Alpha hydroxy amides

Abstract

The present invention relates to alpha hydroxy amides including compounds of formula I: ##STR00001##
and related compounds and their use in the prophylaxis and treatment of inflammatory disorders and diseases, wherein T.sup.1, T.sup.2, W and R.sup.W have the meanings given in claim 1.

Claims

1. A compound of formula (I): ##STR00256## wherein: T.sup.1 denotes one of the following groups: ##STR00257## T.sup.2-W denotes one of the following groups: ##STR00258## W denotes a single bond, or a group selected from CHR.sup.c and CHCH; R.sup.W denotes H, Hal, linear or branched alkyl, or one of the following groups: ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## or wherein R.sup.b and R.sup.w together with the nitrogen atom to which they are linked form one of the following groups: ##STR00264## R.sup.b denotes H or a linear or branched alkyl, or alternatively, R.sup.b and R.sup.w together with the nitrogen atom to which they are linked form a Het group; R.sup.c denotes H, Ar, or alkyl; R.sup.a denotes H and a group selected from the following groups: ##STR00265## Ar denotes one of the following groups ##STR00266## optionally substituted with from 1 to 5 groups independently selected from Hal, CN, CF.sub.3, OCF.sub.3, O-alkyl, SO.sub.2-alkyl, COOR.sup.b, CO-alkyl, O-phenyl, SO.sub.2-phenyl, SO.sub.2Het, O-Het, Het, (CH.sub.2).sub.nHet, SO.sub.2CF.sub.3, O(CH.sub.2).sub.n-Het, O(CH.sub.2).sub.n-alkyl, and A; Het denotes a monocyclic 5-8-membered ring being saturated, unsaturated or aromatic, containing 1 to 3 heteroatoms independently selected from N, O and S, or a group CO, and optionally substituted with from 1 to 5 groups independently selected from Hal, CN, CF.sub.3, OCF.sub.3, O-alkyl, SO.sub.2-alkyl, COOR.sup.b, CO-alkyl, O-phenyl, SO.sub.2-phenyl, SO.sub.2CF.sub.3, O(CH.sub.2).sub.n-alkyl, SO.sub.2Ar, Ar, and A; A is branched or linear alkyl having 1 to 12 C-atoms, wherein one or more H atoms may be replaced by Ar, Het, Hal, OR.sup.b, COOR.sup.b, CN or N(R.sup.b).sub.2 and wherein one or more CH.sub.2-groups may be replaced by O, CO, NR.sup.b, S, SO, SO.sub.2, phenyl, CHCH or CC and/or by one of the following groups: ##STR00267## having Hal or mesylate as counter ion; Hal denotes F, Cl, Br, or I; n is 1, 2 or 3; and pharmaceutically usable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios.

2. A kit consisting of separate packs of: (a) an effective amount of a compound according to claim 1 and/or pharmaceutically usable solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

3. A pharmaceutical composition comprising a compound according to claim 1.

4. A method of treating an inflammatory disease comprising administering a compound according to claim 1 to an individual having an inflammatory disease.

5. The method according claim 4, wherein the inflammatory disease is inflammatory bowel disease.

6. The method according to claim 4, wherein the inflammatory bowel disease is ulcerative colitis.

7. The method according to claim 4, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, psoriasis, amyloidosis, systemic sclerosis, sarcoidosis, osteoarthritis, osteoporosis/bone resorption, septic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, multiple sclerosis, sepsis, uveitis, endometriosis, Behcet's disease, Wegener's granulomatosis, idiopathic thrombocytopenic purpura, immune deficiencies, chronic graft-versus-host disease, transplant rejection, adult respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, cancer, lymphoproliferative disease, myeloproliferative disorder, diabetes, meningitis, skin delayed type hypersensitivity disorders, and allergic asthma.

8. A compound selected from: ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## and pharmaceutically usable solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios.

9. A kit consisting of separate packs of: (a) an effective amount of a compound according to claim 8 and/or pharmaceutically usable solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

10. A pharmaceutical composition comprising a compound according to claim 8.

11. A method of treating an inflammatory disease comprising administering a compound according to claim 8 to an individual having an inflammatory disease.

12. The method according claim 11, wherein the inflammatory disease is inflammatory bowel disease.

13. The method according to claim 11, wherein the inflammatory bowel disease is ulcerative colitis.

Description

EXAMPLES

(1) The commercially available starting materials used in the following experimental description were purchased from Sigma-Aldrich, ACROS or ABCR unless otherwise reported.

(2) .sup.1H NMR analyses were carried out using Bruker NMR, 400 MHz FT-NMR. Residual signal of deuterated solvent was used as internal reference. Chemical shifts () are reported in ppm in relative to the residual solvent signal (=2.50 for .sup.1H NMR in DMSO-d.sub.6, and 7.26 in CDCl.sub.3), together with multiplicity, coupling constants and number of hydrogen atoms. Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), br (broad), m (multiplet).

(3) The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Waters ZMD (ESI).

(4) Method A:

(5) Method: A0.1% TFA in H.sub.2O, B0.1% TFA in ACN: Flow2.0 mL/min.

(6) Column: XBridge C8 (504.6 mm, 3.5 m), positive mode.

(7) HPLC analyses were obtained as followed with UV detection (maxplot).

(8) Method A:

(9) Method: A0.1% TFA in H.sub.2O, B0.1% TFA in ACN: Flow2.0 mL/min.

(10) Column: XBridge C8 (504.6 mm, 3.5 m).

(11) The microwave chemistry was performed on an Emrys Optimiser or Initiator Sixty single mode microwave reactor from Biotage.

(12) Abbreviations:

(13) The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), M (micromolar), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), eq (equivalent), mL (milliliter), L (microliter), AcOH (Acetic acid), ACN (acetonitrile), AMC (7-amino-4-methylcoumarin), DCM (dichloromethane), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d.sub.6 (deuterated dimethylsulfoxide), ESI (Electro-spray ionization), EtOAc (ethyl acetate), Et.sub.2O (diethyl ether), Et.sub.3N (triethylamine), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), LC (Liquid Chromatography), MeOH (methanol), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), MW (microwave), NMR (Nuclear Magnetic Resonance), PTSA (para toluene sulfonic acid), RT (room temperature), Rt (retention time), TEA (triethylamine), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet), vol (Volume).

(14) General Procedures:

(15) General Procedure A: Acetonide Deprotection

(16) ##STR00106##

(17) A compound of Formula (II) (1 eq) was dissolved in 80% AcOH in water (5 mL) and stirred for 3 h at RT. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to get the title compound.

(18) General Procedure B: Oxidation and Deprotection

(19) ##STR00107##

(20) To a solution of compound of Formula (IIg) (1 eq) in dry DCM was added Dess-Martin periodinane (1.5 eq) and stirred at RT for 2 h. After completion of the reaction, the solid was filtered and the filtrate was concentrated under vacuum. The colorless oil was dissolved in 80% AcOH in water (5 mL) and stirred for 3 h at RT. After this time, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography.

(21) General Procedure C: Isocyanides Synthesis

(22) ##STR00108##
Step 1:

(23) A solution of compound of Formula (X) (1 eq) and ethyl formate (2 eq) was stirred at RT for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure and taken as such to the next step.

(24) Step 2:

(25) To a solution of the compound of Formula (Xa) (1 eq), NEt.sub.3 (3 eq) in DCM (50 vol) cooled at 0 C. was added dropwise a solution of triphosgene (0.5 eq) in DCM (15 vol). The reaction mixture was stirred at RT for 30 min. After this time, the reaction mixture was quenched with ice and extracted with DCM. The organic layer was washed with brine and then dried over anhydrous Na.sub.2SO.sub.4 and taken as such to the next step.

(26) General Procedure D: Alpha-Hydroxy Amide Synthesis

(27) ##STR00109##

(28) To a stirred solution of compound of Formulae (IIb) (1 eq) in DCM (20 vol) were added chloroacetic acid (1.1 eq) and isocyanide derivative (IX) (1.1 eq) at 0 C. The reaction mixture was stirred at RT for 12 h after which the solvent was removed under vacuum. The solid residue was dissolved in MeOH:H.sub.2O (1:1) (20 vol) followed by addition of K.sub.2CO.sub.3 (2.5 eq) and stirring at RT for 5 h. After completion of the reaction, the solvent was removed under vacuum and the residue was extracted with EtOAc. The organic layer was washed with water followed by brine and the combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to afford the title compound.

(29) General Procedure E: Acid-Amine Coupling

(30) ##STR00110##

(31) To a solution of compound of Formulae (XIb) (1 eq) in DMF (15 vol) were added amine of Formula (XII) (1 eq), N-methyl morpholine (3 eq) and HATU (1.1 eq) and heated at 100 C. under microwave radiation for 1 h. After this time, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the crude product which was purified by silica gel column chromatography to afford the title compound.

(32) General Procedure F: Synthesis of Ethylene Diamine Derivatives

(33) ##STR00111##
Step 1:

(34) To a solution of the compound of Formula (XV) (1 eq) in dry DCM (50 vol) at 0 C. was added Et.sub.3N (1.2 eq) followed by methane sulfonyl chloride (1.1 eq) and stirred for 1 h at 0 C. After completion of the reaction, it was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the title compound which was taken as such to the next step.

(35) Step 2:

(36) To a solution of the compound of Formula (XVa) (1 eq) in MeOH (5 vol) was added ethylene diamine (3.6 vol) and stirred at room temperature for 16 h. After completion of the reaction, the solvents were removed under reduced pressure to get the crude compound which was purified by silica gel column chromatography to get the title compound.

(37) General Procedure G: Pantolactone Opening

(38) ##STR00112##

(39) A microwave vial was charged with compound of Formula (Vb) (1 eq), D or L-pantolactone (1.5 eq) and EtOH (20 vol) and heated at 120 C. under microwave radiation for 2 h. After completion of the reaction the solvent was removed under reduced pressure and purified by silica gel column chromatography to get the title compound.

(40) General Procedure H: Chloroamide Synthesis

(41) ##STR00113##

(42) To a solution of the compound of Formula (If) (1 eq) in dry DCM (25 vol) at 0 C. was added Et.sub.3N (3.5 eq) followed by chloroacetyl chloride (3.5 eq) and stirred for 1 h at the same temperature. After completion of the reaction, it was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The solid residue was dissolved in THF:H.sub.2O (20 vol) and 10% NaOH (5 eq) was added dropwise at 0 C. and slowly brought to RT. After completion of the reaction, the solvent was removed under vacuum and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by silica gel column chromatography to get the title compound.

Preparation of Intermediates

Intermediate A1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide

Step 1: (R)-2,4-Dihydroxy-N-(3-hydroxy-propyl)-3,3-dimethyl-butyramide

(43) ##STR00114##

(44) To a solution of D-pantolactone (0.5 g, 1 eq) in dry EtOH (5 mL) in a microwave vial were added 3-amino-propan-1-ol (0.53 mL, 1.5 eq) and Et.sub.3N (0.54 mL, 1 eq) and irradiated with MW radiation at 160 C. for 3 h. After this time, the reaction mixture was concentrated and purified by silica gel column chromatography to afford the product as a white solid (800 mg, 95%).

(45) .sup.1H NMR (400 MHz, DMSO d.sub.6): 7.70 (t, J=4.0 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 4.48-4.42 (m, 2H), 3.68 (d, J=8.0 Hz, 1H), 3.40 (dd, J=4.0, 8.0 Hz, 2H), 3.31-3.26 (m, 1H), 3.19-3.07 (m, 3H), 2.56-2.52 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Step 2: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-propyl)-amide

(46) ##STR00115##

(47) To a solution of (R)-2,4-dihydroxy-N-(3-hydroxy-propyl)-3,3-dimethyl-butyramide (1 eq) in dry acetone (20 vol) were added 4 molecular sieves (200 wt %) followed by a slow addition of PTSA (0.05 eq) at 0 C. after which it was stirred at RT for 3 days. After completion of the reaction, the solvent was removed under vacuum and the crude product was purified by flash silica gel column chromatography (CHCl.sub.3/MeOH) to afford the title compound which was taken forward for the next step.

(48) LCMS (Method A, ELSD): 246.2 (M+H)

Step 3: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide

(49) ##STR00116##

(50) To a solution of (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-hydroxy-propyl)-amide (1 eq) in DCM (250 mL, 10 vol) was added Dess-Martin periodinane (1.5 eq) at 0 C. and the reaction mixture was stirred at RT for 6 h. After this time, the solvent was removed under vacuum and the solid residue was washed with MTBE and filtered. The filtrate was partitioned between EtOAc and a saturated aqueous solution of NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc) to afford the title compound as a white solid (1.5 g, 55%).

(51) LCMS (Method A): 244.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.63 (t, J=1.7 Hz, 1H), 7.53 (t, J=5.7 Hz, 1H), 4.01 (s, 1H), 3.63-3.44 (m, 1H), 3.42-3.36 (m, 1H), 3.33-3.27 (m, 1H), 3.17 (d, J=4.4 Hz, 1H), 2.58-2.48 (m, 2H), 1.40-1.42 (m, 6H), 0.90-0.94 (m, 6H).

Intermediate A2: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-butyl)-amide

(52) ##STR00117##

(53) To a solution of (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (244 mg, 1 mmol) in dry THF (10 mL) at 0 C. was added MeMgBr (1.2 mL, 1.0 M solution in THF) and stirred at the same temperature for 1 h after which it was allowed to return to RT and stirred for another hour. After this time, it was quenched with a saturated aqueous solution of NH.sub.4Cl and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a colorless gum (130 mg, 50%).

(54) LCMS (Method A): 260.2 (M+H).

Intermediate A3: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pentyl)-amide

(55) ##STR00118##

(56) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pentyl)-amide was prepared following the procedure described for intermediate A2 from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (242 mg, 1 mmol) and EtMgBr (1.2 mL, 1 M solution in THF) as a colorless liquid (120 mg, 45%).

(57) LCMS (Method A, ELSD): 274.3 (M+H).

Intermediate A4: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pent-4-enyl)-amide

(58) ##STR00119##

(59) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pent-4-enyl)-amide was prepared following the procedure described for intermediate A2 from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (244 mg, 1 mmol) and vinyl magnesium bromide (1.2 mL, 1 M solution in THF) as a colorless liquid (142 mg, 52%).

(60) LCMS (Method A, ELSD): 272.3 (M+H).

Intermediate A5: (S)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide

(61) ##STR00120##

(62) (S)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide was synthesized following the same procedure as intermediate A1 starting from L-pantolactone (0.5 g, 1 eq) to afford the title compound as a white solid (0.67 g, 72%).

(63) LCMS (Method A): 244.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.63 (t, J=1.7 Hz, 1H), 7.53 (t, J=5.7 Hz, 1H), 4.01 (s, 1H), 3.63-3.44 (m, 1H), 3.42-3.36 (m, 1H), 3.33-3.27 (m, 1H), 3.17 (d, J=4.4 Hz, 1H), 2.58-2.48 (m, 2H), 1.40-1.42 (m, 6H), 0.90-0.94 (m, 6H).

Intermediate B1: 1-Isocyanomethyl-3-trifluoromethoxy-benzene

(64) ##STR00121##

(65) 1-Isocyanomethyl-3-trifluoromethoxy-benzene was prepared following the general procedure C from 3-trifluoromethoxy-benzylamine (382 mg, 2 mmol) as a pale yellow liquid.

(66) LCMS (Method A, ELSD): 202.2 (M+H).

Intermediate B2: 1-Isocyanomethyl-4-methanesulfonyl-benzene

(67) ##STR00122##

(68) 1-Isocyanomethyl-4-methanesulfonyl-benzene was prepared following the general procedure C from 4-methyl sulfonyl benzylamine (2 mmol) as a pale yellow liquid.

(69) LCMS (Method A, ELSD): 196.2 (M+H).

Intermediate C1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclopropyl carbamoyl-3-hydroxy-propyl)-amide

(70) ##STR00123##

(71) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclopropyl carbamoyl-3-hydroxy-propyl)-amide was prepared following the general procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and cyclopropyl isocyanide (74 mg, 1.1 mmol) as a colorless liquid (267 mg, 81%).

(72) LCMS (Method A): 329.2 (M+H).

Intermediate C2: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide

(73) ##STR00124##

(74) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide was prepared following the general procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and benzylisocyanide (129 mg, 1.1 mmol) as a colorless liquid (242 mg, 64%).

(75) LCMS (Method A, ELSD): 379.2 (M+H).

Intermediate C3: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(2-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide

(76) ##STR00125##

(77) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(2-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 2-fluorobenzylisocyanide (148 mg, 1.1 mmol) as a colorless liquid (253 mg, 63%).

(78) LCMS (Method A, ELSD): 397.2 (M+H).

Intermediate C4: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(cyclohexylmethyl-carbamoyl)-3-hydroxy-propyl]-amide

(79) ##STR00126##

(80) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(cyclohexylmethyl-carbamoyl)-3-hydroxy-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and isocyanomethyl-cyclohexane (135 mg, 1.1 mmol) as a colorless liquid (278 mg, 72%).

(81) LCMS (Method A, ELSD): 385.2 (M+H).

Intermediate C5: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-phenethylcarbamoyl-propyl)-amide

(82) ##STR00127##

(83) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-phenethylcarbamoyl-propyl)-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and phenylethyl isocyanide (144 mg, 1.1 mmol) as a colorless liquid (267 mg, 68%).

(84) LCMS (Method A, ELSD): 393.3 (M+H).

Intermediate C6: (S)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide

(85) ##STR00128##

(86) (S)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide was prepared following the procedure D from (S)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and benzyl isocyanide (129 mg, 1.1 mmol) as a colorless liquid (242 mg, 64%).

(87) LCMS (Method A, ELSD): 379.2 (M+H).

Intermediate C7: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-thiophen-2-yl-ethylcarbamoyl)-propyl]-amide

(88) ##STR00129##

(89) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-thiophen-2-yl-ethylcarbamoyl)-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 2-(thien-2-yl)ethyl isocyanide (150 mg, 1.1 mmol) as a colorless liquid (191 mg, 48%).

(90) LCMS (Method A): 399.2 (M+H).

Intermediate C8: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-trifluoro methoxy-benzylcarbamoyl)-propyl]-amide

(91) ##STR00130##

(92) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-trifluoro methoxy-benzylcarbamoyl)-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 1-isocyano methyl-3-trifluoro methoxy-benzene (220 mg, 1.1 mmol) as a colorless liquid (311 mg, 67%).

(93) LCMS (Method A, ELSD): 463.3 (M+H).

Intermediate C9: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-phenyl carbamoyl-propyl)-amide

(94) ##STR00131##

(95) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-phenyl carbamoyl-propyl)-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and phenylisocyanate (113 mg, 1.1 mmol) as a colorless liquid (212 mg, 58%).

(96) LCMS (Method A): 365.3 (M+H).

Intermediate C10: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(4-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide

(97) ##STR00132##

(98) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(4-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 4-fluoro benzylisocyanide (148 mg, 1.1 mmol) as a colorless liquid (254 mg, 64%).

(99) LCMS (Method A, ELSD): 397.2 (M+H).

Intermediate C11: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclohexylcarbamoyl-3-hydroxy-propyl)-amide

(100) ##STR00133##

(101) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclohexylcarbamoyl-3-hydroxy-propyl)-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and cyclohexyl isocyanide (119 mg, 1.1 mmol) as a colorless liquid (215 mg, 54%).

(102) LCMS (Method A, ELSD): 397.2 (M+H).

Intermediate C12: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[(naphthalen-1-ylmethyl)-carbamoyl]-propyl}-amide

(103) ##STR00134##

(104) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[(naphthalen-1-ylmethyl)-carbamoyl]-propyl}-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 1-naphthalenemethylisocyanide (184 mg, 1.1 mmol) as a colorless liquid (295 mg, 68%).

(105) LCMS (Method A, ELSD): 429.2 (M+H).

Intermediate C13: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(1-phenyl-ethylcarbamoyl)-propyl]-amide

(106) ##STR00135##

(107) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(1-phenyl-ethylcarbamoyl)-propyl]amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and alpha methyl benzylisocyanide (144 mg, 1.1 mmol) as a colorless liquid (224 mg, 57%).

(108) LCMS (Method A, ELSD): 393.2 (M+H).

Intermediate C14: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(benzhydryl-carbamoyl)-3-hydroxy-propyl]-amide

(109) ##STR00136##

(110) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(benzhydryl-carbamoyl)-3-hydroxy-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and diphenylmethylisocyanide (212 mg, 1.1 mmol) as a colorless liquid (308 mg, 68%).

(111) LCMS (Method A, ELSD): 454.2 (M+H).

Intermediate C15: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-methoxy-benzylcarbamoyl)-propyl]-amide

(112) ##STR00137##

(113) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-methoxy-benzylcarbamoyl)-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 3-methoxybenzylisocyanide (161 mg, 1.1 mmol) as a colorless liquid (196 mg, 48%).

(114) LCMS (Method A, ELSD): 408.2 (M+H).

Intermediate C16: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-trifluoromethyl-benzylcarbamoyl)-propyl]-amide

(115) ##STR00138##

(116) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-trifluoromethyl-benzylcarbamoyl)-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 2-trifluoromethyl benzylisocyanide (203 mg, 1.1 mmol) as a colorless liquid (219 mg, 48%).

(117) LCMS (Method A, ELSD): 447.2 (M+H).

Intermediate C17: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(4-methane sulfonyl-benzyl carbamoyl)-propyl]-amide

(118) ##STR00139##

(119) (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(4-methane sulfonyl-benzyl carbamoyl)-propyl]-amide was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and 1-isocyano methyl-4-methanesulfonyl-benzene (214 mg, 1.1 mmol) as a colorless liquid (206 mg, 45%).

(120) LCMS (Method A): 457.2 (M+H).

Intermediate C18: {2-Hydroxy-4-[((R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carbonyl)-amino] butyryl amino}-acetic acid methyl ester

(121) ##STR00140##

(122) {2-Hydroxy-4-[((R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carbonyl)-amino]-butyryl amino}-acetic acid methyl ester was prepared following the procedure D from (R)-2,2,5,5-tetramethyl-[1,3] dioxane-4-carboxylic acid (3-oxo-propyl)-amide (243 mg, 1 mmol) and isocyano-acetic acid methyl ester (110 mg, 1 mmol) as a colorless liquid (185 mg, 51%).

(123) LCMS (Method A): 361.3 (M+H).

Intermediate D1: 2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid

(124) ##STR00141##

Step 1: 2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid ethyl ester

(125) To a solution of (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (12 g, 45.1 mmol) obtained following the procedure described in Journal Organic Letters, 2004, 6(26), 4801-4803 and diisopropylethylamine (78.6 mL, 0.375 mol) in dry DCM (200 mL) at 0 C. were added HOBt (21.9 g, 0.162 mol) and EDC.HCl (25.8 g, 0.135 mol) followed by ethyl 4-amino-2-hydroxybutanoate.HCl (9 g, 49.6 mmol). The reaction mixture was stirred at 0 C. for 2 h and another 1 h at RT. After completion, it was extracted with DCM dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH, 8:1) to afford a colorless liquid (12 g, 67%).

(126) LCMS (Method A, ELSD): 396.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.52 (t, J=5.9 Hz, 1H), 7.41 (d, J=6.6 Hz, 2H), 6.91 (d, J=4.8 Hz, 2H), 5.50 (s, 1H), 5.46 (d, J=5.6 Hz, 1H), 4.09-4.01 (m, 4H), 3.81 (s, 3H), 3.66-3.59 (m, 2H), 3.27-3.12 (m, 2H), 1.81-1.69 (m, 1H), 1.63-1.60 (m, 1H), 1.21 (t, J=7.1 Hz, 3H), 1.04 (s, 3H), 0.91 (s, 3H).

Step 2: 2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5, 5-dimethyl-[1, 3]dioxane-4-carbonyl]-amino}-butyric acid

(127) To a solution of 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid ethyl ester (10 g, 25.3 mmol) in THF:H.sub.2O (1:1, 80 mL) was added LiOH.H.sub.2O (3 g, 75.9 mmol) and it was stirred at 0 C. for 2 h and at RT for 1 h. After completion of the reaction, the solvent was removed under vacuum and the residue was diluted with water and EtOAc. The aqueous layer was then acidified to pH=6 and extracted with EtOAc. The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the title compound as a colorless gum (9 g, 99%).

(128) LCMS (Method A): 368.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.51 (t, J=4.0 Hz, 1H), 7.44 (d, J=6.9 Hz, 2H), 6.92 (d, J=6.8 Hz, 2H), 5.51 (s, 1H), 4.07 (s, 1H), 3.95-3.94 (m, 1H), 3.75 (s, 3H), 3.65-3.61 (m, 2H), 3.33-3.13 (m, 2H), 1.90-1.82 (m, 1H), 1.61-1.53 (m, 1H), 1.01 (s, 3H), 0.94 (s, 3H).

Intermediate E1: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide

(129) ##STR00142##

(130) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and N-[2-(3-aminomethyl-phenoxy)-ethyl]-methane sulfonamide (243 mg, 1 mmol) as a colorless liquid (225 mg, 38%).

(131) LCMS (Method A): 594.3 (M+H).

Intermediate E2: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-(benzyl-ethyl-carbamoyl)-3-hydroxy-propyl]-amide

(132) ##STR00143##

(133) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-(benzyl-ethyl-carbamoyl)-3-hydroxy-propyl]-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and benzyl-methyl-amine (120 mg, 1 mmol) as a pale yellow liquid (198 mg, 42%).

(134) LCMS (Method A): 470.2 (M+H).

Intermediate E3: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(biphenyl-4-lmethyl)-carbamoyl]-3-hydroxy-propyl}-amide

(135) ##STR00144##

(136) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(biphenyl-4-Imethyl)-carbamoyl]-3-hydroxy-propyl}-amide was synthesized following the general procedure E from (2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and biphenyl-4-yl-methylamine (182 mg, 1 mmol) as a pale yellow liquid (290 mg, 54%).

(137) LCMS (Method A): 553.3 (M+H).

Intermediate E4: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-propyl}-amide

(138) ##STR00145##

(139) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and (tetrahydro-furan-2-yl)-methylamine (100 mg, 1 mmol) as a pale yellow liquid (215 mg, 48%).

(140) LCMS (Method A): 451.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.7 (t, J=5.2 Hz, 1H), 7.5 (t, J=4.9 Hz, 1H), 7.4 (d, J=1.9 Hz, 2H), 6.9 (d, J=6.8 Hz, 2H), 5.7 (t, J=5.4 Hz, 1H), 5.5 (s, 1H), 4.1 (s, 1H), 3.8 (t, J=4.0 Hz, 2H), 3.8 (s, 3H), 3.73-3.58 (m, 4H), 3.15-3.10 (m, 4H), 1.90-1.77 (m, 4H), 1.60-1.42 (m, 2H), 1.0 (s, 3H), 0.9 (s, 3H).

Intermediate E5: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-2-4-methanesulfonyl-phenyl)-ethylcarbamoyl]-propyl}-amide

(141) ##STR00146##

(142) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-2-4-methanesulfonyl-phenyl)-ethylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 2-(4-methanesulfonyl-phenyl)-ethylamine (198 mg, 1 mmol) as a pale yellow liquid (310 mg, 57%).

(143) LCMS (Method A): 549.3 (M+H).

Intermediate E6: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-(4-bromo-benzylcarbamoyl)-3-hydroxy-propyl]-amide

(144) ##STR00147##

(145) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-(4-bromo-benzylcarbamoyl)-3-hydroxy-propyl]-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-bromo-benzylamine (185 mg, 1 mmol) as a pale yellow gummy liquid (285 mg, 62%).

(146) LCMS (Method A): 536.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.4 (t, J=6.0 Hz, 1H), 7.52-7.47 (m, 3H), 7.2 (d, J=11.4 Hz, 2H), 5.7 (t, J=4.0 Hz, 1H), 4.2 (t, J=9.6 Hz, 2H), 4.0 (t, J=7.2 Hz, 1H), 3.9 (d, J=1.6 Hz, 1H), 3.6 (d, J=11.6 Hz, 1H), 3.19-3.16 (m, 4H), 1.91-1.79 (m, 1H), 1.65-1.52 (m, 1H), 1.4 (s, 6H), 1.0 (s, 3H), 0.8 (s, 3H).

Intermediate E7: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-4-2-(4-phenoxy-phenyl)-ethylcarbamoyl]-benzylcarbamoyl}-propyl)-amide

(147) ##STR00148##

(148) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-4-2-(4-phenoxy-phenyl)-ethylcarbamoyl]-benzylcarbamoyl}-propyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 2-(4-phenoxy-phenyl)-ethylamine (12 mg, 1 mmol) as a pale yellow liquid (375 mg, 67%).

(149) LCMS (Method A): 563.3 (M+H).

Intermediate E8: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-piperidine-1-sulfonyl)-benzylcarbamoyl}-propyl)-amide

(150) ##STR00149##

(151) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(piperidine-1-sulfonyl)-benzylamine (253 mg, 1 mmol) as a pale yellow liquid (320 mg, 53%).

(152) LCMS (Method A): 604.2 (M+H).

Intermediate E9: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-benzenesulfonyl-piperidin-4-ylmethyl-carbamoyl]-3-hydroxy-propyl}-amide

(153) ##STR00150##

(154) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-benzenesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-hydroxy-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (300 mg, 1 mmol) and (4-benzenesulfonyl-piperidinyl)-methylamine (243 mg, 1 mmol) as a pale yellow liquid (280 mg, 53%).

(155) LCMS (Method A): 604.2 (M+H).

Intermediate E10: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-3-3-(piperidine-1-sulfonyl)-phenyl]-propylcarbamoyl}-propyl)-amide

(156) ##STR00151##

(157) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-3-3-(piperidine-1-sulfonyl)-phenyl]-propylcarbamoyl}-propyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 3-[3-(piperidine-1-sulfonyl)-phenyl]-propylamine (281 mg, 1 mmol) as a pale yellow liquid (285 mg, 45%).

(158) LCMS (Method A): 632.2 (M+H).

Intermediate E11: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-piperidine-1-sulfonyl)-benzylcarbamoyl}-propyl)-amide

(159) ##STR00152##

(160) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 3-[3-(piperidine-1-sulfonyl)-benzyl amine (253 mg, 1 mmol) as a pale yellow liquid (315 mg, 52%).

(161) LCMS (Method A): 604.2 (M+H).

Intermediate E12: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-pyridin-4-yloxy)-benzylcarbamoyl]-propyl}amide

(162) ##STR00153##

(163) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-pyridin-4-yloxy)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(pyridin-4-yloxy)-benzylamine (199 mg, 1 mmol) as a pale yellow gummy liquid (258 mg, 47%).

(164) LCMS (Method A): 550.2 (M+H).

Intermediate E13: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(biphenyl-4-sulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide

(165) ##STR00154##

(166) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(biphenyl-4-sulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(pyridin-4-yloxy)-benzyl amine (329 mg, 1 mmol) as a pale yellow liquid (320 mg, 47%).

(167) LCMS (Method A): 680.2 (M+H).

Intermediate E14: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid }3-hydroxy-3-[4-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide

(168) ##STR00155##

(169) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[4-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(pyridin-4-yloxy)-benzyl amine (243 mg, 1 mmol) as a pale yellow liquid (290 mg, 49%).

(170) LCMS (Method A): 593.0 (M+H).

Intermediate E15: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-3-oxo-morpholin-4-yl)-propylcarbamoyl]-propyl}-amide

(171) ##STR00156##

(172) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-3-oxo-morpholin-4-yl)-propylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(3-amino-propyl)-morpholin-3-one (157 mg, 1 mmol) as a pale yellow liquid (282 mg, 55%).

(173) LCMS (Method A): 508.3 (M+H).

Intermediate E16: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(4-morpholin-4-yl-benzylcarbamoyl)-propyl]-amide

(174) ##STR00157##

(175) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(4-morpholin-4-yl-benzylcarbamoyl)-propyl]-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(3-amino-propyl)-morpholin-3-one (191 mg, 1 mmol) as a pale yellow liquid (265 mg, 49%).

(176) LCMS (Method A): 542.3 (M+H).

Intermediate E17: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-phenoxy-ethylcarbamoyl)-propyl]-amide

(177) ##STR00158##

(178) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-phenoxy-ethylcarbamoyl)-propyl]-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 2-phenoxy-ethylamine (136 mg, 1 mmol) as a pale yellow liquid (228 mg, 47%).

(179) LCMS (Method A): 487.2 (M+H).

Intermediate E18: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid }3-hydroxy-4-oxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl}-amide

(180) ##STR00159##

(181) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-4-oxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and piperidin-4-yl-(3-trifluoromethanesulfonyl-phenyl)-amine (307 mg, 1 mmol) as a pale yellow liquid (415 mg, 63%).

(182) LCMS (Method A): 659.2 (M+H).

Intermediate E19: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-2-morpholin-4-yl-ethoxy)-benzylcarbamoyl}-propyl)-amide

(183) ##STR00160##

(184) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-2-morpholin-4-yl-ethoxy)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(2-morpholin-4-yl-ethoxy)-benzylamine (235 mg, 1 mmol) as a pale yellow liquid (340 mg, 58%).

(185) LCMS (Method A): 584.2 (M+H).

Intermediate E20: 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-benzoic acid ethyl ester

(186) ##STR00161##

(187) 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-benzoic acid ethyl ester was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (350 mg, 1 mmol) and 4-aminomethyl-benzoic acid ethyl ester (362 mg, 1 mmol) as a pale yellow liquid (412 mg, 45%).

(188) LCMS (Method A): 529.3 (M+H).

Intermediate E21: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-({1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-piperidin-4-ylmethyl}-carbamoyl)-propyl]-amide

(189) ##STR00162##

(190) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-({1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-piperidin-4-ylmethyl}-carbamoyl)-propyl]-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 1-[4-(4-aminomethyl-piperidine-1-sulfonyl)-phenyl]-pyrrolidin-2-one (336 mg, 1 mmol) as a pale yellow liquid (415 mg, 60%).

(191) LCMS (Method A): 688.2 (M+H).

Intermediate E22: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(1-methanesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-propyl}-amide

(192) ##STR00163##

(193) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(1-methanesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and (1-methanesulfonyl-piperidin-4-yl)-methylamine (191 mg, 1 mmol) as a pale yellow liquid (325 mg, 60%).

(194) LCMS (Method A): 542.3 (M+H).

Intermediate E23: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-acetyl-piperidin-4-ylmethyl)-carbamoyl]-3-hydroxy-propyl}-amide

(195) ##STR00164##

(196) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-acetyl-piperidin-4-ylmethyl)-carbamoyl]-3-hydroxy-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (365 mg, 1 mmol) and 1-(4-aminomethyl-piperidin-1-yl)-ethanone (350 mg, 1 mmol) as a pale yellow liquid (285 mg, 56%).

(197) LCMS (Method A): 506.2 (M+H).

Intermediate E24: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-4-morpholin-4-yl-4-oxo-butyl)-amide

(198) ##STR00165##

(199) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-4-morpholin-4-yl-4-oxo-butyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and morpholine (86 mg, 1 mmol) as a pale yellow gummy liquid (230 mg, 53%).

(200) LCMS (Method A): 438.3 (M+H).

Intermediate E25: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[4-(2-methoxy-ethoxy)-benzylcarbamoyl]-propyl}-amide

(201) ##STR00166##

(202) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[4-(2-methoxy-ethoxy)-benzylcarbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-(2-methoxy-ethoxy)-benzylamine (180 mg, 1 mmol) as a pale yellow liquid (375 mg, 70%).

(203) LCMS (Method A): 531.3 (M+H).

Intermediate E26: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide

(204) ##STR00167##

(205) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and (1-((4-fluorophenyl)sulfonyl)piperidin-4-yl) (271 mg, 1 mmol) as a pale yellow gummy liquid (360 mg, 58%).

(206) LCMS (Method A): 623.2 (M+H).

Intermediate E27: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(3-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide

(207) ##STR00168##

(208) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(3-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3] dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and [1-(3-fluoro-benzenesulfonyl)-piperidin-4-yl]-methylamine (271 mg, 1 mmol) as a pale yellow liquid (280 mg, 45%).

(209) LCMS (Method A): 623.0 (M+H).

Intermediate E28: (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(4-methanesulfonyl-biphenyl-4-ylmethyl)-carbamoyl]-propyl}-amide

(210) ##STR00169##

(211) (R)-2-(4-Methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(4-methanesulfonyl-biphenyl-4-ylmethyl)-carbamoyl]-propyl}-amide was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and (4-methanesulfonyl-biphenyl-4-yl)-methylamine (260 mg, 1 mmol) as a pale yellow liquid (325 mg, 53%).

(212) LCMS (Method A): 611.2 (M+H).

Intermediate E29: 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-benzoic acid methyl ester

(213) ##STR00170##

(214) 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]amino}-butyrylamino)-methyl]-benzoic acid methyl ester was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-aminomethyl-benzoic acid methyl ester (167 mg, 1 mmol) as a pale yellow liquid (250 mg, 49%).

(215) LCMS (Method A): 515.3 (M+H).

Intermediate E30: 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-biphenyl-4-carboxylic acid methyl ester

(216) ##STR00171##

(217) 4-[(2-Hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-biphenyl-4-carboxylic acid methyl ester was synthesized following the general procedure E from 2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyric acid (367 mg, 1 mmol) and 4-aminomethyl-biphenyl-4-carboxylic acid methyl ester (240 mg, 1 mmol) as a pale yellow liquid (215 mg, 36%).

(218) LCMS (Method A): 591.2 (M+H).

Intermediate F1: N-(3-Phenyl-propyl)-ethane-1,2-diamine

(219) ##STR00172##

(220) N-(3-Phenyl-propyl)-ethane-1,2-diamine was prepared following the general procedure F from methanesulfonic acid 3-phenyl-propyl ester (1.92 g, 9 mmol) as a colorless liquid (1.15 g, 72%).

(221) LCMS (Method A): 179.2 (M+H).

Intermediate F2: N-Phenethyl-ethane-1,2-diamine

(222) ##STR00173##

(223) N-Phenethyl-ethane-1,2-diamine was prepared following the general procedure F from methanesulfonic acid phenethyl ester (2.5 g, 12.5 mmol) as a colorless liquid (1.65 g, 80%).

(224) LCMS (Method A): 165.3 (M+H).

Intermediate F3: 4-[2-(2-Amino-ethylamino)-ethoxy]-benzonitrile

(225) ##STR00174##

(226) 4-[2-(2-Amino-ethylamino)-ethoxy]-benzonitrile was prepared following the general procedure F from methanesulfonic acid 2-(4-cyano-phenoxy)-ethyl ester (1.56 g, 7.5 mmol) as a colorless liquid (920 mg, 60%).

(227) LCMS (Method A): 206.3 (M+H).

Intermediate F4: 4-{4-[(2-Amino-ethylamino)-methyl]-piperidin-1-yl}-benzonitrile

(228) ##STR00175##

(229) 4-{4-[(2-Amino-ethylamino)-methyl]-piperidin-1-yl}-benzonitrile was prepared following the general procedure F from methane sulfonic acid 4-(4-cyano-phenyl)-cyclohexyl methyl ester (2.02 g, 6 mmol) as a pale yellow liquid (920 mg, 60%).

(230) LCMS (Method A): 259.3 (M+H).

Intermediate F5: N-(2-Phenoxy-ethyl)-ethane-1,2-diamine

(231) ##STR00176##

(232) N-(2-Phenoxy-ethyl)-ethane-1,2-diamine was prepared following the general procedure F from methanesulfonic acid 2-phenoxy-ethyl ester (1.56 g, 7.2 mmol) as a colorless liquid (820 mg, 63%).

(233) LCMS (Method A): 181.2 (M+H).

Intermediate F6: N-(2-(4-(Methylsulfonyl)phenoxy)ethyl)ethane-1,2-diamine

(234) ##STR00177##

(235) N-(2-(4-(Methylsulfonyl)phenoxy)ethyl)ethane-1,2-diamine was prepared following the general procedure F from methanesulfonic acid 2-(4-methanesulfonyl-phenoxy)-ethyl ester (1.1 g, 3.7 mmol) as a colorless liquid (750 mg, 78%).

(236) LCMS (Method A, ELSD): 259.3 (M+H).

Intermediate F7: 4-[2-(2-Amino-ethylamino)-ethoxy]-benzoic acid methyl ester

(237) ##STR00178##

(238) 4-[2-(2-Amino-ethylamino)-ethoxy]-benzoic acid methyl ester was prepared following the general procedure F from 4-(2-methanesulfonyloxy-ethoxy)-benzoic acid methyl ester (1.6 g, 5.8 mmol) as a colorless liquid (650 mg, 47%).

(239) LCMS (Method A, ELSD): 239.3 (M+H).

Intermediate F8: N-(2-(4-bromophenoxy)ethyl)ethane-1,2-diamine

(240) ##STR00179##

(241) N-(2-(4-bromophenoxy)ethyl)ethane-1,2-diamine was prepared following general procedure F from 2-(4-bromophenoxy) ethanol (4.34 g, 20 mmol) as a colourless liquid to get the title compound (3.86 g, 72%).

(242) LCMS (Method A): 261.2 (M+H).

Intermediate G1: (R)N-(2-Amino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(243) ##STR00180##

(244) (R)N-(2-Amino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was prepared following the general procedure G from ethane-1,2-diamine (150 mg, 2 mmol) and D-pantolactone (390 mg, 3 mmol) as a pale yellow liquid (150 mg, 37%).

(245) LCMS (Method A, ELSD): 191.0 (M+H).

Intermediate G2: (R)-2,4-Dihydroxy-3,3-dimethyl-N-[2-(3-phenyl-propylamino)-ethyl]-butyramide

(246) ##STR00181##

(247) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[2-(3-phenyl-propylamino)-ethyl]-butyramide was prepared following general procedure G from N-(3-phenyl-propyl)-ethane-1,2-diamine (445 mg, 2.5 mmol) and D-pantolactone (487 mg, 3.75 mmol) as a colorless liquid (200 mg, 26%).

(248) LCMS (Method A): 309.2 (M+H).

Intermediate G3: (R)-2,4-Dihydroxy-3,3-dimethyl-N-(2-phenethylamino-ethyl)-butyramide

(249) ##STR00182##

(250) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(2-phenethylamino-ethyl)-butyramide was prepared following the general procedure G from N-phenethyl-ethane-1,2-diamine (489 mg, 3 mmol) and D-pantolactone (585 mg 4.5 mmol) as a pale yellow liquid (510 mg, 58%).

(251) LCMS (Method A): 295.2 (M+H).

Intermediate G4: (R)N-(2-Benzylamino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(252) ##STR00183##

(253) (R)N-(2-Benzylamino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was prepared following the general procedure G using N-benzyl-ethane-1,3-diamine (656 mg, 4 mmol) and D-pantolactone (640 mg, 6 mmol) as a colorless liquid (305 mg, 26%).

(254) LCMS (Method A, ELSD): 281.0 (M+H).

Intermediate G5: (R)N-{2-[2-(4-Cyano-phenoxy)-ethylamino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(255) ##STR00184##

(256) (R)N-{2-[2-(4-Cyano-phenoxy)-ethylamino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was prepared following the general procedure G from 4-(2-((2-aminoethyl)amino)ethoxy)benzonitrile (717 mg, 3.5 mmol) and D-pantolactone (682 mg, 5.25 mmol) as a colorless liquid (520 mg, 44%).

(257) LCMS (Method A): 336.3 (M+H).

Intermediate G6: (R)N-(2-{[1-(4-Cyano-phenyl)-piperidin-4-ylmethyl]-amino}ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(258) ##STR00185##

(259) (R)N-(2-{[1-(4-Cyano-phenyl)-piperidin-4-ylmethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was prepared following the general procedure G from 4-{4-[(2-amino-ethylamino)-methyl]-piperidin-1-yl}-benzonitrile (600 mg, 2.33 mmol) and D-pantolactone (453 mg, 3.49 mmol) as a pale yellow liquid (560 mg, 62%).

(260) LCMS (Method A): 389.3 (M+H).

Intermediate G7: (R)-2,4-Dihydroxy-3,3-dimethyl-N-[2-(2-phenoxy-ethylamino)-ethyl]butyramide

(261) ##STR00186##

(262) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[2-(2-phenoxy-ethylamino)-ethyl]-butyramide was prepared following the general procedure G from N-(2-phenoxyethyl)ethane-1,2-diamine (1.56 g, 8.7 mmol) and D-pantolactone (1.51 mmol, 13 mmol) as a colorless liquid (820 mg, 29%).

(263) LCMS (Method A): 312.3 (M+H).

Intermediate G8: (R)-2,4-Dihydroxy-N-{2-[2-(4-methanesulfonyl-phenoxy)-ethylamino]-ethyl}-3,3-dimethyl-butyramide

(264) ##STR00187##

(265) (R)-2,4-Dihydroxy-N-{2-[2-(4-methanesulfonyl-phenoxy)-ethylamino]-ethyl}-3,3-dimethyl-butyramide was prepared following the general procedure G from N-(2-(4-(methylsulfonyl)phenoxy)ethyl)ethane-1,2-diamine (1.1 g, 4.2 mmol) and D-pantolactone (744 mg, 6.4 mmol) as a colorless liquid (750 mg, 46%).

(266) LCMS (Method A): 389.2 (M+H).

Intermediate G9: 4-{2-[2-((R)-2,4-Dihydroxy-3,3-dimethyl-butrylamino)-ethylamino]ethoxy}-benzoic acid methyl ester

(267) ##STR00188##

(268) 4-{2-[2-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-ethylamino]-ethoxy}-benzoic acid methyl ester was prepared following the general procedure G from 4-[2-(2-amino-ethylamino)-ethoxy]-benzoic acid methyl ester (1.6 g, 6.7 mmol) and D-pantolactone (1.16 g, 10 mmol) as a colorless liquid (650 mg, 26%).

(269) LCMS (Method A): 369.2 (M+H).

Intermediate G10: (R)N-(2-[2-(4-Bromo-phenoxy)-ethylamino]-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(270) ##STR00189##

(271) (R)N-{2-[2-(4-Bromo-phenoxy)-ethylamino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was prepared following the general procedure G from N-(2-(4-bromophenoxy)ethyl)ethane-1,2-diamine (520 mg, 2 mmol) and D-pantolactone as a pale yellow oil (410 mg, 52%).

(272) LCMS (Method A): 391.0 (M+H]).

Example 1

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-butyl)-butyramide

(273) ##STR00190##

(274) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-butyl)-butyramide was synthesized following the general procedure B from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-butyl)-amide (180 mg, 0.7 mmol) as a colorless gummy liquid (8 mg, 4%).

(275) HPLC (Method A, ELSD): Rt 2.4 min (Purity 99.2%). LCMS (Method A, ELSD): 218 (M+H). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): 7.71 (t, J=4.0 Hz, 1H), 5.31 (d, J=4.0 Hz, 1H), 4.52 (t, J=4.0 Hz, 1H), 3.71 (d, J=4.0 Hz, 1H), 3.32-3.14 (m, 4H), 2.60-2.57 (m, 2H), 2.11 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 2

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-pentyl)-butyramide

(276) ##STR00191##

(277) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-pentyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pentyl)-amide (118 mg, 0.43 mmol) as a pale yellow oil (65 mg, 65%).

(278) HPLC (Method B): Rt 2.93 min (Purity 87.93%). LCMS (Method A, ELSD): 232 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.71 (t, J=4.0 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 4.52 (t, J=4.0 Hz, 1H), 3.71 (d, J=4.0 Hz, 1H), 3.32-3.14 (m, 4H), 2.60-2.57 (m, 2H), 2.49-2.41 (m, 2H), 1.98-1.94 (m, 3H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 3

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-pent-4-enyl)-butyramide

(279) ##STR00192##

(280) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-pent-4-enyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pent-4-enyl)-amide (118 mg, 0.43 mmol) as a pale yellow solid (22 mg, 22%).

(281) HPLC (Method A, ELSD): Rt 1.64 min (Purity 89.55%). LCMS (Method A, ELSD): 230 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.82 (t, J=4.0 Hz, 1H), 6.36-6.21 (m, 1H), 5.94-5.91 (m, 1H), 5.30 (dd, J=4.0, 8.0 Hz, 1H), 4.41 (t, J=4.0 Hz, 1H), 3.72 (d, J=4.0 Hz, 1H), 3.36-3.24 (m, 2H), 3.17-3.13 (m, 3H), 2.81 (dd, J=4.0, 8.0 Hz, 2H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 4

(R)-2,4-Dihydroxy-3,3-dimethyl-N-((E)-3-oxo-6-phenyl-hex-4-enyl)-butyramide

(282) ##STR00193##

Step 1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-3-hydroxy-6-phenyl-hex-4-enyl)-amide

(283) To a solution (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pent-4-enyl)-amide (448 mg, 1.84 mmol) in dry DCM (10 mL) was added allylbenzene (424 mg, 3.6 mmol) followed by Grubbs 2.sup.nd generation catalyst (75 mg, 0.088 mmol) and heated at reflux for 16 h. After completion of the reaction the solvent was removed and the crude product was purified by silica gel column chromatography (pet ether:EtOAc, 9:1) to afford a colorless gum (260 mg, 39%).

(284) LCMS (Method A): 362.3 (M+H).

Step 2: (R)-2, 4-Dihydroxy-3, 3-dimethyl-N-((E)-3-oxo-6-phenyl-hex-4-enyl)-butyramide

(285) (R)-2,4-Dihydroxy-3,3-dimethyl-N-((E)-3-oxo-6-phenyl-hex-4-enyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-pent-4-enyl)-amide (250 mg, 0.7 mmol) as a colorless gum (6 mg, 10%).

(286) HPLC (Method A): Rt 3.53 (Purity 91.77%). LCMS (Method A): 320.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.61 (t, J=4.0 Hz, 1H), 7.33-7.29 (m, 2H), 7.24-7.20 (m, 3H), 6.97-6.92 (m, 1H), 6.08-6.04 (m, 1H), 5.32 (d, J=8.0 Hz, 1H), 4.41 (t, J=4.0 Hz, 1H), 3.72 (d, J=8.0 Hz, 1H), 3.51 (d, J=8.0 Hz, 2H), 3.32-3.26 (m, 3H), 3.25-3.16 (m, 1H), 2.76-2.73 (m, 2H), 0.80 (s, 3H), 0.76 (s, 3H).

Example 5

(R)-2,4-Dihydroxy-3,3-dimethyl-N-((E)-5-oxo-hex-3-enyl)-butyramide

(287) ##STR00194##

(288) Step 1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-5-oxo-hex-3-enyl)-amide

(289) To a solution of (2-oxo-propyl)-phosphonic acid diethyl ester (388 mg, 2 mmol) in dry THF (10 mL) was added 60% NaH in mineral oil (80 mg, 2 mmol) at 0 C. and stirred for 15 min. A solution of (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (485 mg, 2 mmol) in THF (10 mL) was added dropwise and stirred for 1 h at 0 C. and another 1 h at RT. After completion of the reaction, a saturated aqueous solution of NH.sub.4Cl was added and extracted with EtOAc, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure to get crude compound which was purified by silica gel column chromatography (pet ether:EtOAc, 9:1) to afford a white solid (345 mg, 61%).

Step 2: (R)-2, 4-Dihydroxy-3, 3-dimethyl-N-((E)-5-oxo-hex-3-enyl)-butyramide

(290) (R)-2,4-Dihydroxy-3,3-dimethyl-N-((E)-5-oxo-hex-3-enyl)-butyramide was synthesized following the general procedure A starting from (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-5-oxo-hex-3-enyl)-amide as a yellow gum (61 mg, 54%).

(291) HPLC (Method A): Rt 1.64 min (Purity 99.16%). LCMS (Method A): 244.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.92 (t, J=4.0 Hz, 1H), 6.82-6.81 (m, 1H), 6.02 (d, J=4.0 Hz, 1H), 5.41 (d, J=8.0 Hz, 1H), 4.52 (t, J=4.0 Hz, 1H), 3.72 (d, J=8.0 Hz, 1H), 3.32-3.25 (m, 2H), 3.18-3.13 (m, 2H), 2.38-2.32 (m, 2H), 2.22 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 6

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(E)-5-oxo-7-phenyl-hept-3-enyl)-butyramide

(292) ##STR00195##

Step 1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-5-oxo-7-phenyl-hept-3-enyl)-amide

(293) To a solution of diethyl (2-oxo-3-phenylpropyl) phosphonate (1.08 g, 4 mmol) in dry THF (20 mL) was added 60% NaH in mineral oil (160 mg, 4 mmol) at 0 C. and stirred for 15 min. A solution of (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (970 mg, 4 mmol) in THF (20 mL) was added dropwise and stirred for 1 h at 0 C. and another 1 h at RT. After completion of reaction, a saturated aqueous solution of NH.sub.4Cl was added and extracted with EtOAc, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to get the crude compound which was purified by silica gel column chromatography (pet ether:EtOAc, 9:1 to afford the title compound as a colorless liquid (746 mg, 52%).

(294) LCMS (Method A): 374.2 (M+H).

Step 2: (R)-2,4-Dihydroxy-3,3-dimethyl-N-(E)-5-oxo-7-phenyl-hept-3-enyl)-butyramide

(295) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(E)-5-oxo-7-phenyl-hept-3-enyl)-butyramide was synthesized following the general procedure A starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid ((E)-5-oxo-7-phenyl-hept-3-enyl)-amide as a colorless gum (15 mg, 87%).

(296) HPLC (Method A): Rt 3.46 min (Purity 98.4%). LCMS (Method A): 334.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.81 (t, J=4.0 Hz, 1H), 7.27-7.15 (m, 5H), 6.83-6.79 (m, 1H), 6.11-6.07 (m, 1H), 5.42 (d, J=8.0 Hz, 1H), 4.52 (t, J=4.0 Hz, 1H), 3.71 (d, J=4.0 Hz, 1H), 3.31-3.12 (m, 4H), 2.88-2.76 (m, 4H), 2.36-2.31 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 7

(R)N-(3-Carbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(297) ##STR00196##

Step 1: (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-carbamoyl-3-hydroxy-propyl)-amide

(298) To a solution of (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-oxo-propyl)-amide (500 mg, 2.05 mmol) in H.sub.2O:Et.sub.2O (1:1, 10 mL) was added NaHSO.sub.3 (442 mg, 4.1 mmol) and cooled to 0 C. for 30 min. To this reaction mixture KCN (382 mg, 5.8 mmol) was added and stirred at RT for 2 h. After completion of the reaction, the reaction was quenched with sodium hypochlorite and extracted with Et.sub.2O, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The solid residue was dissolved in MeOH (10 mL) to which LiOH.H.sub.2O (164 mg, 4 mmol) and H.sub.2O.sub.2 (0.52 mL) were added and allowed to stir at RT for 12 h. After completion of the reaction, the reaction mixture was diluted with a saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 and extracted with DCM. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum to afford the crude product which was purified by silica gel column chromatography (pet ether:EtOAc, 7:3) to afford the title compound as a white solid (237 mg, 40%).

(299) LCMS (Method A, ELSD): 229.2 (M+H).

Step 2: (R)N-(3-Carbamoyl-3-oxo-propyl)-2, 4-dihydroxy-3, 3-dimethyl-butyramide

(300) (R)N-(3-Carbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-carbamoyl-3-hydroxy-propyl)-amide (230 mg, 1 mmol) as a colorless gum (120 mg, 45%).

(301) HPLC (Method B): Rt 5.25 (Purity 98.05%). LCMS (Method A, ELSD): 247.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.93 (s, 1H), 7.72 (t, J=4.0 Hz, 1H), 7.63 (s, 1H), 5.31 (d, J=8.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 3.72 (d, J=4.0 Hz, 1H), 3.37-3.25 (m, 3H), 3.11 (dd, J=4.0, 8.0 Hz, 1H), 2.95-2.91 (m, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 8

(R)N-(3-Cyclopropylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(302) ##STR00197##

(303) (R)N-(3-Cyclopropylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclopropyl carbamoyl-3-hydroxy-propyl)-amide as a colorless gum (23 mg, 31%).

(304) HPLC (Method A, ELSD): Rt 1.72 min (Purity 94.2%). LCMS (Method A, ELSD): 287.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.81 (t, J=4.0 Hz, 1H), 7.72 (t, J=4.0 Hz, 1H), 5.33 (d, J=8.0 Hz, 1H), 4.41 (t, J=4.0 Hz, 1H), 3.72 (d, J=4.0 Hz, 1H), 3.31-3.12 (m, 4H), 2.97-2.95 (m, 2H), 2.72-2.70 (m, 1H), 0.80 (s, 3H), 0.78 (s, 3H), 0.64-0.56 (m, 4H).

Example 9

(R)N-(3-Benzylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(305) ##STR00198##

(306) (R)N-(3-Benzylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide (137 mg, 0.36 mmol) as a white solid (83 mg, 68%).

(307) HPLC (Method A, ELSD): Rt 2.85 min (Purity 97.9%). LCMS (Method A, ELSD): 337.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.10 (t, J=4.0 Hz, 1H), 7.76 (s, 1H), 7.31-7.22 (m, 5H), 5.33 (d, J=8.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 4.30-3.68 (m, 2H), 3.67-3.36 (m, 1H), 3.37-3.29 (m, 1H), 3.28-3.25 (m, 2H), 3.17-3.13 (m, 1H), 3.01-2.97 (m, 2H), 0.80 (s, 3H), 0.75 (s, 3H).

Example 10

(R)N-[3-(2-Fluoro-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(308) ##STR00199##

(309) (R)N-[3-(2-Fluoro-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid [3-(2-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide (90 mg, 0.23 mmol) as a white solid (32 mg, 40%).

(310) HPLC (Method A, ELSD): Rt 2.8 min (Purity 98.8%). LCMS (Method A, ELSD): 355.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.10 (t, J=4.0 Hz, 1H), 7.77 (s, 1H), 7.32-7.28 (m, 2H), 7.18-7.12 (m, 2H), 5.34 (d, J=5.5 Hz, 1H), 4.74 (t, J=5.5 Hz, 1H), 4.35 (d, J=6.3 Hz, 2H), 3.68 (d, J=5.6 Hz, 1H), 3.38-3.28 (m, 1H), 3.27-3.25 (m, 2H), 3.17-3.13 (m, 1H), 3.00-2.96 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 11

(R)N-[3-(Cyclohexylmethyl-carbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(311) ##STR00200##

(312) (R)N-[3-(Cyclohexylmethyl-carbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [3-(cyclohexylmethyl-carbamoyl)-3-hydroxy-propyl]-amide (136 mg, 0.35 mmol) as a white solid (96 mg, 79%).

(313) HPLC (Method A): Rt 3.3 min (Purity 99.4%). LCMS (Method A, ELSD): 343.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.51 (d, J=6.2 Hz, 1H), 7.73 (t, J=5.8 Hz, 1H), 5.33 (d, J=5.6 Hz, 1H), 4.43 (t, J=5.6 Hz, 1H), 3.67 (d, J=5.5 Hz, 1H), 3.33-3.27 (m, 1H), 3.26-3.14 (m, 2H), 3.13-2.96 (m, 1H), 2.96-2.92 (m, 4H), 1.61 (d, J=13.4 Hz, 5H), 1.46 (s, 1H), 1.16-1.10 (m, 3H), 0.84 (d, J=9.8 Hz, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 12

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenethylcarbamoyl-propyl)-butyramide

(314) ##STR00201##

(315) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenethylcarbamoyl-propyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid (3-hydroxy-3-phenethylcarbamoyl-propyl)-amide (102 mg, 0.26 mmol) as a white solid (60 mg, 66%).

(316) HPLC (Method A, ELSD): Rt 3.08 min (Purity 98.2%). LCMS (Method A, ELSD): 351.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60 (t, J=4.2 Hz, 1H), 7.73 (t, J=4.2 Hz, 1H), 7.30-7.26 (m, 2H), 7.20-7.17 (m, 3H), 5.33 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 3.67 (d, J=5.5 Hz, 1H), 3.36-3.30 (m, 2H), 3.29-3.17 (m, 3H), 3.16-3.13 (m, 1H), 2.97-2.93 (m, 2H), 2.76 (t, J=7.1 Hz, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 13

(S)N-(3-Benzylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(317) ##STR00202##

(318) (S)N-(3-Benzylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (S)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-benzylcarbamoyl-3-hydroxy-propyl)-amide (73 mg, 0.19 mmol) as a white solid (31 mg, 48%).

(319) HPLC (Method A, ELSD): Rt 2.8 min (Purity 94.4%). LCMS (Method A, ELSD): 337.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.10 (t, J=4.2 Hz, 1H), 7.76 (s, 1H), 7.31-7.22 (m, 5H), 5.33 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.30 (d, J=6.4 Hz, 2H), 3.68 (d, J=5.6 Hz, 1H), 3.36-3.27 (m, 1H), 3.26-3.16 (m, 1H), 3.15-3.13 (m, 2H), 3.01-2.97 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 14

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-thiophen-2-yl-ethylcarbamoyl)-propyl]-butyramide

(320) ##STR00203##

(321) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-thiophen-2-yl-ethylcarbamoyl)-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-thiophen-2-yl-ethylcarbamoyl)-propyl]-amide (69 mg, 0.17 mmol) as an off-white solid (19 mg, 31%).

(322) HPLC (Method A, ELSD): Rt 2.9 min (Purity 99.1%). LCMS (Method A, ELSD): 357.3, (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.81 (t, J=4.0 Hz, 1H), 7.72 (t, J=4.0 Hz, 1H), 7.31 (dd, J=4.0, 8.0 Hz, 1H), 6.94-6.86 (m, 2H), 5.31 (dd, J=6.0, 4.0 Hz, 1H), 4.4 (t, J=4.0 Hz, 1H), 3.71 (dd, J=8.0, 4.2 Hz, 1H), 3.37-3.25 (m, 5H), 3.22 (dd, J=8.0, 4.2 Hz, 1H), 2.99-2.94 (m, 4H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 15

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(3-trifluoromethoxy-benzylcarbamoyl)-propyl]-butyramide

(323) ##STR00204##

(324) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(3-trifluoromethoxy-benzylcarbamoyl)-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-trifluoro methoxy-benzylcarbamoyl)-propyl]-amide (166 mg, 0.36 mmol) as a off-white solid (130 mg, 86%).

(325) HPLC (Method B): Rt 5.04 min (Purity 99.6%). LCMS (Method A, ELSD): 421.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.11 (d, J=8.0 Hz, 1H), 7.81 (t, J=4.0 Hz, 1H), 7.42 (t, J=4.0 Hz, 1H), 7.31-7.21 (m, 3H), 5.31 (d, J=8.0 Hz, 1H), 4.42 (t, J=4.0 Hz, 1H), 4.31 (d, J=4.0 Hz, 2H), 3.71 (d, J=8.0 Hz, 1H), 3.39-3.25 (m, 3H), 3.23 (t, J=4.0 Hz, 1H), 3.00-2.96 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 16

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenylcarbamoyl-propyl)-butyramide

(326) ##STR00205##

(327) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenylcarbamoyl-propyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-phenyl carbamoyl-propyl)-amide (31 mg, 0.09 mmol) as a white solid (3 mg, 11%).

(328) HPLC (Method A, ELSD): Rt 2.85 min (Purity 99.4%). LCMS (Method A, ELSD): 323.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.41 (s, 1H), 7.83-7.80 (m, 3H), 7.35-7.31 (m, 2H), 7.13 (t, J=4.0 Hz, 1H), 5.31 (d, J=4.0 Hz, 1H), 4.51 (t, J=4.0 Hz, 1H), 3.7 (d, J=8.0 Hz, 1H), 3.41-3.26 (m, 3H), 3.17-3.03 (m, 3H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 17

(R)N-[3-(4-Fluoro-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(329) ##STR00206##

(330) (R)N-[3-(4-Fluoro-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid [3-(4-fluoro-benzylcarbamoyl)-3-hydroxy-propyl]-amide (154 mg, 0.39 mmol) as an off-white solid (91 mg, 66%).

(331) HPLC (Method A, ELSD): Rt 2.97 min (Purity 95.6%). LCMS (Method A, ELSD): 355.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.11 (t, J=4.0 Hz, 1H), 7.81 (t, J=4.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.13-7.09 (m, 2H), 5.33 (d, J=8.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 4.31 (d, J=4.0 Hz, 2H), 3.73 (d, J=4.0 Hz, 1H), 3.67-3.25 (m, 3H), 3.13 (dd, J=4.0, 8.0 Hz, 1H), 2.99-2.95 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 18

(R)N-(3-Cyclohexylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl butyramide

(332) ##STR00207##

(333) (R)N-(3-Cyclohexylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid (3-cyclohexylcarbamoyl-3-hydroxy-propyl)-amide (61 mg, 0.17 mmol) as a white solid (17 mg, 31%).

(334) HPLC (Method A, ELSD): Rt 2.98 min (Purity 99.1%). LCMS (Method A, ELSD): 329.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.33 (t, J=4.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 3.71 (d, J=4.0 Hz, 1H), 3.54-3.51 (m, 1H), 3.34-3.24 (m, 3H), 3.1 (dd, J=4.0, 8.0 Hz, 1H), 2.97-2.93 (m, 2H), 1.68-1.54 (m, 5H), 1.30-1.22 (m, 4H), 1.07-1.05 (m, 1H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 19

(R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-[(naphthalen-1-ylmethyl)-carbamoyl]-3-oxo-propyl}-butyramide

(335) ##STR00208##

(336) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-[(naphthalen-1-ylmethyl)-carbamoyl]-3-oxo-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[(naphthalen-1-ylmethyl)-carbamoyl]-propyl}-amide (131 mg, 0.36 mmol) as a white gum (96 mg, 81%).

(337) HPLC (Method A): Rt 3.52 min (Purity 91%). LCMS (Method A): 387.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.21 (t, J=4.0 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.91 (t, J=4.0 Hz, 1H), 7.82-7.77 (m, 2H), 7.56-7.52 (m, 2H), 7.42 (t, J=4.0 Hz, 2H), 5.31 (d, J=8.0 Hz, 1H), 4.82 (d, J=4.0 Hz, 2H), 4.42 (t, J=4.0 Hz, 1H), 3.71 (d, J=4.0 Hz, 2H), 3.31-3.25 (m, 2H), 3.21 (t, J=4.0 Hz, 1H), 3.02-3.00 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 20

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenethylcarbamoyl-propyl)-butyramide

(338) ##STR00209##

(339) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-phenethylcarbamoyl-propyl)-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid [3-hydroxy-3-(1-phenyl-ethylcarbamoyl)-propyl]-amide (133 mg, 0.34 mmol) as a white solid (19 mg, 16%).

(340) HPLC (Method A): Rt 3.02 min (Purity 94.7%). LCMS (Method A, ELSD): 351.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.02 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.35-7.20 (m, 5H), 5.32 (dd, J=4.0, 8.0 Hz, 1H), 4.95-4.91 (m, 1H), 4.42 (t, J=4.0 Hz, 1H), 3.72 (d, J=4.0 Hz, 1H), 3.35-3.24 (m, 3H), 3.12 (dd, J=4.0, 8.0 Hz, 3H), 1.42 (d, J=8.0 Hz, 3H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 21

(R)N-[3-(Benzhythyl-carbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(341) ##STR00210##

(342) (R)N-[3-(Benzhydryl-carbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid [3-(benzhydryl-carbamoyl)-3-hydroxy-propyl]-amide (87 mg, 0.20 mmol) as a pale yellow gum (25 mg, 31%).

(343) HPLC (Method A, ELSD): Rt 3.59 min (Purity 98.5%). LCMS (Method A): 413.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.32 (t, J=4.0 Hz, 1H), 7.82 (t, J=4.0 Hz, 1H), 7.34-7.24 (m, 10H), 6.22 (d, J=8.0 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 4.42 (t, J=4.0 Hz, 1H), 3.71 (d, J=8.0 Hz, 1H), 3.33-3.25 (m, 3H), 3.21 (t, J=4.0 Hz, 1H), 3.00-2.97 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H)

Example 22

(R)-2,4-Dihydroxy-N-[3-(3-methoxy-benzylcarbamoyl)-3-oxo-propyl]-3,3-dimethyl-butyramide

(344) ##STR00211##

(345) (R)-2,4-Dihydroxy-N-[3-(3-methoxy-benzylcarbamoyl)-3-oxo-propyl]-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1, 3]dioxane-4-carboxylic acid [3-hydroxy-3-(3-methoxy-benzylcarbamoyl)-propyl]-amide (17 mg, 0.04 mmol) as a pale yellow gum (12 mg, 79%).

(346) HPLC (Method B): Rt 4.01 min (Purity 99.3%). LCMS (Method A, ELSD): 367.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.13 (t, J=4.0 Hz, 1H), 7.83 (t, J=4.0 Hz, 1H), 7.22 (t, J=4.0 Hz, 1H), 6.83-6.77 (m, 3H), 5.32 (d, J=4.0 Hz, 1H), 4.42 (t, J=4.0 Hz, 1H), 4.33 (d, J=4.0 Hz, 2H), 3.71-3.66 (m, 4H), 3.32-3.25 (m, 3H), 3.23 (t, J=4.0 Hz, 1H), 3.00-2.96 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 23

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-trifluoromethyl-benzylcarbamoyl)-propyl]-butyramide

(347) ##STR00212##

(348) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-trifluoromethyl-benzylcarbamoyl)-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-trifluoromethyl-benzylcarbamoyl)-propyl]-amide (200 mg, 0.5 mmol) as a colorless gum (138 mg, 76%).

(349) HPLC (Method A, ELSD): Rt 3.59 min (Purity 98%). LCMS (Method A, ELSD): 405.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.24 (d, J=8.0 Hz, 1H), 7.83 (t, J=4.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.59-7.44 (m, 2H), 5.42 (d, J=4.0 Hz, 1H), 4.50-4.43 (m, 3H), 3.74 (d, J=4.0 Hz, 1H), 3.32-3.26 (m, 2H), 3.17-3.13 (m, 2H), 3.00-2.96 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 24

(R)-2,4-Dihydroxy-N-[3-(4-methanesulfonyl-benzylcarbamoyl)-3-oxo-propyl]-3,3-dimethyl-butyramide

(350) ##STR00213##

(351) (R)-2,4-Dihydroxy-N-[3-(4-methanesulfonyl-benzylcarbamoyl)-3-oxo-propyl]-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(4-methane sulfonyl-benzyl carbamoyl)-propyl]-amide (32 mg, 0.07 mmol) as a pale yellow gum (4 mg, 14%).

(352) HPLC (Method B): Rt 3.33 min (Purity 90.12%). LCMS (Method B): 415.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.24 (t, J=4.0 Hz, 1H), 7.86-7.78 (m, 3H), 7.53 (d, J=8.0 Hz, 2H), 5.34 (d, J=8.0 Hz, 1H), 4.45-4.39 (m, 3H), 3.72 (d, J=4.0 Hz, 1H), 3.31-3.27 (m, 3H), 3.17-3.15 (m, 4H), 2.99-2.96 (m, 2H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 25

[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-acetic acid methyl ester

(353) ##STR00214##

(354) [4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-acetic acid methyl ester was synthesized following the general procedure B starting from {2-hydroxy-4-R(R)-2,2,5,5-tetramethyl-[1,3]dioxane-4-carbonyl)-amino] butyryl amino}-acetic acid methyl ester (93 mg, 0.26 mmol) as a colorless gum (33 mg, 40%).

(355) HPLC (Method B): Rt 2.56 min (Purity 95%). LCMS (Method B): 319.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.93 (t, J=4.0 Hz, 1H), 7.84 (t, J=4.0 Hz, 1H), 5.33 (d, J=4.0 Hz, 1H), 4.54 (t, J=4.0 Hz, 1H), 3.92 (d, J=4.0 Hz, 2H), 3.68-3.61 (m, 4H), 3.39-3.24 (m, 3H), 3.17-3.12 (m, 1H), 2.90-2.50 (m, 2H), 0.78 (s, 3H), 0.76 (s, 3H).

Example 26

(R)-2,4-Dihydroxy-N-{3-[3-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide

(356) ##STR00215##

(357) (R)-2,4-Dihydroxy-N-{3-[3-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide (149 mg, 0.25 mmol) as an off-white solid (22 mg, 19%).

(358) HPLC (Method A, ELSD): Rt 2.52 min (Purity 98.9%). LCMS (Method A, ELSD): 474.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.33 (t, J=4.0 Hz, 1H), 7.83 (t, J=4.0 Hz, 1H), 7.27-7.19 (m, 2H), 6.85-6.80 (m, 3H), 5.33 (d, J=8.0 Hz, 1H), 4.42 (t, J=4.0 Hz, 1H), 4.3 (d, J=8.0 Hz, 2H), 3.72 (d, J=8.0 Hz, 2H), 3.36-3.25 (m, 6H), 3.02 (dd, J=4.0, 8.0 Hz, 3H), 2.92 (s, 3H), 0.79 (m, 3H), 0.76 (m, 3H).

Example 27

(R)N-[3-(Benzyl-methyl-carbamoyl-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(359) ##STR00216##

(360) (R)N-[3-(Benzyl-methyl-carbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3, 3-di methyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-di methyl-[1,3]dioxane-4-carboxylic acid [3-(benzyl-ethyl-carbamoyl)-3-hydroxy-propyl]-amide (108 mg, 0.23 mmol) as an off-white gum (26 mg, 32%).

(361) HPLC (Method A): Rt 3.13 min (Purity 92.1%). LCMS (Method A): 351.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.80-7.76 (m, 1H), 7.39-7.24 (m, 5H), 5.42 (t, J=4.0 Hz, 1H), 4.52 (s, 1H), 4.43 (t, J=4.0 Hz, 2H), 3.73 (dd, J=4.0, 8.0 Hz, 1H), 3.41-3.37 (m, 1H), 3.28-3.25 (m, 2H), 3.17-3.13 (m, 1H), 3.00-2.85 (m, 2H), 2.75-2.50 (m, 3H), 0.79 (m, 3H), 0.75 (m, 3H).

Example 28

(R)N-{3-[(Biphenyl-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(362) ##STR00217##

(363) (R)N-{3-[(Biphenyl-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(biphenyl-4-lmethyl)-carbamoyl]-3-hydroxy-propyl}-amide (75 mg, 0.14 mmol) as a pale yellow solid (9 mg, 16%).

(364) HPLC (Method A): Rt 3.94 min (Purity 96.5%). LCMS (Method A): 413.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.32-9.18 (m, 1H), 7.73 (t, J=4.0 Hz, 1H), 7.63-7.58 (m, 4H), 7.46-7.42 (m, 2H), 7.36-7.32 (m, 3H), 5.34 (d, J=8.0 Hz, 1H), 4.53 (t, J=4.0 Hz, 1H), 4.32 (d, J=8.0 Hz, 2H), 3.73 (d, J=4.0 Hz, 1H), 3.37-3.25 (m, 3H), 3.12 (dd, J=4.0, 8.0 Hz, 1H), 3.01-2.98 (m, 2H), 0.78 (m, 3H), 0.76 (m, 3H).

Example 29

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-propyl)-butyramide

(365) ##STR00218##

(366) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-propyl}-amide (132 mg, 0.29 mmol) as an off-white gum (37 mg, 38%).

(367) HPLC (Method A, ELSD): Rt 1.95 min (Purity 99%). LCMS (Method A ELSD): 331.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.65-8.55 (m, 1H), 7.85-7.83 (m, 1H), 5.33 (d, J=8.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 3.93 (t, J=4.0 Hz, 1H), 3.73-3.72 (m, 3H), 3.67-3.57 (m, 3H), 3.31-3.12 (m, 3H), 2.97-2.94 (m, 2H), 1.83-1.77 (m, 3H), 1.65-1.62 (m, 1H), 0.79 (m, 3H), 0.77 (m, 3H).

Example 30

(R)-2,4-Dihydroxy-N-{3-[2-(4-methanesulfonyl-phenyl)-ethylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide

(368) ##STR00219##

(369) (R)-2,4-Dihydroxy-N-{3-[2-(4-methanesulfonyl-phenyl)-ethylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-2-4-methanesulfonyl-phenyl)-ethylcarbamoyl]-propyl}-amide (64 mg, 0.12 mmol) as a colorless gum (11 mg, 22%).

(370) HPLC (Method A): Rt 3.46 min (Purity 94.7%). LCMS (Method A): 429.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.74 (t, J=4.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.53 (d, J=8.0 Hz, 2H), 5.32 (d, J=8.0 Hz, 1H), 4.43 (t, J=4.0 Hz, 1H), 3.73 (d, J=4.0 Hz, 1H), 3.38-3.25 (m, 4H), 3.16-3.12 (m, 4H), 2.96-2.86 (m, 3H), 2.50-2.49 (m, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 31

(R)N-[3-(4-Bromo-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(371) ##STR00220##

(372) (R)N-[3-(4-Bromo-benzylcarbamoyl)-3-oxo-propyl]-2,4-dihydroxy-3, 3-di methyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-(4-bromo-benzylcarbamoyl)-3-hydroxy-propyl]-amide (44 mg, 0.08 mmol) as a pale yellow solid (11 mg, 32%).

(373) HPLC (Method B): Rt 4.64 min (Purity 92.55%). LCMS (Method B): 417.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.14 (t, J=4.0 Hz, 1H), 7.80 (t, J=4.0 Hz, 1H), 7.53 (dd, J=4.0, 6.6 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.30 (d, J=8.0 Hz, 1H), 4.40 (t, J=4.0 Hz, 1H), 4.34 (d, J=8.0 Hz, 2H), 3.74 (d, J=8.0 Hz, 1H), 3.33-3.25 (m, 3H), 3.23 (t, J=4.0 Hz, 1H), 2.99-2.97 (m, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 32

4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butrylamino)-2-oxo-butyrylamino]-methyl)-N-[2-(4-phenoxy-phenyl)-ethyl]-benzamide

(374) ##STR00221##

(375) 4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-N-[2-(4-phenoxy-phenyl)-ethyl]-benzamide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-4-2-(4-phenoxy-phenyl)-ethylcarbamoyl]-benzylcarbamoyl}-propyl)-amide (159 mg, 0.28 mmol) as a white solid (40 mg, 38%).

(376) HPLC (Method B): Rt 5.49 min (Purity 92.11%). LCMS (Method B): 576.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.14-9.10 (m, 1H), 8.50-8.45 (m, 1H), 7.78-7.73 (m, 3H), 7.38-7.32 (m, 4H), 7.24 (d, J=8.4 Hz, 2H), 7.10 (s, 1H), 6.97-6.92 (m, 4H), 5.34 (d, J=5.3 Hz, 1H), 4.45 (s, 1H), 3.68 (d, J=5.6 Hz, 2H), 3.47-3.37 (m, 7H), 3.00 (t, J=4.0 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 33

(R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[4-(piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-butyramide

(377) ##STR00222##

(378) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[4-(piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-amide (125 mg, 0.21 mmol) as a white solid (58 mg, 50%).

(379) HPLC (Method B): Rt 4.65 min (Purity 97.48%). LCMS (Method B): 484.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.20-9.19 (m, 1H), 7.85-7.82 (m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 5.35 (d, J=5.6 Hz, 1H), 4.45-4.40 (m, 3H), 3.68 (d, J=5.6 Hz, 1H), 3.36-3.17 (m, 4H), 2.99 (t, J=4.0 Hz, 2H), 2.84 (t, J=5.0 Hz, 4H), 1.52 (t, J=5.0 Hz, 6H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 34

(R)N-(3-[(1-Benzenesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(380) ##STR00223##

(381) (R)N-{3-[(1-Benzenesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-benzenesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-hydroxy-propyl}-amide (260 mg, 0.43 mmol) as a white solid (184 mg, 88%).

(382) HPLC (Method B): Rt 4.46 min (Purity 96.97%). LCMS (Method B): 484.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.54-8.52 (m, 1H), 7.74-7.61 (m, 6H), 6.67 (d, J=5.6 Hz, 1H), 4.43 (t, J=5.6 Hz, 1H), 3.67-3.57 (m, 3H), 3.57-3.48 (m, 4H), 2.96-2.91 (m, 4H), 2.18 (d, J=2.4 Hz, 2H), 1.66-1.63 (m, 2H), 1.51-1.42 (m, 1H), 1.21-1.01 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 35

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-{3-[4-(piperidine-1-sulfonyl)-phenyl]-propylcarbamoyl}-propyl)-butyramide

(383) ##STR00224##

(384) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-oxo-3-{3-[4-(piperidine-1-sulfonyl)-phenyl]-propylcarbamoyl}-propyl)-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-3-3-3-(piperidine-1-sulfonyl)-phenyl]-propylcarbamoyl}-propyl)-amide (111 mg, 0.18 mmol) as a colorless gum (19 mg, 21%).

(385) HPLC (Method B): Rt 5.01 min (Purity 86.53%). LCMS (Method B): 512.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.63-8.61 (m, 1H), 7.62 (d, J=8.3 Hz, 3H), 7.46 (d, J=8.3 Hz, 2H), 5.34 (d, J=5.5 Hz, 1H), 4.45 (d, J=5.60 Hz, 1H), 3.67 (d, J=5.5 Hz, 1H), 3.32-3.11 (m, 5H), 2.98-2.94 (m, 2H), 2.85-2.83 (m, 4H), 2.67-2.65 (m, 2H), 2.50-2.46 (m, 1H), 1.78 (t, J=7.1 Hz, 2H), 1.51 (t, J=5.6 Hz, 4H), 1.34 (d, J=4.4 Hz, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 36

(R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[3-(piperidine-1-sulfonyl)-benzylcarbamoyl}-propyl)-butyramide

(386) ##STR00225##

(387) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[3-(piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-piperidine-1-sulfonyl)-benzylcarbamoyl]-propyl}-amide (107 mg, 0.18 mmol) as a white solid (60 mg, 70%).

(388) HPLC (Method B): Rt 4.27 min (Purity 98.5%). LCMS (Method B): 484.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.22-9.21 (m, 1H), 7.64-7.58 (m, 5H), 5.33 (d, J=5.2 Hz, 1H), 4.45-4.40 (m, 3H), 3.67 (d, J=5.6 Hz, 1H), 3.68-3.58 (m, 4H), 2.99-2.96 (m, 2H), 2.86-2.84 (m, 4H), 1.53-1.43 (m, 4H), 1.32-1.30 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 37

(R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[4-(pyridin-4-yloxy)-benzylcarbamoyl]-propyl}-butyramide

(389) ##STR00226##

(390) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[4-(pyridin-4-yloxy)-benzylcarbamoyl]-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-pyridin-4-yloxy)-benzylcarbamoyl]-propyl}-amide (146 mg, 0.26 mmol) as a white solid (86 mg, 75%).

(391) HPLC (Method B): Rt 4.17 min (Purity 96.38%). LCMS (Method B): 430.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.14-9.12 (m, 1H), 8.44-8.43 (m, 2H), 7.38 (d, J=8.4 Hz, 3H), 7.13-7.11 (m, 2H), 6.89-6.87 (m, 2H), 5.34 (d, J=5.6 Hz, 1H), 4.45 (d, J=5.6 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 4.03 (t, J=4.0 Hz, 2H), 3.32-3.13 (m, 3H), 3.02-2.98 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 38

(R)N-(3-{[1-(Biphenyl-4-sulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(392) ##STR00227##

(393) (R)N-(3-{[1-(Biphenyl-4-sulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(biphenyl-4-sulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide (124 mg, 0.18 mmol) as a white solid (99 mg, 97%). 37

(394) HPLC (Method B): Rt 5.54 min (Purity 97.27%). LCMS (Method B): 560.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.55-8.52 (m, 1H), 7.93-7.91 (m, 2H), 7.80-7.74 (m, 5H), 7.54-7.44 (m, 3H), 5.32 (d, J=5.5 Hz, 1H), 4.43 (s, 1H), 3.66-3.61 (m, 4H), 3.32-3.23 (m, 4H), 2.98-2.92 (m, 3H), 2.24 (d, J=1.92 Hz, 2H), 1.76-1.66 (m, 2H), 1.53-1.43 (m, 1H), 1.18-1.15 (m, 2H), 0.76 (s, 3H), 0.75 (s, 3H).

Example 39

(R)-2,4-Dihydroxy-N-(3-[4-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-3-oxo-propyl)-3,3-dimethyl-butyramide

(395) ##STR00228##

(396) (R)-2,4-Dihydroxy-N-{3-[4-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[4-(2-methanesulfonylamino-ethoxy)-benzylcarbamoyl]-propyl}-amide (97 mg, 0.16 mmol) as a colorless liquid (14 mg, 18%).

(397) HPLC (Method B): Rt 3.63 min (Purity 99.18%). LCMS (Method B): 474.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.12-9.10 (m, 1H), 7.78-7.76 (m, 1H), 7.18 (d, J=4.0 Hz, 3H), 6.87 (d, J=4.8 Hz, 2H), 5.34 (d, J=5.2 Hz, 1H), 4.44 (t, J=4.0 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.67 (d, J=5.6 Hz, 2H), 3.36-3.15 (m, 5H), 2.98 (d, J=5.00 Hz, 2H), 2.93 (s, 3H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 40

(R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[3-(3-oxo-morpholin-4-yl)-propylcarbamoyl}-propyl)butyramide

(398) ##STR00229##

(399) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-oxo-3-[3-(3-oxo-morpholin-4-yl)-propylcarbamoyl]-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-3-3-oxo-morpholin-4-yl)-propylcarbamoyl]-propyl}-amide (94 mg, 0.18 mmol) as a brown gum (28 mg, 39%).

(400) HPLC (Method B): Rt 2.71 min (Purity 95.79%). LCMS (Method B): 388.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.65-8.64 (m, 1H), 7.85-7.83 (m, 1H), 5.34 (d, J=5.5 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.00 (s, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.67 (d, J=5.6 Hz, 1H), 3.35-3.25 (m, 7H), 3.17-2.94 (m, 5H), 1.67 (t, J=6.8 Hz, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 41

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-(4-morpholin-4-yl-benzylcarbamoyl)-3-oxo-propyl]-butyramide

(401) ##STR00230##

(402) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-(4-morpholin-4-yl-benzylcarbamoyl)-3-oxo-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-4-morpholin-4-yl-benzylcarbamoyl)-propyl]-amide (95 mg, 0.18 mmol) as a brown gum (29 mg, 39%).

(403) HPLC (Method B): Rt 3.75 min (Purity 95.51%). LCMS (Method B): 422.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.01-8.98 (m, 1H), 7.76-7.75 (m, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.33 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 3.72-3.66 (m, 5H), 3.32-3.25 (m, 3H), 3.17-3.13 (m, 1H), 3.05-2.86 (m, 6H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 42

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-phenoxy-ethylcarbamoyl)-propyl]-butyramide

(404) ##STR00231##

(405) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-(2-phenoxy-ethylcarbamoyl)-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-(2-phenoxy-ethylcarbamoyl)-propyl]-amide (81 mg, 0.17 mmol) as a colorless liquid (11 mg, 18%).

(406) HPLC (Method B): Rt 4.29 min (Purity 95.56%). LCMS (Method B): 367.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.75-8.70 (m, 1H), 7.75-7.70 (m, 1H), 7.29-7.25 (m, 2H), 6.94-6.91 (m, 3H), 5.34 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.03 (t, J=5.9 Hz, 2H), 3.67 (d, J=5.2 Hz, 1H), 3.50-3.25 (m, 5H), 3.15 (t, J=5.0 Hz, 1H), 3.00-2.96 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 43

(R)N-{3,4-Dioxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(407) ##STR00232##

(408) (R)N-{3,4-Dioxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-4-oxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl}-amide (143 mg, 0.26 mmol) as an off-white solid (77 mg, 66%).

(409) HPLC (Method B): Rt 5.55 min (Purity 97.61%). LCMS (Method A): 538.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.76 (t, J=5.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.19-7.15 (m, 3H), 6.58 (d, J=8.0 Hz, 1H), 5.39-5.37 (m, 1H), 4.30-4.29 (m, 1H), 4.10-4.09 (m, 1H), 3.70-3.62 (m, 3H), 3.40-3.24 (m, 6H), 2.93 (t, J=6.6 Hz, 2H), 1.94-1.90 (m, 2H), 1.41-1.11 (m, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 44

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(3-[4-(2-morpholin-4-yl-ethoxy)-benzylcarbamoyl]-3-oxo-propyl)-butyramide

(410) ##STR00233##

(411) (R)-2,4-Dihydroxy-3,3-dimethyl-N-{3-[4-(2-morpholin-4-yl-ethoxy)-benzylcarbamoyl]-3-oxo-propyl}-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-4-2-morpholin-4-yl-ethoxy)-benzylcarbamoyl]-propyl}-amide (54 mg, 0.1 mmol) as a colorless gum (27 mg, 63%).

(412) HPLC (Method B): Rt 3.79 min (Purity 93.47%). LCMS (Method B): 466.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.10-9.02 (m, 1H), 7.75-7.72 (m, 1H), 7.17 (d, J=4.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.34 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.22 (d, J=6.3 Hz, 2H), 4.03 (t, J=5.7 Hz, 2H), 3.62-3.61 (m, 1H), 3.56 (t, J=4.4 Hz, 4H), 3.38-3.13 (m, 4H), 3.00-2.96 (m, 2H), 2.65 (t, J=5.6 Hz, 2H), 2.50-2.44 (m, 4H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 45

4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-benzoic acid ethyl ester

(413) ##STR00234##

(414) 4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-benzoic acid ethyl ester was synthesized following the general procedure B starting from 4-[(2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]amino}-butyrylamino)-methyl]-benzoic acid ethyl ester (49 mg, 0.1 mmol) as a white solid (17 mg, 45%).

(415) HPLC (Method B): Rt 4.40 min (Purity 95.88%). LCMS (Method B): 409.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.28-9.26 (m, 1H), 7.89 (d, J=6.4 Hz, 2H), 7.82-7.80 (m, 1H), 7.40 (d, J=8.4 Hz, 2H), 5.35 (d, J=5.6 Hz, 1H), 4.45 (t, J=5.6 Hz, 1H), 4.36 (t, J=8.0 Hz, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.68 (d, J=5.6 Hz, 1H), 3.37-3.25 (m, 3H), 3.16 (t, J=5.2 Hz, 1H), 3.00-2.97 (m, 2H), 1.30 (t, J=7.0 Hz, 3H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 46

(R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-({1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-piperidin-4-ylmethyl}-carbamoyl)-propyl]-butyramide

(416) ##STR00235##

(417) (R)-2,4-Dihydroxy-3,3-dimethyl-N-[3-oxo-3-({1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-piperidin-4-ylmethyl}-carbamoyl)-propyl]-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid [3-hydroxy-3-{1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-piperidin-4-ylmethyl}-carbamoyl)-propyl]-amide (200 mg, 0.29 mmol) as a white solid (33 mg, 20%).

(418) HPLC (Method B): Rt 4.21 min (Purity 98.52%). LCMS (Method B): 567.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.65-8.62 (m, 1H), 7.91 (d, J=5.2 Hz, 2H), 7.90-7.69 (m, 3H), 5.33 (d, J=5.5 Hz, 1H), 3.87 (t, J=7.2 Hz, 2H), 3.66 (d, J=5.5 Hz, 1H), 3.56 (d, J=8.0 Hz, 2H), 3.32-3.14 (m, 4H), 2.97-2.92 (m, 4H), 2.56-2.51 (m, 3H), 2.15-2.05 (m, 4H), 1.71-1.62 (m, 2H), 1.49-1.32 (m, 1H), 1.17-1.05 (m, 2H), 0.76 (s, 3H), 0.75 (s, 3H).

Example 47

(R)-2,4-Dihydroxy-N-(3-[(1-methanesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl)-3,3-dimethyl-butyramide

(419) ##STR00236##

(420) (R)-2,4-Dihydroxy-N-{3-[(1-methanesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(1-methanesulfonyl-piperidin-4-ylmethyl)-carbamoyl]-propyl}-amide (128 mg, 0.24 mmol) as an off-white gum (50 mg, 50%).

(421) HPLC (Method B): Rt 3.21 min (Purity 98.08%). LCMS (Method B): 422.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.80-8.76 (m, 1H), 7.75-7.72 (m, 1H), 5.34 (d, J=5.5 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 3.67 (d, J=5.6 Hz, 1H), 3.51 (d, J=8.0 Hz, 2H), 3.37-3.25 (m, 3H), 3.16-3.12 (m, 2H), 3.04-2.94 (m, 3H), 2.82 (s, 3H), 2.69-2.59 (m, 2H), 1.71-1.55 (m, 3H), 1.15-1.12 (m, 2H), 0.78 (d, 3H), 0.77 (d, 3H).

Example 48

(R)N-(3-[(1-Acetyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(422) ##STR00237##

(423) (R)N-{3-[(1-Acetyl-piperidin-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-[(1-acetyl-piperidin-4-ylmethyl)-carbamoyl]-3-hydroxy-propyl}-amide (139 mg, 0.26 mmol) as a yellow gum (72 mg, 68%).

(424) HPLC (Method B): Rt 2.92 min (Purity 97.15%). LCMS (Method B): 386.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60-8.58 (m, 1H), 7.75-7.72 (m, 1H), 5.34 (d, J=5.4 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.30 (d, J=8.0 Hz, 1H), 3.75 (d, J=8.0 Hz, 1H), 3.67 (d, J=5.5 Hz, 1H), 3.37-2.93 (m, 8H), 2.51-2.44 (m, 1H), 1.95 (s, 3H), 1.90 (s, 1H), 1.56-1.60 (m, 3H), 1.06-0.88 (m, 2H), 0.77 (s, 3H), 0.76 (s, 3H).

Example 49

(R)-2,4-Dihydroxy-3,3-dimethyl-N-(4-morpholin-4-yl-3,4-dioxo-butyl)-butyramide

(425) ##STR00238##

(426) (R)-2,4-Dihydroxy-3,3-dimethyl-N-(4-morpholin-4-yl-3,4-dioxo-butyl)-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-di methyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-4-morpholin-4-yl-4-oxo-butyl)-amide (116 mg, 0.26 mmol) as an off-white solid (59 mg, 70%).

(427) HPLC (Method B): Rt 2.91 min (Purity 98.15%). LCMS (Method B): 317.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.79 (t, J=4.5 Hz, 1H), 5.37 (d, J=5.5 Hz, 1H), 4.45 (t, J=5.6 Hz, 1H), 3.68 (d, J=5.5 Hz, 1H), 3.59-3.53 (m, 4H), 3.48-3.26 (m, 7H), 3.28-3.17 (m, 1H), 2.93 (t, J=6.6 Hz, 2H), 0.77 (s, 3H), 0.75 (s, 3H).

Example 50

(R)-2,4-Dihydroxy-N-(3-[4-(2-methoxy-ethoxy)-benzylcarbamoyl]-3-oxo-propyl)-3,3-dimethyl-butyramide

(428) ##STR00239##

(429) (R)-2,4-Dihydroxy-N-{3-[4-(2-methoxy-ethoxy)-benzylcarbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-[4-(2-methoxy-ethoxy)-benzylcarbamoyl]-propyl}-amide (67 mg, 0.13 mmol) as a white solid (36 mg, 69%).

(430) HPLC (Method B): Rt 3.93 min (Purity 93.74%). LCMS (Method B): 411.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.15-9.13 (m, 1H), 7.75 (t, J=4.0 Hz, 1H), 7.17 (d, J=8.6 Hz, 2H), 6.85 (d, J=6.6 Hz, 2H), 5.34 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.22 (d, J=6.3 Hz, 2H), 4.05-4.03 (m, 2H), 3.68-3.61 (m, 3H), 3.32-3.13 (m, 7H), 3.00-2.96 (m, 2H), 0.77 (s, 3H), 0.75 (s, 3H).

Example 51

(R)N-(3-{[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(431) ##STR00240##

(432) (R)N-(3-{[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-hydroxy-propyl)-amide (99 mg, 0.16 mmol) as a white solid (36 mg, 45%).

(433) HPLC (Method B): Rt 4.69 min (Purity 99.15%). LCMS (Method B): 502.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.56 (s, 1H), 7.74-7.53 (m, 5H), 5.33 (d, J=5.6 Hz, 1H), 4.45-4.44 (m, 1H), 3.67-3.59 (m, 3H), 3.32-3.12 (m, 3H), 2.97-2.93 (m, 4H), 2.32-2.22 (m, 2H), 1.65 (m, 2H), 1.45-1.42 (m, 2H), 1.19-1.05 (m, 2H), 0.76 (s, 3H), 0.75 (s, 3H).

Example 52

(R)N-(3-{[1-(3-Fluoro-phenylmethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(434) ##STR00241##

(435) (R)N-(3-{[1-(3-Fluoro-phenylmethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-5,5-Dimethyl-2-phenyl-[1,3]dioxane-4-carboxylic acid (3-{[1-(3-fluoro-phenylmethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-3-oxo-propyl)-amide (98 mg, 0.12 mmol) as a white solid (28 mg, 44%).

(436) HPLC (Method B): Rt 4.67 min (Purity 97.86%). LCMS (Method B): 516.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.75-8.72 (m, 1H), 7.75-7.73 (m, 1H), 7.41 (t, J=4.0 Hz, 1H), 7.25-7.19 (m, 3H), 5.34 (d, J=5.6 Hz, 1H), 4.46-4.41 (m, 3H), 3.67 (d, J=5.4 Hz, 1H), 3.52 (m, 2H), 3.32-3.14 (m, 4H), 2.99-2.94 (m, 4H), 2.66 (m, 2H), 1.63-1.62 (m, 3H), 1.05-1.03 (m, 2H), 0.78 (s, 3H), 0.77 (s, 3H).

Example 53

(R)-2,4-Dihydroxy-N-{3-[(4-methanesulfonyl-biphenyl-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide

(437) ##STR00242##

(438) (R)-2,4-Dihydroxy-N-{3-[(4-methanesulfonyl-biphenyl-4-ylmethyl)-carbamoyl]-3-oxo-propyl}-3,3-dimethyl-butyramide was synthesized following the general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carboxylic acid {3-hydroxy-3-(4-methanesulfonyl-biphenyl-4-ylmethyl)-carbamoyl]-propyl}-amide (71 mg, 0.11 mmol) as an off-white solid (16 mg, 28%).

(439) HPLC (Method B): Rt 4.31 min (Purity 98.94%). LCMS (Method B): 491.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.17 (t, J=6.4 Hz, 1H), 7.99-7.90 (m, 4H), 7.72 (t, J=8.2 Hz, 3H), 7.41 (d, J=8.2 Hz, 2H), 5.35 (d, J=5.5 Hz, 1H), 4.45 (t, J=5.6 Hz, 1H), 4.37 (d, J=6.4 Hz, 2H), 3.68 (d, J=5.4 Hz, 1H), 3.37-2.98 (m, 9H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 54

4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butrylamino)-2-oxo-butyrylamino]-methyl}-benzoic acid

(440) ##STR00243##

(441) 4-{[4-((R)-2,4-Dihydroxy-3, 3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-benzoic acid was synthesized following the general procedure B starting from 4-[(2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5, 5-dimethyl-[1, 3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-benzoic acid methyl ester followed by hydrolysis using LiOH.H.sub.2O (2 eq) to afford a white solid (17 mg, 24%).

(442) HPLC (Method B): Rt 2.16 min (Purity 94.12%). LCMS (Method B): 381.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.88 (bs, 1H), 9.17 (t, J=6.4 Hz, 1H), 7.87 (d, J=6.6 Hz, 2H), 7.78 (t, J=5.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 5.35 (d, J=5.4 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H), 4.37 (d, J=6.3 Hz, 2H), 3.68 (d, J=5.6 Hz, 1H), 3.37-2.97 (m, 6H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 55

4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-biphenyl-4-carboxylic acid

(443) ##STR00244##

(444) 4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-biphenyl-4-carboxylic acid was synthesized following the general procedure B starting from 4-[(2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-biphenyl-4-carboxylic acid methyl ester followed by hydrolysis using LiOH.H.sub.2O (2 eq) to afford a pale yellow solid (35 mg, 50%).

(445) HPLC (Method B): Rt 3.08 min (Purity 95.35%). LCMS (Method B): 457.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.12 (s, 1H), 9.16 (t, J=6.4 Hz, 1H), 8.00 (d, J=6.4 Hz, 2H), 7.76 (d, J=2.0 Hz, 3H), 7.67 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 5.34 (d, J=1.8 Hz, 1H), 4.45 (s, 1H), 4.36 (d, J=6.4 Hz, 2H), 3.68 (d, J=5.2 Hz, 1H), 3.39-3.15 (m, 6H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 56

4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-biphenyl-4-carboxylic acid methyl ester

(446) ##STR00245##

(447) 4-{[4-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-2-oxo-butyrylamino]-methyl}-biphenyl-4-carboxylic acid methyl ester was synthesized following the general procedure E starting from 4-[(2-hydroxy-4-{[(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane-4-carbonyl]-amino}-butyrylamino)-methyl]-biphenyl-4-carboxylic acid methyl ester as a white solid (14 mg, 32%).

(448) HPLC (Method B): Rt 5.08 min (Purity 96.85%). LCMS (Method B): 471.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.16 (t, J=4 Hz, 1H), 8.02 (d, J=6.8 Hz, 2H), 7.79 (d, J=6.0 Hz, 3H), 7.68 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.35 (d, J=5.6 Hz, 1H), 4.45 (t, J=5.6 Hz, 1H), 4.36 (d, J=6.4 Hz, 2H), 3.86 (s, 3H), 3.68 (d, J=5.3 Hz, 1H), 3.37-3.13 (m, 3H), 3.02-2.98 (m, 3H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 57

(R)N-[2-(2-Chloro-acetylamino)-ethyl]-2,4-dihydroxy-3,3-dimethyl-butyramide

(449) ##STR00246##

(450) (R)N-[2-(2-Chloro-acetylamino)-ethyl]-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)N-(2-amino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide (148 mg, 0.72 mmol) as a colorless gum (147 mg, 76%).

(451) HPLC (Method A ELSD): Rt 1.35 min (Purity 99.62%). LCMS (Method A): 267.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.20 (s, 1H), 7.81 (d, J=5.4 Hz, 1H), 5.36 (d, J=5.5 Hz, 1H), 4.46 (t, J=5.6 Hz, 1H), 4.03 (s, 2H), 3.70 (d, J=5.4 Hz, 1H), 3.32-3.19 (m, 5H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 58

(R)N-{2-[(2-Chloro-acetyl)-(3-phenyl-propyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(452) ##STR00247##

(453) (R)N-{2-[(2-Chloro-acetyl)-(3-phenyl-propyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)-2,4-dihydroxy-3,3-dimethyl-N-[2-(3-phenyl-propylamino)-ethyl]-butyramide (34 mg, 0.11 mmol) as a colorless gum (13 mg, 30%).

(454) HPLC (Method A ELSD): Rt 3.57 min (Purity 98.28%). LCMS (Method A): 385.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.93 (s, 1H), 7.28-7.16 (m, 5H), 5.47 (d, J=5.4 Hz, 2H), 4.46 (s, 1H), 4.36 (s, 2H), 3.72-3.71 (m, 3H), 3.32-3.14 (m, 4H), 2.55-2.44 (m, 2H), 1.82-1.75 (m, 3H), 0.8 (s, 3H), 0.78 (s, 3H).

Example 59

(R)N-{2-[(2-Chloro-acetyl)-phenethyl-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(455) ##STR00248##

(456) (R)N-{2-[(2-Chloro-acetyl)-phenethyl-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)-2,4-dihydroxy-3,3-dimethyl-N-(2-phenethylamino-ethyl)-butyramide (162 mg, 0.55 mmol) as an off white gum (34 mg, 36%).

(457) HPLC (Method A): Rt 3.24 min (Purity 99.49%). LCMS (Method A): 371.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.92-7.72 (m, 1H), 7.29-7.20 (m, 5H), 5.47-5.35 (m, 1H), 4.47-4.44 (m, 1H), 4.36 (s, 1H), 4.20 (s, 1H), 3.69 (d, J=5.1 Hz, 1H), 3.50-3.24 (m, 8H), 2.85-2.75 (m, 2H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 60

(R)N-{2-[Benzyl-(2-chloro-acetyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(458) ##STR00249##

(459) (R)N-{2-[Benzyl-(2-chloro-acetyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)N-(2-benzylamino-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide (77 mg, 0.26 mmol) as a colorless gum (71 mg, 76%).

(460) HPLC (Method A): Rt 3.10 min (Purity 99.75%). LCMS (Method A): 357.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.94 (s, 1H), 7.39-7.20 (m, 5H), 5.47 (s, 1H), 4.61-4.37 (m, 5H), 3.72-3.68 (m, 1H), 3.32-3.13 (m, 6H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 61

(R)N-(2-{(2-Chloro-acetyl)-[2-(4-cyano-phenoxy)-ethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(461) ##STR00250##

(462) (R)N-(2-{(2-Chloro-acetyl)-[2-(4-cyano-phenoxy)-ethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)N-{2-[2-(4-cyano-phenoxy)-ethylamino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide (332 mg, 0.99 mmol) as an off-white solid (98 mg, 24%).

(463) HPLC (Method A): Rt 3.05 min (Purity 99.75%). LCMS (Method A): 412.3 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.79-7.75 (m, 3H), 7.12 (d, J=8.8 Hz, 2H), 5.49-5.34 (m, 1H), 4.48-4.42 (m, 3H), 4.25-4.16 (m, 2H), 3.76-3.64 (m, 3H), 3.44-3.24 (m, 6H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 62

(R)N-(2-{(2-Chloro-acetyl)-[1-(4-cyano-phenyl)-piperidin-4-ylmethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(464) ##STR00251##

(465) (R)N-(2-{(2-Chloro-acetyl)-[1-(4-cyano-phenyl)-piperidin-4-ylmethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)N-(2-{[1-(4-cyano-phenyl)-piperidin-4-ylmethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide (25 mg, 0.06 mmol) as an off-white solid (10 mg, 33%).

(466) HPLC (Method A): Rt 3.38 min (Purity 90.54%). LCMS (Method A): 465.2 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.92 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.46 (s, 1H), 4.48-4.35 (m, 4H), 3.94-3.90 (m, 3H), 3.71 (t, J=4.3 Hz, 1H), 3.25-3.23 (m, 4H), 2.86-2.75 (m, 3H), 1.91 (bs, 1H), 1.60-1.58 (m, 2H), 1.23-1.12 (m, 3H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 63

(R)N-{2-[(2-Chloro-acetyl)-(2-phenoxy-ethyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(467) ##STR00252##

(468) (R)N-{2-[(2-Chloro-acetyl)-(2-phenoxy-ethyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)-2,4-dihydroxy-3,3-dimethyl-N-[2-(2-phenoxy-ethylamino)-ethyl]-butyramide (396 mg, 1.27 mmol) as a beige gum (74 mg, 15%).

(469) HPLC (Method A): Rt 3.29 min (Purity 98.05%). LCMS (Method A): 387.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.02-7.79 (m, 1H), 7.31-7.25 (m, 2H), 6.94-6.92 (m, 3H), 5.75-5.33 (m, 1H), 4.48-4.42 (m, 3H), 4.13-4.04 (m, 2H), 3.74-3.62 (m, 3H), 3.44-3.23 (m, 6H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 64

(R)N-(2-{(2-Chloro-acetyl)-[2-(4-methanesulfonyl-phenoxy)-ethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide

(470) ##STR00253##

(471) (R)N-(2-{(2-Chloro-acetyl)-[2-(4-methanesulfonyl-phenoxy)-ethyl]-amino}-ethyl)-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)-2,4-dihydroxy-N-{2-[2-(4-methanesulfonyl-phenoxy)-ethylamino]-ethyl}-3,3-dimethyl-butyramide (38 mg, 0.11 mmol) as a brown gum (20 mg, 44%).

(472) HPLC (Method B): Rt 3.81 min (Purity 95.91%). LCMS (Method A): 465.0 (M+H.sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.97 (s, J=4.0 Hz 1H), 7.85 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 5.50-5.35 (m, 2H), 4.49-4.42 (m, 3H), 4.26-4.12 (m, 3H), 3.77-3.66 (m, 4H), 3.32-3.30 (m, 3H), 3.14 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 65

4-(2-{(2-Chloro-acetyl)-[2-((R)-2,4-dihydroxy-3,3-dimethyl-butyrylamino)-ethyl]-amino}-ethoxy)-benzoic acid methyl ester

(473) ##STR00254##

(474) 4-(2-{(2-Chloro-acetyl)-[2-((R)-2,4-di hydroxy-3,3-dimethyl-butyrylamino)-ethyl]-amino}-ethoxy)-benzoic acid methyl ester was synthesized following the general procedure H starting from 4-{2-[2-((R)-2,4-dihydroxy-3,3-dimethyl-butyrylamino)-ethylamino]-ethoxy}-benzoic acid methyl ester (33 mg, 0.09 mmol) as a yellow gum (4 mg, 10%).

(475) HPLC (Method A): Rt 3.21 min (Purity 96.01%). LCMS (Method A): 445.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.92-7.88 (m, 3H), 6.52 (d, J=8.0 Hz, 2H), 5.49-5.35 (m, 1H), 4.48-4.46 (m, 3H), 4.42-4.25 (m, 4H), 3.80 (s, 3H), 3.76-3.66 (m, 3H), 3.43-3.18 (m, 4H), 0.80 (s, 3H), 0.78 (s, 3H).

Example 66

(R)N-{2-[[(2-(4-Bromo-phenoxy)-ethyl]-(2-chloro-acetyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide

(476) ##STR00255##

(477) (R)N-{2-[[2-(4-Bromo-phenoxy)-ethyl]-(2-chloro-acetyl)-amino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide was synthesized following the general procedure H starting from (R)N-{2-[2-(4-bromo-phenoxy)-ethylamino]-ethyl}-2,4-dihydroxy-3,3-dimethyl-butyramide (577 mg, 1.55 mmol) as a yellow gum (190 mg, 18%).

(478) HPLC (Method A): Rt 3.86 min (Purity 98.1%). LCMS (Method A): 465.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.95 (t, J=4.0 Hz, 1H), 7.46-7.42 (m, 2H), 6.93-6.91 (m, 2H), 5.49-5.34 (m, 1H), 4.47-4.42 (m, 4H), 4.13-4.05 (m, 2H), 3.73-3.63 (m, 3H), 3.42-3.18 (m, 5H), 0.8 (s, 3H), 0.78 (s, 3H).

(479) Vanin-1 Enzymatic Assay:

(480) Human recombinant Vanin-1 (VNN1) was purchased from Sino Biological Inc. (Catalog Number: 11662-H08H).

(481) Measurement of VNN1 inhibition is performed in 384-well format based on fluorescence intensity assay. Purified recombinant human Vanin-1 (0.5 nM) and threefold serial diluted compounds in 3% DMSO (range of concentrations from 30 M to 1.524 nM) or controls (3.0% DMSO) are incubated for 30 minutes at 30 C. with gentle agitation in assay buffer containing 100 mM potassium Phosphate Buffer (KPi), pH 7.5, 0.001% Bovine Serum Albumin (BSA), 0.5 mM dithiothreitol (DTT) and 0.0025% Brij-35. The reaction is initiated by the addition of the fluorogenic substrate, Pantothenate-AMC, at a concentration of 30 M. After 60 minutes of incubation at 30 C. with gentle agitation, fluorescence intensity is measured at .sub.ex=350 nm and .sub.em=450 nm with a fluorescence reader (BMG PHERAstar reader or equivalent).

(482) Vanin-1 Cell-Based Mechanistic Assay:

(483) The cellular activity of the examples is measured in 96-well format based on fluorescence intensity assay using SUIT-S2 cell line (ATCC # CRL1596).

(484) Cells are cultured at 37 C. with 5% CO.sub.2 to 80-90% confluence and then washed once with phosphate-buffered saline (PBS). Adherent cells are detached with PBS-EDTA and once in suspension 40000 cells are dispensed in 90 l of PBS in 96-well black plates with clear bottoms. Threefold serial dilutions of test compounds are made in DMSO and then solubilized in PBS, dilution range 1:30. Cells and serial diluted test compounds (final concentrations 10 M to 4.6 nM) or controls (PBS/0.3% DMSO) are incubated for 2 hours at 37 C. with 5% CO.sub.2. The reaction is initiated by the addition of the fluorogenic substrate, Pantothenate-AMC, at a concentration of 30 M. After 30 minutes of incubation at 30 C. with gentle agitation, fluorescence intensity is measured at .sub.ex=350 nm and .sub.em=450 nm with a fluorescence reader (BMG PHERAstar reader or equivalent).