0.16 ml) were dissolved in dry dichloromethane (2 ml). The mixture was cooled to 0° C. and 2,2-dimethylbutanoylchloride (120 mg) was added, then allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The organic layers were combined and concentrated. The residue was purified by column chromatography to give compound 30 (50 mg, total yield 10%) as colorless oil. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.27-7.35 (m, 5H), 5.37 (dd, 1H, J=3.6, 9.2 Hz), 4.12-4.13 (m, 2H), 3.91 (t, 1H, J=9.2 Hz), 3.32 (dd, 1H, J=3.6, 9.2 Hz), 2.27 (t, 1H, J=2.4 Hz), 1.89 (dq, 2H, J=1.6, 7.6 Hz), 1.28 (s, 3H), 1.29 (s, 3H), 0.70 (t, 3H, J=7.6 Hz). MS(ES) [M+H].sup.+ calad for C.sub.18H.sub.22N.sub.2O.sub.2, 299.2; found, 299.3.

Compound 31: Preparation of (R)-3-(2,2-dimethylbutanoyl)-1-methyl-4-phenylimidazolidin-2-one

[0181] ##STR00129##

[0182] The titled compound 31 was prepared from (R)-3-(2,2-dimethylbutanoyl)-1-methyl-4-phenylimidazolidin-2-one (50 mg) and 2,2-dimethylbutanoyl chloride (45 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.31-7.35 (m, 2H), 7.24-7.30 (m, 3H), 5.33 (dd, 1H, J=4.0, 9.2 Hz), 3.813 (t, 1H, J=9.2 Hz), 3.20 (dd, 1H, J=4.0, 9.2 Hz), 2.900 (s, 3H), 1.92 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H), 0.73 (t, 3H, J=7.2 Hz). MS(ES)[M+H].sup.+ calad for C.sub.16H.sub.22N.sub.2O.sub.2, 275.2; found 275.4.

Compound 32: Preparation of 1-(2,2-dimethylbutanoyl)-3,3-difluoro-4-phenylazetidin-2-one

[0183] ##STR00130##

[0184] The titled compound 32 was prepared in 60% yield from 3,3-difluoro-4-phenylazetidin-2-one (30 mg) and 2,2-dimethylbutanoyl chloride (44 mg) according to the procedure outlined for compound 164. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.39-7.43 (m, 3H), 7.24-7.27 (m, 2H), 5.35 (dd, 1H, J=3.2, 10.4 Hz), 1.79-1.92 (m, 2H), 1.32 (s, 3H), 1.30 (s, 3H), 0.86 (t, 3H, J=7.6 Hz). MS(ES)[M+H].sup.+ calad for C.sub.15H.sub.17F.sub.2NO.sub.2, 282.1;found, 282.3.

Compound 33: Preparation of 2-(2,2-dimethylbutanoyl)-1-phenylpyrazolidin-3-one

[0185] ##STR00131##

[0186] The titled compound 33 was prepared in 25% yield from phenylpyrazolidin-3-one (50 mg) and 2,2-dimethylbutanoyl chloride(50 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.19-7.35 (m, 2H), 6.97-7.07 (m, 2H), 6.85 (t, 1H, J=8.0 Hz), 3.916 (t, 2H, J=8.0 Hz), 3.14 (t, 2H, J=8.0 Hz), 1.69 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.93 (t, 3H, J=7.6 Hz). MS(ES)[M+H].sup.+ calad for C.sub.15H.sub.20N.sub.2O.sub.2, 261.2; found, 261.3.

Compound 34: Prepared of 1-(2,2-dimethylbutanoyl)-5-phenylpyrazolidin-3-one

[0187] ##STR00132##

[0188] To a solution of 5-phenylpyrazolidin-3-one (65 mg) and triethylamine(0.066 ml) in dry tetrahydrofuran (4 ml) was slowly added 2,2-dimethylbutanoyl chloride (0.06 ml) at 0° C. under nitrogen. Then the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether=1/3) to give 1, 1′-(3-oxo-5-phenylpyrazolidine-1,2-diyl)bis(2,2-dimethylbutan-1-one) (50 mg, 34%) as an white solid.

[0189] The above intermediate (10 mg) was dissolved in tetrahydrofuran (1 ml) and 1M sodium hydroxide (0.05 ml) was added. The mixture was stirred for 2 h and diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic was washed with brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petrol-eumether=1/2) to give compound 34 (5.1 mg, 69%) as a white solid. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.28-7.40 (m, 5H), 5.82 (d, 1H, J=9.6 Hz), 3.34 (dd, 1H, J=9.6, 16.4 Hz), 2.60 (d, 1H, J=16.4 Hz), 1.57 (q, 2H, J=7.6 Hz), 1.17 (s, 3H), 1.14 (s, 3H), 0.81 (t, 3H, J=7.6 Hz). LC-MS (ESI)[M+H].sup.+ calad for C.sub.15H.sub.20N.sub.2O.sub.2, 261.2; found, 261.3.

Compound 35: Preparation of (2-(3-fluorophenyl)pyrrolidin-1-yl)(1-(trifluoromethyl)cyclopentyl)methanone

[0190] ##STR00133##

[0191] 2-(3-fluorophenyl)pyrrolidine (9 mg), which was prepared according the literature reported procedures, and 1-(trifluoromethyl)cyclopentanecarboxylic acid (10 mg) were dissolved in dry DMF(1 ml). 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (31 mg) and N,N-Diisopropylethylamine (14 mg) were added to the solution. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give

[0192] the desired product (8 mg, 44.2%). .sup.1H NMR: (CDCl.sub.3, 400 M Hz): δ7.24-7.28 (m, 1H), 6.87-6.92 (m, 2H), 6.79-6.82 (m, 1H), 5.16-5.19 (m, 1H), 3.90-3.96 (m, 1H), 3.73-3.79 (m, 1H), 2.46-2.50 (m, 1H), 2.28-2.36 (m, 2H), 2.09-2.19 (m, 2H), 1.95-2.06 (m, 1H), 1.83-1.93 (m, 1H), 1.64-1.78 (m, 5H). LC-MS (ESI)[M+H].sup.+ calad for C.sub.17H.sub.19F.sub.4NO, 330.1; found 3303.

Compound 36: Preparation of (2-(3-fluorophenyl)pyrrolidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone

[0193] ##STR00134##

[0194] The titled compound 36 was prepared in 32% yield from 1-(trifluoromethyl)cyclobutanecarboxylic acid (20 mg) and 2-(3-fluorophenyl)pyrrolidine (19.6 mg) according to the procedure outlined for compound 35. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): δ7.23-7.29 (m, 1H), 6.81-6.95 (m, 3H), 5.13-5.16 (m, 1H), 3.58-3.70 (m, 2H), 2.71-2.82 (m, 1H), 2.59-2.67 (m, 1H), 2.41-2.56 (m, 2H), 2.31-2.39 (m, 1H), 2.08-2.18 (m, 1H), 1.95-2.05 (m, 1H), 1.76-1.92 (m, 3H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.17F.sub.4NO, 316.1; found 316.3.

Compound 37: Preparation of adamantan-1-yl(2-(3-fluorophenyl)pyrrolidin-1-yl)methanone

[0195] ##STR00135##

[0196] The titled compound 37 was prepared in 46% yield from 2-(3-fluorophenyl)pyrrolidine (60 mg) and adamantane-1-carbonyl chloride (81 mg) according to the procedure outlined for compound 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.21-7.26 (m, 1H), 6.78-6.92 (m, 3H), 5.25 (m, 1H), 3.91 (m, 2H), 2.17-2.26 (m, 1H), 1.89-1.20 (m, 10H), 1.71-1.76 (m, 8H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.21H.sub.26FNO, 328.2;found, 328.4.

Compound 38: Preparation of (S)-1-(2,2-dimethylbut-3-enoyl)-4-phenylazetidin-2-one

[0197] ##STR00136##

[0198] The titled compound 38 was prepared in 34% yield from (S)-4-phenylazetidin-2-one (100 mg) and 2,2-dimethylbut-3-enoyl chloride (107 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl3, 400 M Hz): δ 7.27-7.39 (m, 5H), 6.26 (dd, 1H, J=10.8, 17.2 Hz), 5.18 (dd, 1H, J=0.8, 10.8 Hz), 5.12 (d, 1H, J=0.8, 17.2 Hz), 4.94 (dd, 1H, J=3.6, 6.4 Hz), 3.39 (dd, 1H, J=6.4, 16.4 Hz), 2.82 (dd, 1H, J=3.6, 16.4 Hz), 1.41 (s, 3H), 1.39 (s, 3H). LC-MS (ESI) [M+H]+ calad for C15H17NO2, 244.1; found, 244.3.

Compound 39: Preparation of (R)-3-acetyl-4-phenyloxazolidin-2-one

[0199] ##STR00137##

[0200] The titled compound 39 was prepared in 60% yield from (R)-4-phenyloxazolidin-2-one (80 mg) and acetyl chloride (46 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.29-7.41 (m, 5H), 5.425 (dd, 1H, J=3.6, 8.8 Hz), 4.69 (t, 1H, J=8.8 Hz), 4.29 (dd, 1H, J=3.6, 8.8 Hz), 1.53 (s, 3H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.11H.sub.11NO.sub.3,206.1; found, 206.2.

Compound 40: Preparation of (S)-1-(3-chloroacryloyl)-4-phenylazetidin-2-one

[0201] ##STR00138##

[0202] A solution of (S)-4-phenylazetidin-2-one (40 mg, 0.272 mmoL) and DIEA (35.1 mg, 0.272 mmoL) in 0.5 mL of CH.sub.2Cl.sub.2 was added slowly to a mixture of 3-chloroacryloyl chloride (37.1 mg, 0.299 mmoL) and DIEA(38.6 mg, 0.299 mmoL) in 1.5 mL of CH.sub.2Cl.sub.2 at 0° C. The mixture was allowed to stir at room temperature for 16 h. After removing of solvents and the brown residue was purified by preparative TLC plate to give 0.4 mg of compound 40 as brown oil (yield=0.6%). .sup.1H NMR: (CDCl.sub.3, 400 M Hz) δ7.31-7.40 (m, 5H), 7.14 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 5.11 (dd, 1H, J=3.6, 6.4 Hz), 3.53 (dd, 1H, J=6.4, 16.4 Hz), 3.03 (dd, 1H, J=3.6, 16.4 Hz). LC-MS (ESI) [M+H].sup.+ calad forC.sub.12H.sub.10ClNO.sub.2, 236.0; found, 236.2.

Compound 41: Prepared of (4S)-1-(tert-butylsulfinyl)-4-phenylazetidin-2-one

[0203] ##STR00139##

[0204] To a solution of (S)-4-phenylazetidin-2-one (50 mg) and triethylamine (0.1 mL) in dry THF (2 mL) was slowly added 2-methylpropane-2-sulfinic chloride (50 ul) at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/5) to give compound 167 (20 mg, 24%) as an white solid. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.33-7.46 (m, 5H), 5.12 (dd, 1H, J=3.6, 6.8 Hz), 3.60 (dd, 1H, J=16.0, 6.8 Hz), 3.21 (dd, 1H, J=16.0, 3.6 Hz), 0.98 (s, 9H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.13H.sub.17NO.sub.2S, 252.1; found 252.2.

Compound 42: Prepared of (S)-1-(isopropylsulfonyl)-4-phenylazetidin-2-one

[0205] ##STR00140##

[0206] The titled compound 42 was prepared in 34% yield from (S)-4-phenylazetidin-2-one (50 mg) and propane-2-sulfonyl chloride (58 mg) according to the procedure outlined for compound 23. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.37-7.46 (m, 5H), 5.20 (dd, 1H, J=3.2, 6.4 Hz), 3.61 (dd, 1H, J=6.4, 16.0 Hz), 3.17 (dd, 1H, J=3.2, 16.0 Hz), 2.93-3.00 (m, 1H), 1.29 (d, 3H, J=3.2 Hz), 1.27 (d, 3H, J=3.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.12H.sub.15NO.sub.3S, 254.1; found 254.2.

Compound 43: Prepared of (S)-1-(ethylsulfonyl)-4-phenylazetidin-2-one

[0207] ##STR00141##

[0208] The titled compound 43 was prepared in 33% yield from(S)-4-phenylazetidin-2-one (50 mg) and ethanesulfonyl chloride(52.5 mg) according to the procedure outlined for compound 23. .sup.1H NMR (CDCl.sub.3, 400 M Hz):7.37-7.45 (m, 5H), 5.19 (dd, 1H, J=3.6, 6.4 Hz), 3.61 (dd, 1H, J=6.4, 16.4 Hz), 3.16 (dd, 1H, J=3.6, 16.4 Hz), 2.80 (q, 2H, J=7.2 Hz), 1.31 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.11H.sub.13NO.sub.3S, 240.1; found 240.2.

Compound 44: Preparation of 4-(3-azidophenyl)-1-(2,2-dimethylbut-3-ynoyl)azetidin-2-one

[0209] ##STR00142##

[0210] Compound 44 was prepared in 1.3% yield from 4-(3-azidophenyl)azetidin-2-one (50 mg) (prepared according to the procedure outlined for compound 25) and 2,2-dimethylbut-3-ynoyl chloride(69 mg) according to the procedure outlined for compound 24. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ 7.34-7.38 (m, 1H), 7.09-7.11 (m, 1H), 6.97-7.00 (m, 2H), 4.98 (dd, 1H, J=3.2, 6.8 Hz), 3.48 (dd, 1H, J=6.8, 16.4 Hz), 2.88 (dd, 1H, J=3.2, 16.4 Hz), 2.35 (s, 1H), 1.59 (s, 3H), 1.57 (s, 3H). MS(ES)[M+H].sup.+ calad for C.sub.15H.sub.14N.sub.4O.sub.2, 283.1; found, 283.3.

Compound 45: Prepared of (S)-1-(tert-butylsulfonyl)-4-phenylazetidin-2-one

[0211] ##STR00143##

[0212] To a solution of compound 41 (9 mg) in dichloromethane (4 ml) was added m-CPBA (12.3 mg). The mixture was stirred at room temperature for 16 h and diluted with water. The aqueous layer was extracted with dichloromethane and the combined organic layers was washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by preparation TLC plate(ethyl acetate/petroleum ether=1/3) to give compound 45 (5 mg, 52%) as an white solid. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.34-7.47 (m, 5H), 5.24 (dd, 1H, J=3.6, 6.4 Hz), 3.61 (dd, 1H, J=6.4, 16.4 Hz), 3.238 (dd, 1H, J=3.6, 16.4 Hz), 1.20 (s, 9H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.13H.sub.17NO.sub.3S, 268.1; found 268.2.

Compound 46

Preparation of (S)-2,2-dimethyl-1-(2-phenylazetidin-1-yl)but-3-yn-1-one

[0213] ##STR00144##

[0214] Compound 46 was prepared in 13% yield from (S)-2-phenylazetidine (50 mg) and 2,2-dimethylbut-3-ynoic acid (69 mg) according to the procedure outlined for compound 35. .sup.1HNMR(CDCl.sub.3, 400 M Hz): δ7.34-7.37 (m, 5H), 5.35-5.39 (dd, 1H, J=6.0, 8.4 Hz), 4.56-4.66 (m, 2H), 2.70-2.79 (m, 1H), 2.40 (s, 1H), 2.11-2.19 (m, 1H), 1.47 (s, 3H), 1.45 (s, 3H). MS(ES)[M+H].sup.+ calad for C.sub.15H.sub.17NO, 228.1; found, 228.1.

Compound 47: Preparation of (S)-1-(adamantane-2-carbonyl)-4-phenylazetidin-2-one

[0215] ##STR00145##

[0216] The titled compound 47 was prepared in 32% yield from (S)-4-phenylazetidin-2-one (50 mg) and adamantane-2-carbonyl chloride (81 mg) according to the procedure outlined for compound 24. .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ 7.27-7.38 (m, 5H), 4.94 (dd, 1H, J=3.2, 6.8 Hz), 3.37 (dd, 1H, J=6.8, 16.4 Hz), 2.79 (dd, 1H, J=3.2, 16.4 Hz), 1.93-2.10 (m, 10H), 1.72-1.79 (m, 5H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.20H.sub.23NO.sub.2, 310.2; found, 310.3.

Compound 48: Preparation of(S)-1-ethyl-4-phenylazetidin-2-one

[0217] ##STR00146##

[0218] (S)-4-phenylazetidin-2-one (15 mg) was dissolved in 2 mL of dry THF and NaH (5 mg, 60% in material oil) was added in portions at 0° C. under nitrogen. After stirring at 0° C. for 30 min, iodoethane (17.5 mg) was added. The mixture was stirred at room temperature for 16 h, quenched with 1 mL of water and extracted with EtOAc. The extracts were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 2.6 mg of compound 48 as white solid (14.6%). .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ7.31-7.41 (m, 5H), 4.56 (dd, 1H, J=2.4, 5.2 Hz), 3.43-3.52 (m, 1H), 3.34 (dd, 1H, J=5.2 Hz, J=14.4 Hz), 2.90-2.99 (m, 1H), 2.81 (dd, 1H, J=2.4 Hz, 14.4 Hz), 1.07 (t, 3H, J=7.2 Hz). [M+H].sup.+ calad for C.sub.11H.sub.13NO, 176.1; found 176.2.

Compound 49: Preparation of (S)-4-phenyl-1-(prop-2-ynyl)azetidin-2-one

[0219] ##STR00147##

[0220] A solution of (S)-4-phenylazetidin-2-one (30 mg, 0.204 mmoL) and 3-iodoprop-1-yne (26.8 mg, 0.227 mmoL) in 2 mL of THF was added drop wise to the mixture of KOH (13.7 mg, 0.245 mmoL) and tetrabutyl ammonium bromide (26.8 mg, 0.227 mmoL) in 2 mL of THF at 0° C. The mixture was allowed to stir at room temperature for 16 h. After filtering, the filtrate was evaporated to dryness and the brown residue was purified by preparative TLC plate(ethyl acetate/petroleum ether=1/4) to give 30 mg of compound 49 as light yellow solid (yield=79.6%). .sup.1H NMR (CDCl.sub.3, 400 M Hz): δ7.28-7.38 (m, 5H), 6.70 (t, 1H, J=6.4 Hz), 5.20 (dd, 1H, J=6.4, 10.8 Hz), 4.98 (dd, 1H, J=6.4, 10.8 Hz), 4.69 (dd, 1H, J=2.8, 5.6 Hz), 3.46 (dd, 1H, J=5.6, 14.8 Hz), 2.884 (dd, 1H, J=2.8, 14.8 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.12H.sub.11NO, 186.1;found 186.2.

Compound 50: Preparation of (S)-1-(cyclopropylmethyl)-4-phenylazetidin-2-one

[0221] ##STR00148##

[0222] The titled compound 50 was prepared in 9.7% yield from(S)-4-phenylazetidin-2-one (15 mg), (bromomethyl)cyclopropane (15 mg) and NaH (4.5 mg, 60% in material oil) according to the procedure outlined for compound 48. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): δ7.31-7.40 (m, 5H), 4.67 (dd, 1H, J=2.4, 5.2 Hz), 3.43 (dd, 1H, J=6.4, 14.4 Hz), 3.38 (dd, 1H, J=5.2, 14.8 Hz), 2.82 (dd, 1H, J=2.4, 14.8 Hz), 2.57 (dd, 1H, J=7.6, 14.4 Hz), 0.82-0.88 (m, 1H), 0.36-0.46 (m, 2H), 0.01-0.07 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.15NO, 202.1;found, 202.2.

Compound 51: Preparation of (R)-3-ethyl-4-phenyloxazolidin-2-one

[0223] ##STR00149##

[0224] (R)-4-phenyloxazolidin-2-one (50 mg, 0.31 mmoL) was dissolved in 2 mL of dry THF and NaH (15 mg, 0.38 mmoL, 60% in material oil) was added in portions at 0° C. under nitrogen. After stirring at 0° C. for 30 min, iodoethane (57.4 mg, 0.37 mmoL) was added. The mixture was stirred at room temperature for 16 h, quenched with 1 mL of water and extracted with EtOAc. The extracts were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 12 mg of compound 51 as white solid (yield=20.5%). .sup.1H NMR:(CDCl.sub.3, 400M Hz) δ7.38-7.44 (m, 3H), 7.30-7.32 (m, 2H), 4.80 (dd, 1H, J=7.2, 8.8 Hz), 4.61 (t, 1H, J=8.8 Hz), 4.10 (dd, 1H, J=7.2, 8.8 Hz), 3.47-3.56 (m, 1H), 2.80-2.89 (m, 1H), 1.05 (t, 3H, J=7.2 Hz). MS(ES) [M+H].sup.+ calad for C.sub.11H.sub.13NO.sub.2, 192.1;found 192.2.

Compound 52: Preparation of (R)-4-phenyl-3-(prop-2-yn-1-yl)oxazolidin-2-one

[0225] ##STR00150##

[0226] The titled compound 52 was prepared in 46% yield from (R)-4-phenyloxazolidin-2-one (80 mg) and 3-bromoprop-1-yne (116 mg) according to the procedure outlined for compound 51. .sup.1HNMR(CDCl.sub.3, 400 MHz): δ7.37-7.46 (m, 3H), 7.32-7.35 (m, 2H), 4.96 (t, 1H, J=8.4 Hz), 4.67 (t, 1H, J=8.4 Hz), 4.41 (dd, 1H, J=2.4, 17.6 Hz), 4.16 (dd, 1H, J=8.4, 8.4 Hz), 3.39 (dd, 1H, J=2.4, 17.6 Hz), 2.25 (t, 1H, J=2.4 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.12H.sub.11NO.sub.2, 202.1; found, 202.2.

Compound 53 and 54

Compound 53 and 54 are Prepared According to the Procedure Outlined in Scheme 1

[0227] ##STR00151##

[0228] Scheme 1: reagent and conditions: (a) Na/THF, −78° C. (b) NaH, 2,2-dimethylbutanoyl chloride(for 53) or 2,2-dimethylbut-3-enoyl chloride(for 54), THF.

Compound 56 and 57

Compound 56 and 57 are Prepared According to the Procedure Outlined in Scheme 2

[0229] ##STR00152##

[0230] Scheme 2: reagent and conditions: (a) Pd/C, H.sub.2 (b) NaH, 2,2-dimethylbutanoyl chloride(for 56) or 2,2-dimethylbut-3-enoyl chloride(for 57), THF.

Compound 55 and 58

Compound 55 and 58 are Prepared According to the Procedure Outlined in Scheme 3

[0231] ##STR00153##

[0232] Scheme 3: reagent and conditions: (a) NaH, 2,2-dimethylbutanoyl chloride (for 55) or 2,2-dimethylbut-3-enoyl chloride(for 58), THF.

Compound 59-68

Compound 59-68 are Prepared According to the Procedure Outlined in Scheme 4

[0233] ##STR00154##

[0234] Scheme 4: reagent and conditions: (a) LiAlH.sub.4, THF, reflux (b) Et.sub.3N, 2,2-dimethylbutanoyl chloride(for 59-61, 65,67) or 2,2-dimethylbut-3-enoyl chloride(62-64,66,68) THF.

Compound 69

Compound 69 are Prepared According to the Procedure Outlined in Scheme 5

[0235] ##STR00155##

[0236] Scheme 5: reagent and conditions: (a) Et.sub.3N, 2,2-dimethylbut-3-enoyl chloride, THF.

Compound 70

Compound 70 is Prepared According to the Procedure of Scheme 6

[0237] ##STR00156##

[0238] Scheme 6: reagent and conditions: (a) LiAlH.sub.4, THF, reflux (b) Et.sub.3N, 2-methylbutane-2-sulfonyl chloride, THF.

Compound 72 and 73

Compound 72 and 73 are Prepared According to the Procedure of Scheme 7

[0239] ##STR00157##

[0240] Scheme 7: reagent and conditions: (a) TFA/DCM (b) Et.sub.3N, 2,2-dimethylbutanoyl chloride (for 72) or 2,2-dimethylbut-3-enoyl chloride (for 73), THF.

Compound 74 and 75

Compound 74 and 75 are Prepared According to the Procedure of Scheme 8

[0241] ##STR00158##

[0242] Scheme 8: reagent and conditions: (a) K.sub.2CO.sub.3, thiophenol, DMF (b) Et.sub.3N, 2,2-dimethylbutanoyl chloride (for 74) or 2,2-dimethylbut-3-enoyl chloride (for 75), THF.

Compound 76 and 77

Compound 76 and 77 are Prepared According to the Procedure of Scheme 9

[0243] ##STR00159##

[0244] Scheme 9: reagent and conditions: (a) Et.sub.3N, 2,2-dimethylbutanoyl chloride (for 76) or 2,2-dimethylbut-3-enoyl chloride (for 77), THF.

Compound 78: Preparation of 2,2-dimethyl-1-(2-phenyl-1H-pyrrol-1- yl)butan-1-one

[0245] ##STR00160##

[0246] To a stirred suspension of NaH (30 mg, 0.7 mmol) in dry THF (3 ml) was added a solution of 2-phenyl-1H-pyrrole (50 mg) in dry THF (1 mll), under an argon atmosphere. After stirring at rt for 5 min, hydrogen evolution ceased and 2,2-dimethylbutanoyl chloride(56 mg) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was poured onto saturated aqueous NH.sub.4Cl, which was extracted with CH2Cl2 (3×10 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated to yield the desired product (30 mg, 36%). .sup.1HNMR(CDCl.sub.3, 400 MHz): δ 7.45-7.47 (m, 2H), 7.34-7.39 (m, 2H), 7.18-7.23 (m, 1H), 6.85-6.88 (d, 1H, J=8.0 Hz), 6.51-6.54 (m, 1H), 6.29-6.32 (d, 1H, J=8.0 Hz), 1.39 (q, 2H, J=7.6 Hz), 0.97 (s, 6H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.19NO, 242.1; found, 242.4.

Compound S1: Preparation of 1-((2R,3S)-3-hydroxy-2-phenylpyrrolidin-1-yl)-2,2-dimethylbutan-1-one

[0247] ##STR00161##

[0248] (2R,3S)-2-phenyl-1-tosylpyrrolidin-3-ol was prepared according to methods previously described (US2009/0012120A1) (35 mg) and phenol(31 mg) were added in 4 mL of HBr(48%, w/w). The mixture was strried at 100° C. for 12 h and then cooled to room temperature, extracted with ether(2 mL) and the ether layer was discarded. The aqueous was freeze-dried to give (2R,3S)-2-phenylpyrrolidin-3-ol (30 mg) without further purification.

[0249] The above amino-alcohol compound (30 mg) dissolved in 2 mL of THF/H.sub.2O (1:1) and 0.45 mL of saturated aqueous NaHCO.sub.3. The solution was cooled to 0° C. and 2,2-dimethylbutanoylchloride(16 mg) was added and the mixture was stirred at room temperature for 12 h. The mixture was extracted with EtOAc and the combined organic layer washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification by pre-HPLC to give compound S1 (15 mg, 52% in two steps) as a colorlesss oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.30 (t, J=7.3 Hz, 2H), 7.22 (t, J=7.0 Hz, 1H), 7.12 (d, J=7.4 Hz, 2H), 5.33 (brs, 1H), 4.19 (brs, 1H), 4.05-3.94 (m, 2H), 2.05 (brs, 1H), 1.91 (brs, 1H), 1.73-1.60 (m, 2H), 1.25 (s, 3H), 1.20 (s, 3H), 0.88 (t, J=6.8 Hz, 3H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.24NO.sub.2, 262.18; found, 262.44.

Compound S2: Preparation of 1-((2R,3R)-3-hydroxy-2-phenylpyrrolidin-1-yl)-2,2-dimethylbutan-1-one

[0250] ##STR00162##

[0251] To a solution of compound S1 (30 mg) in dry DCM (4 mL) was added 4-toluene sulfonyl chloride (27 mg) and the mixture was stirred at room temperature for 16 h and quenched with water(2 mL). The aqueous layers were extracted with DCM (15 mL×3) and the organic layers was combined, washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by column chromatography to give (2R,3S)-1-(2,2-dimethylbutanoyl)-2-phenylpyrrolidin-3-yl-4-methylbenzenesulfonate (36 mg, 75%). LC-MS (ESI) [M+H].sup.+ calad for C.sub.23H.sub.30NO.sub.4S, 416.19; found, 416.52.

[0252] The above intermediate was dissolved in dry DMSO (2 mL) and sodium acetate trihydrate (12 mg) was added. The mixture was stirred at 100° C. for 60 h and 4 mL of water was added. The aqueous layers were extracted with DCM (15 mL×3) and the organic layers was combined, washed with brine, dried with Na.sub.2SO.sub.4 and evaporated to dryness. The residue was used for next step without further purification. The above intermediate (15 mg) was dissolved in THF(1 mL) and MeOH(0.2 mL) and 0.01 mL 1N NaOH was added. The mixture was stirred at 0° C. for 1 h and neutralized with 1N HCl. The aqueous layers were extracted with DCM and the organic layers was combined and evaporated to dryness. The residue was purified by Pre-TLC to give the titled compound S2 (5 mg, 17%, in three steps). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.33 (t, J=7.2 Hz, 2H), 7.27-7.24 (m, 1H), 7.15 (d, J=7.8 Hz, 2H), 5.18 (d, J=4.5 Hz, 1H), 3.93 (brs, 2H), 2.08 (brs, 1H), 1.71 (brs, 1H), 1.62-1.53 (m, 2H), 1.19 (s, 6H), 0.85 (t, J=6.8 Hz, 3H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.24NO.sub.2, 262.18; found, 262.44.

Compound S3: Preparation of (R)-1-(2,2-dimethylbutanoyl)-2-phenylpyrrolidin-3-one

[0253] ##STR00163##

[0254] To a mixture of compound S2 (6 mg) and 4A MS (10 mg) in DCM(2 mL) was added PCC (15 mg) at 0° C. The mixture was stirred for 1 hour at room temperature, followed by filtering through a pad of Al.sub.2O.sub.3. The filtrate was concentrated in vacuo. The resulting residue was purified by pre-TLC to afford the desired product S3 (4 mg, 67%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.21 (m, 5H), 4.50-4.41 (m, 1H), 4.07-3.98 (m, 1H), 2.75-2.62 (m, 2H), 1.72-1.59 (m, 2H), 1.22 (d, J=15.1 Hz, 6H), 0.85 (t, J=7.3 Hz, 3H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.22NO.sub.2, 260.16; found, 262.30.

Synthetic Route for Compound S4 and S5

[0255] ##STR00164##

Compound S4: Preparation of 1-((2R,3R)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one

[0256] ##STR00165##

[0257] (R)-2-phenyl-1-tosylazetidin-3-one was prepared according to methods previously described (Tetrahedron 2008, 64, 9928-9936) and NaBH4 (75.5 mg) in methanol (15 mL) were stirred at room temperature for 3 h. The reaction mixture was quenched by addition of solid citric acid until pH reached 5 to 6. To the reaction mixture was added silica gel and the solvent was distilled off. The residue was purified by column chromatography on silica gel (EtOAc: hexane, 1:3) to afford the desired products, two isomers a and b, and its absolute configuration was confirmed by .sup.1H-.sup.1H nuclear overhauser effects (NOE). Product a: 1-((2R,3R)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (d, J=8.3 Hz, 2H), 7.44-7.31 (m, 7H), 5.11 (d, J=6.7 Hz, 1H), 4.37 (td, J=6.7, 2.8 Hz, 1H), 4.05 (dd, J=9.5, 6.6 Hz, 1H), 3.74 (ddd, J=9.5, 2.8, 1.1 Hz, 1H), 2.45 (s, 3H). Product b: 1-((2R,3S)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one, .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66 (d, J=8.2 Hz, 2H), 7.41-7.28 (m, 7H), 4.50 (d, J=5.7 Hz, 1H), 4.24 (dd, J=12.5, 6.4 Hz, 1H), 4.02 (t, J=7.3 Hz, 1H), 3.52-3.45 (m, 1H), 2.44 (s, 3H).

[0258] 1-((2R,3R)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one(50 mg) and triethylamine (33.2 mg) were dissolved in 2 mL of DCM, and 34 mg of p-toluenesulfonyl chloride was added at 0° C. The mixture was allowed to stir at room temperature for 12 h, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: hexane, 1:5) to afford (2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-phenyl-1-tosylazetidine (63 mg, 92%). .sup.1H NMR (400 MHz, cdcl.sub.3) δ 7.68 (d, J=8.3 Hz, 2H), 7.38-7.26 (m, 7H), 4.99 (d, J=6.6 Hz, 1H), 4.38 (td, J=6.5, 2.7 Hz, 1H), 4.04 (dd, J=8.9, 6.4 Hz, 1H), 3.69 (ddd, J=8.9, 2.7, 1.0 Hz, 1H), 2.43 (s, 3H), 0.63 (s, 9H), −0.19 (s, 3H), −0.42 (s, 3H).

[0259] To a solution of (2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-phenyl-1-tosylazetidine (30 mg) in absolute 1,2-dimethoxyethane (6 mL) was added dropwise the prepared sodium naphthalene(0.67 M, 1.2 mL) at −78° C. The reaction mixture was stirred for 90 min, diluted with water and extracted with chloroform. The combined organic layer was washed with saturated brine, and concentrated to afford the crude (2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-phenylazetidine (45 mg), which was dissolved in methanol (4 mL), and added concentrated hydrochloric acid (0.2 mL). The mixture was stirred for 2 h, and added saturated NaHCO.sub.3 solution until pH reached 8. The mixture was concentrated in vacuo, and the residue was diluted with DCM and water, the aqueous was extracted with DCM, the combined organic layer was washed with saturated brine, and concentrated to afford crude product,(2R,3R)-2-phenylazetidin-3-ol(32 mg), which was used for next step without further purification.

[0260] To a solution of (2R,3R)-2-phenylazetidin-3-ol (32 mg) in THF (2 mL) and H.sub.2O(2 mL) was added sat. NaHCO.sub.3 (0.5 mL). The mixture was cooled to 0° C., and 2,2-dimethylbutanoyl chloride(29 mg) was added and stirred at room temperature for overnight. The mixture was extracted with DCM and the combined organic layers were washed with water and concentrated. The crude product was purified by Pre-HPLC to give compound S4 (6.8 mg, 36% in three steps). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.39-7.22 (m, 5H), 5.12 (d, J=3.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.31 (dd, J=10.3, 3.9 Hz, 1H), 4.14 (dd, J=9.4, 4.5 Hz, 1H), 1.56-1.52 (m, 2H), 1.16 (d, J=2.4 Hz, 6H), 0.88 (t, J=7.5 Hz, 3H). LC-MS (ESI) [M+H]+ calad for C.sub.15H.sub.22NO.sub.2, 248.16, found, 248.25.

Compound S5: Preparation of 1-((2R,3S)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one

[0261] ##STR00166##

[0262] Compound S5 was prepared from 1-((2R,3S)-3-hydroxy-2-phenylazetidin-1-yl)-2,2-dimethylbutan-1-one according to the procedure outlined for compound S4. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.43-7.22 (m, 5H), 4.76-4.71 (m, 1H), 4.65-4.58 (m, 1H), 4.16-4.09 (m, 1H), 3.72-3.65 (m, 1H), 1.54-1.52 (m, 2H), 1.23 (s, 6H), 0.86 (t, J=6.8 Hz, 3H). LC-MS (ESI) [M+H]+ calad for C.sub.15H.sub.22NO.sub.2, 248.16, found, 248.25.

Compound S6: Preparation of (S)-1-(ethylsulfonyl)-2-phenylazetidine

[0263] ##STR00167##

[0264] (S)-2-phenylazetidine (35 mg, 0.263 mmol) and triethylamine (53.2 mg, 0.526 mmol) were dissolved in 2 mL of dry CH.sub.2Cl.sub.2. Ethanesulfonyl chloride (40.4 mg, 0.316 mmol) was added slowly to the solution at 0° C. under nitrogen. The mixture was stirred at room temperature for 2 h, diluted with CH.sub.2Cl.sub.2 and water. The organic layer were washed with saturated NaHCO.sub.3 solution, brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound S6 (20 mg, 33%) as an light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.40-7.27 (m, 5H), 5.01 (dd, J=9.0, 5.5 Hz, 1H), 3.32 (dd, J=13.2, 6.4 Hz, 2H), 3.08-3.02 (m, 2H), 2.32 (m, 2H), 1.37 (t, J=7.4 Hz, 3H). LC-MS (ESI) [M+H]+ calad for C.sub.11H.sub.16NO.sub.2S, 226.09; found, 226.21.

Compound S7: Preparation of (2S)-1-(tert-butylsulfinyl)-2-phenylazetidine

[0265] ##STR00168##

[0266] Compound S7 was prepared in 47% yield from (S)-2-phenylazetidine (55 mg) and 2-methylpropane-2-sulfinic chloride(69.4 mg)according to procedure outlined for compound S6. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47 (d, J=8.0 Hz, 2H), 7.37-7.31 (m, 2H), 7.28-7.23 (m, 1H), 5.43-5.33 (t, J=8.0 Hz, 1H), 3.98 (dd, J=17.4, 8.0 Hz, 1H), 3.89-3.79 (m, 1H), 2.74-2.65 (m, 1H), 2.37-2.20 (m, 1H), 0.90 (s, 9H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.13H.sub.20NOS, 238.13; found, 238.28.

Compound S8: Preparation of (S)-1-(tert-butylsulfonyl)-2-phenylazetidine

[0267] ##STR00169##

[0268] To a solution of compound S7 (11 mg) in DCM (4 mL) was added m-CPBA(75%, w/w, 16 mg) at 0° C. The mixture was stirred at room temperature for 12 h, and concentrated in vacuo. The residue was purified by pre-TLC to give compound S8. .sup.1H NMR (400 MHz, cdcl.sub.3) δ 7.49 (d, J=8.0 Hz, 2H), 7.39-7.33 (m, 2H), 7.30-7.25 (m, 1H), 5.45-5.35 (m, 1H), 4.00 (dd, J=17.4, 8.0 Hz, 1H), 3.91-3.81 (m, 1H), 2.76-2.68 (m, 1H), 2.39-2.22 (m, 1H), 0.92 (s, 9H).

Compound S9: Preparation of (S)-1-(tert-butylsulfonyl)-2-phenylazetidine

[0269] ##STR00170##

[0270] A mixture of benzyl 2,2-dimethyl-3-oxobutanoate(400 mg), bis(2-methoxyethyl) aminosulfur trifluoride(5 mL) and a drop of ethanol was stirred at 50° C. for 12 h. The mixture was cooled to 0° C., and cold water was added. The mixture was added saturated NaHCO.sub.3 solution until pH reached 8, extracted with DCM. The combined organic layer washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification by chromatography to benzyl 3,3-difluoro-2,2-dimethylbutanoate(206 mg, 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.30 (m, 5H), 5.15 (s, 2H), 1.63 (t, J=19.2 Hz, 3H), 1.34 (t, J=0.9 Hz, 6H).

[0271] To a stirred solution of benzyl 3,3-difluoro-2,2-dimethylbutanoate(206 mg) in methanol(5 mL) was added Pd/C(10%, 20.6 mg) and the resulting mixture was subjected to hydrogenation under 1 atm pressure for 12 h at room temperature. The mixture was filtered through celite pad and the filter cake was washed with methanol. The filtrate was evaporated under reduced pressure to give 3,3-difluoro-2,2-dimethyl butanoic acid(105 mg, 81%) as a white solid, which was used for next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.73 (t, J=18 Hz, 3H), 1.38 (s, 3H).

[0272] To a solution of (S)-2-phenylazetidine (70 mg) and 3,3-difluoro-2,2-dimethylbutanoic acid(40 mg) in dry DMF (1 mL) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(150 mg) and DIEA (0.14 mL). The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with CH.sub.2Cl.sub.2. The organic layer were washed with saturated brine, dried with Na.sub.2SO.sub.4 and concentrated.

[0273] The residue was purified by pre-TLC to give compound S9 (35 mg, 50%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.22 (m, 5H), 5.39-5.31 (m, 1H), 4.59-4.45 (m, 2H), 2.73-2.65 (m, 1H), 2.16-2.06 (m, 1H), 1.59 (t, J=19.5 Hz, 3H), 1.32 (s, 6H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.20F.sub.2NO, 268.15; found, 268.19.

Compound S10: Preparation of 3,3-difluoro-2,2-dimethyl-1-(2-phenylpyrrolidin-1-yl) butan-1-one

[0274] ##STR00171##

[0275] Compound S10 was prepared in 65% yield from 2-phenylpyrrolidine(48 mg) and 3,3-difluoro-2,2-dimethylbutanoic acid(50 mg)according to procedure outlined for compound S9. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.09 (m, 5H), 5.30-5.13 (m, 1H), 3.95 (m, 2H), 2.25-2.16 (m, 1H), 2.09-1.68 (m, 3H), 1.54 (t, J=19.5 Hz, 3H), 1.39 (s, 6H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.16H.sub.22F.sub.2NO, 282.17; found, 282.36.

Compound S11: Preparation of 2,2-dimethyl-1-(2-phenylpyrrolidin-1-yl)propan-1-one

[0276] ##STR00172##

[0277] Compound S11 was prepared in 74% yield from 2-phenylpyrrolidine (51 mg) and pivaloyl chloride (50 mg) according to procedure outlined for compound S6. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.25 (m, 2H), 7.12-7.10 (m, 3H), 5.31-5.16 (m, 1H), 3.88-3.74 (m, 2H), 2.26-2.17 (m, 1H), 1.88-1.77 (m, 3H), 1.24 (s, 9H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.15H.sub.22NO, 232.17; found, 232.20.

Compound S12: Preparation of (S)-2,2-dimethyl-1-(2-phenylazetidin-1-yl)propan-1-one

[0278] ##STR00173##

[0279] Compound S12 was prepared in 44% yield from (S)-2-phenylazetidine (10 mg) and pivaloyl chloride (13.5 mg) according to procedure outlined for compound S6. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37-7.31 (m, 2H), 7.28-7.25 (m, 3H), 5.14-5.05 (m, 1H), 4.08-3.98 (m, 2H), 2.20-2.08 (m, 2H), 1.20 (s, 9H). LC-MS (ESI) [M+H].sup.+ calad for C.sub.14H.sub.20NO

[0280] , 218.15; found, 218.20.

Compound S13

Compound S13 is Prepared According to the Procedure Outlined in Scheme 1

[0281] ##STR00174##

Compound S14

Compound S14 is Prepared According to the Procedure Outlined in Scheme 2

[0282] ##STR00175##

Compound S15

Compound S15 is Prepared According to the Procedure Outlined in Scheme 3

[0283] ##STR00176##

Compound S16

Compound S16 is Prepared According to the Procedure Outlined in Scheme 4

[0284] ##STR00177##

Compound S17

Compound S17 is Prepared According to the Procedure Outlined in Scheme 5

[0285] ##STR00178##

[0286] 3. Kinase Assay of RIPK1

[0287] Materials: Recombinant full-length RIPK1 protein with N-terminal GST-tag (Cat#R07-34G) was purchased from SignalChem. The ADP-Glo™ kinase assay kit (Cat#V9102) was from Promega. MBP (cat# M2295) protein and all the other chemicals were from Sigma. The 384-well assay plates (Cat#3674, white, opaque) were purchased from Corning.

[0288] Kinase activity assay and data analysis: The RIPK1 kinase assay was performed in white 384-well plate. The assay buffer contained 25 mM HEPES (pH7.2), 20 mM MgCl2, 12.5 mM MnCl2, 5 mM EGTA, 2 mM EDTA, 12.5 mM β-glycerol phosphate and 2 mM DTT. RIPK1 was first incubated with compounds or DMSO control for 15 mM, then ATP/MBP substrate mixture was added to initiate the reaction. The final concentration of RIPK1 was 161 nM, while the final concentration of ATP was 50 uM, and MBP 20 uM. After 90 min reaction at room temperature, the ADP-Glo reagent and detection solution were added following the technical manual of ADP-Glo™ kinase assay kit (Promega). The luminescence was measured on PerkinElmer Enspire. The data was analyzed using Graphpad Prism (GraphPad Software; www.graphpad.com). The curves were fitted using a non-linear regression model with a sigmoidal dose response.

[0289] Results: pIC50 of hRIP1 kinase assay correlated with our pIC50 of cell necrosis assay. Exemplary data are shown below:

TABLE-US-00002 RIP1 Cell viability hRIP1 kinase assay, IC50 (nM) or # CMPD ID assay, EC50 (nM) % inhibition at 2 uM 10 TC001124 9.882 IC50 = 22.5 nM 2 TC001129 29.64 IC50 = 34.8 nM 25 TC001273 555.6 IC50 = 152 nM 38 TC001262 8.39 IC50 = 13.7 nM 15 TC001287 396 IC50 = 460 nM 24 TC001207 7 IC50 = 19.8 nM 31 TC001265 609.4 IC50 = 1065 nM 13 TC001252 2615 69% inhibition at 2 uM

[0290] 4. Necrosis Assay

[0291] Methods:

[0292] HT-29 cells were cultured in McCoy's 5A culture medium (Invitrogen). On day one, HT-29 cells were plated in 96-well assay plates at density of 2,500-3,500 cells per well. On day two, necrosis were induced by adding 20 ng/ml TNF-α (T), 100 nM Smac mimetic (S), and 20 mM z-VAD (Z). At the same time, 10 mM compound from a chemical library of ˜200,000 compounds was delivered into each well. After 24 hrs treatment, cell viability was determined by measuring ATP level using the CellTiter-Glo Luminescent Cell Viability Assay kit. A CellTiter-Glo Assay (Promega) was performed according to the manufacturer's instructions Luminescence was recorded with a PerkinElmer EnSpire Multimode Plate Reader. Survived cells were normalized to those cells treated with DMSO. Nec-1 was used as a positive control for screening necrosis inhibitors. Data are represented as mean±standard deviation of duplicates

[0293] Dose-dependent inhibition of necrosis by compound #9 and the derivative compounds in HT-29 cells were determined by measuring ATP levels as described above. Compound necrosis activity data are reported below:

TABLE-US-00003 # EC50 # EC50 # EC50  1 1-100 uM 27 1-1000 nM 53 1-1000 uM  2 1-1000 nM 28 1-10 uM 54 1-1000 uM  3 1-1000 nM 29 1-100 uM 55 1-1000 uM  4 1-1000 nM 30 1-10 uM 56 1-1000 uM  5 1-1000 nM 31 1-1000 nM 57 1-1000 uM  6 1-100 uM 32 1-1000 nM 58 1-1000 uM  7 1-100 uM 33 1-100 uM 59 1-1000 uM  8 1-1000 nM 34 1-100 uM 60 1-1000 uM  9 1-1000 nM 35 1-1000 nM 61 1-1000 uM 10 1-1000 nM 36 1-1000 nM 62 1-1000 uM 11 1-100 uM 37 1-100 uM 63 1-1000 uM 12 1-100 uM 38 1-1000 nM 64 1-1000 uM 13 1-10 uM 39 1-10 uM 65 1-1000 uM 14 1-1000 nM 40 1-100 uM 66 1-1000 uM 15 1-1000 nM 41 1-100 uM 67 1-1000 uM 16 1-10 uM 42 1-100 uM 68 1-1000 uM 17 1-100 uM 43 1-100 uM 69 1-1000 uM 18 1-100 uM 44 1-10 uM 70 1-1000 uM 19 1-100 uM 45 1-100 uM 71 1-1000 uM 20 1-1000 nM 46 1-1000 nM 72 1-1000 uM 21 1-1000 nM 47 1-10 uM 73 1-1000 uM 22 1-1000 nM 48 1-100 uM 74 1-1000 uM 23 1-1000 nM 49 1-100 uM 75 1-1000 uM 24 1-1000 nM 50 1-100 uM 76 1-1000 uM 25 1-1000 nM 51 1-100 uM 77 1-1000 uM 26 1-1000 nM 52 1-100 uM 78 1-100 uM S1 1-10 uM S2 1-100 uM S3 1-10 uM S4 1-10 uM S5 1-100 uM S6 1-100 uM S7 1-10 uM S8 1-100 uM S9 1-1000 nM S10 1-1000 nM S11 1-1000 nM S12 1-1000 nM S13 1-100 uM S14 1-100 uM S15 1-100 uM S16 1-100 uM S17 1-100 uM