Necrosis inhibitors

Abstract

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

Claims

1. A pharmaceutical composition comprising an inhibitor of cellular necrosis and/or human receptor interacting protein 1 (RIP1) kinase selected from an amide, or a pharmaceutically acceptable salt, hydrate or stereoisomer of the amide, the composition formulated in a unit dosage form with a pharmaceutically-acceptable excipient, and suitable for administration to a person in need thereof, the amide of formula: ##STR00330## wherein: R.sub.1 is phenyl or phenyl substituted only with one or more of: CH.sub.3, COOCH.sub.3, OH, OCH.sub.3OCH.sub.2CH.sub.2OH, OCF.sub.3, CN, F, Cl or Br; R.sub.2 is hydroxyl or methyl; R.sub.3 is H; and R.sub.4 is 1,1-dimethylpropyl or 1,1-dimethylprop-1-enyl, optionally fluorinated.

2. The composition of claim 1, wherein R.sub.1 is phenyl or F-, Cl- or Br-substituted phenyl.

3. The composition of claim 1, wherein R.sub.2 is hydroxyl.

4. The composition of claim 2, wherein R.sub.2 is hydroxyl.

5. The composition of claim 1, wherein R.sub.4 is 1,1-dimethylpropyl, optionally fluorinated.

6. The composition of claim 2, wherein R.sub.4 is 1,1-dimethylpropyl, optionally fluorinated.

7. The composition of claim 3, wherein R.sub.4 is 1,1-dimethylpropyl, optionally fluorinated.

8. The composition of claim 4, wherein R.sub.4 is 1,1-dimethylpropyl, optionally fluorinated.

9. The composition of claim 1, the amide having a formula of Table 1: TABLE-US-00015 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 31 32 33 48 49 50 51 56 57 58 75 90 91 92 93 94 95 96 97 98 99 147 S5 S6 S7 S8 S9 S10 S11 S12 S13 S14

10. A pharmaceutical composition of claim 1 wherein the form is a pill, tablet, capsule, or lozenge, and the dosage is 1 to 1000 mg.

11. A method of inhibiting human receptor interacting protein 1 (RIP1) kinase, comprising administering an effective amount of a composition of claim 1 to a patient in need thereof.

12. A method of inhibiting human receptor interacting protein 1 (RIP1) kinase, comprising administering an effective amount of a composition of claim 1 to a patient in need thereof, and further comprising the antecedent step of diagnosing a disease or condition associated with the need for inhibiting the kinase, or the subsequent step of detecting a resultant amelioration of the disease or condition.

Description

EXAMPLES

(1) TABLE-US-00012 TABLE 1 1. Compound List 1 2 3 0 4 5 6 7 8 9 10 11 12 13 0 14 15 16 17 18 19 20 21 22 23 0 24 25 26 27 28 29 30 31 32 33 0 34 35 36 37 38 39 40 41 42 43 0 44 45 46 47 48 49 50 51 52 53 0 54 55 56 57 58 59 60 61 62 63 0 64 65 66 67 68 69 70 71 72 73 0 74 75 76 77 78 79 80 81 82 83 00 84 01 85 02 86 03 87 04 88 05 89 06 90 07 91 08 92 09 93 0 94 95 96 97 98 99 100 101 102 103 0 104 105 106 107 108 109 110 111 112 113 0 114 115 116 117 118 119 120 121 122 123 0 124 125 126 127 128 129 130 131 132 133 0 134 135 136 137 138 139 140 141 142 143 0 144 145 146 147 148 149 150 151 S1 S2 0 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 0 S13 S14 S15 S16 S17 S18 S19 S20

2. Compound Preparation

Compound 1 Preparation of N-(2-fluorobenzyl)-2,2-dimethylbutanamide

(2) ##STR00188##

(3) SOCl.sub.2 (30 ml) was added to the 2,2-dimethylbutanoic acid (5.22 g) in toluene with stirring. Then the reaction mixture was warmed to 80 C. for 5 h. After removal of the solvent, 4.268 g of 2,2-dimethylbutanoyl chloride was obtained, which was dissolved in DCM and added dropwise to the (2-fluorophenyl)methanamine (1.698 g) dissolved in DCM contains TEA (4.8 g) at 0 C. Stirring was continued at room temperature for 10 h. After all amines had been consumed as judged by TLC, the mixture was quenched with ice-water. Extracted with DCM, dried over Na.sub.2SO.sub.4, concentrated and purified by silca gel chromatography to give the desired product (2.57 g, 72.6%). .sup.1H NMR (CDCl.sub.3): 7.30-7.34 (m, 1H), 7.23-7.25 (m, 1H), 7.00-7.11 (m, 2H), 6.06 (br, 1H), 4.48 (d, 2H, J=6.0 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.16 (s, 6H), 0.81 (t, 3H, J=7.6 Hz).

Compound 2 Preparation of N-benzylpivalamide

(4) ##STR00189##

(5) Phenylmethanamine (80.3 mg) and triethylamine 0.625 ml) were dissolved in DCM (2 ml), pivaloyl chloride (120 mg) was added at 0 C. and the mixture was stirred at room temperature for 3 h. The mixture was quenched with ice-water. Extracted with DCM, dried over Na.sub.2SO.sub.4, concentrated and purified by silca gel chromatography to give the desired product (58.6 mg, 40.9%). .sup.1H NMR (CDCl.sub.3): 7.25-7.37 (m, 5H), 5.89 (br, 1H), 4.45 (d, 2H, J=5.6 Hz), 1.23 (s, 9H).

Compound 3 Preparation of N-(2-bromobenzyl)-2,2-dimethylbutanamide

(6) ##STR00190##

(7) The titled compound 3 was prepared in 58.3% from (2-bromophenyl)methanamine (93 mg) and 2,2-dimethylbutanoyl chloride (80.76 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 7.55 (d, 1H, J=8.0 Hz), 7.37-7.40 (m, 1H), 7.26-7.30 (m, 1H), 7.12-7.17 (m, 1H) 6.14 (br, 1H), 4.50 (d, 2H, J=6.0 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.16 (s, 6H), 0.80 (t, 3H, J=7.6 Hz).

Compound 4 Preparation of 2,2-dimethyl-N-(2-(trifluoromethyl)benzyl)butanamide

(8) ##STR00191##

(9) The titled compound 4 was prepared in 71% from 2-(trifluoromethyl)phenyl)-

(10) methanamine (87.6 mg) and 2,2-dimethylbutanoyl chloride (105 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 7.64-7.66 (d, 1H, J=8.0 Hz), 7.50-7.56 (m, 2H), 7.36-7.40 (m, 1H), 5.97 (br, 1H), 4.62 (d, 2H, J=4.8 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.15 (s, 6H), 0.80 (t, 3H, J=7.6 Hz).

Compound 5 Preparation of N-(3-fluorobenzyl)-2,2-dimethylbutanamide

(11) ##STR00192##

(12) The titled compound 5 was prepared in 70% yield from (3-fluorophenyl)methanamine (93 mg) and 2,2-dimethylbutanoyl chloride (80.74 mg) according to the procedure outlined for compound 1. .sup.1H NMR (400 MHz, CDCl.sub.3) :7.33-7.27 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.93-6.98 (m, 2H), 4.45 (d, J=5.8 Hz, 2H), 1.58 (q, J=7.5 Hz, 3H), 1.19 (s, 6H), 0.86 (t, J=7.5 Hz, 3H).

Compound 6 Preparation of N-(3-bromobenzyl)-2,2-dimethylbutanamide

(13) ##STR00193##

(14) The titled compound 6 was prepared in 87% from (3-bromophenyl)methanamine (93 mg) and 2,2-dimethylbutanoyl chloride (105 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 7.38-7.41 (m, 2H), 7.17-7.21 (m, 2H), 5.96 (br, 1H), 4.42 (d, 2H, J=6.0 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.15 (s, 6H), 0.80 (t, 3H, J=7.6 Hz).

Compound 7 Preparation of N-(2,4-difluorobenzyl)-2,2-dimethylbutanamide

(15) ##STR00194##

(16) The titled compound 7 was prepared in 40.9% yield form (2,4-difluorophenyl)methanamine (228.8 mg) and 2,2-dimethylbutanoyl chloride (430.3 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 7.30-7.36 (m, 1H), 6.77-6.86 (m, 2H), 5.97 (br, 1H), 4.44 (d, 2H, J=6.0 Hz), 1.55 (q, 2H, J=7.6 Hz), 1.17 (s, 6H), 0.80 (t, 3H, J=7.6 Hz).

Compound 8 Preparation of N-(3,4-difluorobenzyl)-2,2-dimethylbutanamide

(17) ##STR00195##

(18) The titled compound 8 was prepared in 71.3% yield form (3,4-difluorophenyl)methanamine (114.4 mg) and 2,2-dimethylbutanoyl chloride (215 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 7.06-7.14 (m, 2H), 6.97-7.00 (m, 1H), 5.95 (br, 1H), 4.40 (d, 2H, J=6.0 Hz), 1.56 (q, 2H, J=7.6 Hz), 1.17 (s, 6H), 0.84 (t, 3H, J=7.6 Hz).

Compound 9 Preparation of 2,2-dimethyl-N-(pyridin-3-ylmethyl)butanamide

(19) ##STR00196##

(20) The titled compound 9 was prepared in 51.2% yield form pyridin-3-ylmethanamine (54.07 mg) and 2,2-dimethylbutanoyl chloride (134.6 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3): 8.52 (s, 2H) 7.61-7.64 (m, 1H), 7.25-7.28 (m, 1H), 6.05 (br, 1H), 4.47 (d, 2H, J=6.0 Hz), 1.58 (q, 2H, J=7.6 Hz), 1.18 (s, 6H), 0.84 (t, 3H, J=7.6 Hz).

Compound 10 Preparation of N-ethyl-N-(2-fluorobenzyl)-2,2-dimethylbutanamide

(21) ##STR00197##

(22) N-(2-fluorobenzyl)-2,2-dimethylbutanamide (40 mg) was dissolved in 4 ml of dry DMF, 8.61 mg of NaH was added at 0 C. under N2 and stirred for 2 h. Iodoethane (56.2 mg) was added and the mixture was allowed to warm to room temperature and stirred for 11 h. The mixture was quenched with cold water and extracted with DCM, the combined organic layers was washed with water, brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by silica gel column chromatography to give the product (9.3 mg, 20.6%). .sup.1H NMR (CDCl.sub.3): 7.22-7.26 (m, 2H), 7.03-7.12 (m, 2H), 4.69 (s, 2H), 3.43 (d, 2H, J=5.2 Hz), 1.67 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 1.17 (t, 3H, J=6.8 Hz), 0.89 (t, 3H, J=7.6 Hz).

Compound 11 Preparation of N-(2-fluorobenzyl)-2,2-dimethyl-N-(prop-2-yn-1-yl)butanamide

(23) ##STR00198##

(24) N-(2-fluorobenzyl)prop-2-yn-1-amine was prepared in 42% yield according to the procedure outlined for compound 10, 68.2 mg of the amide was used as starting

(25) Material and reacted with 2,2-dimethylbutanoyl chloride (170 mg) and the desired compound 11 was prepared in 30% yield. .sup.1H NMR (CDCl.sub.3): 7.23-7.26 (m, 2H), 7.03-7.13 (m, 2H), 4.83 (s, 2H), 4.15 (d, 2H, J=2.4 Hz), 2.23 (t, 1H, J=2.4 Hz), 1.70 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.89 (t, 3H, J=7.6 Hz).

Compound 12 Preparation of N-(2-fluorobenzyl)-2,2-dimethyl-N-(3-oxobutyl)butanamide

(26) ##STR00199##

(27) A mixture of (2-fluorophenyl)methanamine (125 mg), paraformaldehyde (36 mg), acetone (116 mg) and concentrated hydrochloric acid (0.1 ml) in EtOH (1 ml) was heated in a sealed flask at 110 C. for 16 h After the mixture was cooled to room temperature, the solvent was removed and EtOAc was added, the resulting suspension was vigorously stirred for 1 h and then filtered and washed with EtOAc to afford 200 mg of 4-((2-fluorobenzyl)amino)butan-2-one, which was used directly in the next step without further purification.

(28) The resulting amide (200 mg) was dissolve in dry THF (10 ml), and TEA (0.3 ml) was added. The mixture was cooled to 0 C., 2,2-dimethylbutanoylchloride (274 mg) was added and stirred for 4 h at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic layer were washed with brine and dried over Na.sub.2SO.sub.4. After removal of the solvent, the residue was purified by silica gel chromatography to afford the compound 12 (180 mg, 60%). .sup.1H NMR (CDCl.sub.3): 7.23-7.28 (m, 1H), 7.10-7.19 (m, 2H), 7.02-7.07 (m, 1H), 4.75 (s, 2H), 3.54 (br, 2H), 2.77 (t, 2H, J=7.2 Hz), 2.13 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.23 (s, 6H), 0.89 (t, 3H, J=7.6 Hz).

Compound 13: Preparation of N-(2-fluorobenzyl)-N,2,2-trimethylbutanamide

(29) ##STR00200##

(30) Reagent and conditions: (a): (1) CH.sub.3NH.sub.2.HCl, K.sub.2CO.sub.3, MeOH, rt, 1.5 h; (b): NaBH.sub.4 (c) 2,2-dimethylbutanoyl chloride, DIEA, THF, rt, 2 h.

(31) A mixture of K.sub.2CO.sub.3 (207 mg, 1.5 mmoL) and methanamine hydrochloride (202 mg, 3.0 mmoL) in 5 mL of MeOH was stirred at room temperature for 30 min. Then 2-fluorobenzaldehyde (248 mg, 2.0 mmoL) was added to the mixture and stirred at room temperature for 1 h. The mixture was cooled to 0 C., and NaBH.sub.4 (113.5 mg, 3.0 mmoL) was added in portions. The mixture was stirred at 0 C. for 1 h. The solid was filtered and washed with EtOAc. The filtrate was evaporated to dryness and the

(32) residue was dissolved in EtOAc and was washed with water, brine, dried over Na.sub.2SO.sub.4. The residue was dissolved in 10 mL of dry THF. DIEA (264 mg, 2.05 mmoL) was added, 2,2-dimethylbutanoyl chloride (275 mg, 2.05 mmoL) was added slowly to the solution at 0 C. under nitrogen, then stirred at room temperature for 2 h. 15 mL of water was added to the solution and extracted with EtOAc (10 mL3). The combined organic was washed with 1M HCl, brine, dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/2) to give the 230 mg of 1 as a brown solid (total yield=45.1%).

(33) .sup.1H NMR (CDCl.sub.3, 400 M Hz): (ppm) 7.22-7.28 (m, 2H), 7.01-7.12 (m, 2H), 4.68 (s, 2H), 3.05 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.89 (t, 3H, J=7.6 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20FNO, 238.2; found, 238.4.

Compound 14: Preparation of N-(2-chlorobenzyl)-N,2,2-trimethylbutanamide

(34) ##STR00201##

(35) The titled compound 14 was prepared in 48% yield from 2-chlorobenzaldehyde (281 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.35-7.37 (m, 1H), 7.16-7.25 (m, 3H), 4.74 (s, 2H), 3.05 (s, 3H), 1.70 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20ClNO, 254.2; found, 254.4.

Compound 15: Preparation of N-(2-methoxybenzyl)-N,2,2-trimethylbutanamide

(36) ##STR00202##

(37) The titled compound 15 was prepared in 65% yield from 2-methoxybenzaldehyde (136 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.21-7.26 (m, 1H), 7.09-7.13 (m, 1H), 6.86-6.95 (m, 2H), 4.66 (s, 2H), 3.83 (s, 3H), 2.99 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.90 (t, 3H, J=7.6 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.23NO.sub.2, 250.1; found 250.3.

Compound 16: Preparation of N-(3-fluorobenzyl)-N,2,2-trimethylbutanamide

(38) ##STR00203##

(39) The titled compound 16 was prepared in 65% yield from 3-fluorobenzaldehyde (124 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.25-7.31 (m, 1H), 6.91-7.01 (m, 3H), 4.61 (s, 2H), 3.01 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20FNO, 238.1; found 238.4.

Compound 17: Preparation of N-(3-cyanobenzyl)-N,2,2-trimethylbutanamide

(40) ##STR00204##

(41) The titled compound 17 was prepared in 62% yield from 3-formylbenzonitrile (131 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.41-7.56 (m, 4H), 4.61 (s, 2H), 3.05 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.20N.sub.2O, 245.1; found 245.3.

Compound 18: Preparation of N-(3-chlorobenzyl)-N,2,2-trimethylbutanamide

(42) ##STR00205##

(43) The titled compound 18 was prepared in 48% yield from 3-chlorobenzaldehyde (140 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.20-7.26 (m, 3H), 7.10-7.12 (m, 1H), 4.59 (s, 2H), 3.01 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20ClNO, 254.1; found 254.3.

Compound 19: Preparation of N-(3-bromobenzyl)-N,2,2-trimethylbutanamide

(44) ##STR00206##

(45) The titled compound 19 was prepared in 48% yield from 3-bromobenzaldehyde (185 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7 7.36-7.40 (m, 2H), 7.16-7.22 (m, 2H), 4.59 (s, 2H), 3.01 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20BrNO, 298.1; found, 298.3, 300.4.

Compound 20: Preparation of N-(3-methoxybenzyl)-N,2,2-trimethylbutanamide

(46) ##STR00207##

(47) The titled compound 8 was prepared in 57% yield from 3-methoxybenzaldehyde (136 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.22-7.25 (m, 1H), 6.76-6.81 (m, 3H), 4.61 (s, 2H), 3.78 (s, 3H), 2.98 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.23NO.sub.2, 250.2; found 250.4.

Compound 21: Preparation of N-(3-hydroxybenzyl)-N,2,2-trimethylbutanamide

(48) ##STR00208##

(49) The titled compound 21 was prepared in 33% yield from 3-hydroxybenzaldehyde (122 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.17 (t, 1H, J=7.6 Hz), 6.71-6.79 (m, 3H), 4.58 (s, 2H), 2.98 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.21NO.sub.2, 236.2; found, 236.4.

Compound 22: Preparation of N-(3-(2-hydroxyethoxy)benzyl)-N,2,2-trimethylbutanamide

(50) ##STR00209##

(51) The titled compound 22 was prepared in 48% yield from 4-(2-hydroxyethoxy)benzaldehyde (166 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.14-7.17 (m, 2H), 6.85-6.89 (m, 2H), 4.56 (s, 2H), 4.06-4.08 (m, 2H), 3.94-3.96 (m, 2H), 2.96 (s, 3H), 1.67 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.25NO.sub.3, 280.2; found, 280.4.

Compound 23

Preparation of methyl 3-((N,2,2-trimethylbutanamido)methyl)benzoate

(52) ##STR00210##

(53) The titled compound 23 was prepared in 46% yield from methyl 3-formylbenzoate (164 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.87-7.94 (m, 2H), 7.38-7.45 (m, 2H), 4.66 (s, 2H), 3.90 (s, 3H), 3.01 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.16H.sub.23NO.sub.3, 278.2; found, 278.4.

Compound 24: Preparation of N-(2,4-difluorobenzyl)-N,2,2-trimethylbutanamide

(54) ##STR00211##

(55) The titled compound 24 was prepared in 56% yield from 2,4-difluorobenzaldehyde (284 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.25-7.31 (m, 1H), 6.76-6.86 (m, 2H), 4.60 (s, 2H), 3.06 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.19F.sub.2NO, 256.1; found, 256.3.

Compound 25: Preparation of N-(2,5-difluorobenzyl)-N,2,2-trimethylbutanamide

(56) ##STR00212##

(57) The titled compound 25 was prepared in 59% yield from 2,5-difluorobenzaldehyde (284 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 6.89-7.02 (m, 3H), 4.63 (s, 2H), 3.08 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.19F.sub.2NO, 256.1; found, 256.4.

Compound 26: Preparation of N-(3,5-difluorobenzyl)-N,2,2-trimethylbutanamide

(58) ##STR00213##

(59) The titled compound 14 was prepared in 59% yield from 3,5-difluorobenzaldehyde (284 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 1. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 6.89-6.75 (m, 3H), 4.57 (s, 2H), 3.04 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.19F.sub.2NO, 256.1; found, 256.3.

Compound 27: Preparation of N-(4-chloro-2-fluorobenzyl)-N,2,2-trimethylbutanamide

(60) ##STR00214##

(61) The titled compound 27 was prepared in 59% yield from 4-chloro-2-fluorobenzaldehyde (316 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoylchloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.21-7.26 (m, 1H), 7.05-7.11 (m, 2H), 4.60 (s, 2H), 3.06 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.19ClFNO, 272.1; found, 272.4.

Compound 28: Preparation of N-(2-fluoro-4-methoxybenzyl)-N,2,2-trimethylbutanamide

(62) ##STR00215##

(63) The titled compound 16 was prepared in 57% yield from 2-fluoro-4-methoxybenzaldehyde (208 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.20 (t, 1H, J=8.8 Hz), 6.57-6.67 (m, 2H), 4.59 (s, 2H), 3.78 (s, 3H), 3.01 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.15H.sub.22FNO.sub.2, 268.2; found, 268.4.

Compound 29: Preparation of N-(2,4-difluorobenzyl)-N-ethyl-2,2-dimethylbutanamide

(64) ##STR00216##

(65) The titled compound 29 was prepared in 57% yield from 2,4-difluorobenzaldehyde (284 mg), ethylamine hydrochloride (248 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.22-7.26 (m, 1H), 6.74-6.83 (m, 2H), 4.59 (s, 2H), 3.41-3.42 (m, 2H), 1.63 (q, 2H, J=7.6 Hz), 1.23 (s, 6H), 1.15 (t, 3H, J=7.6 Hz), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.15H.sub.21F.sub.2NO, 270.2; found, 270.4.

Compound 30

Preparation of N,2,2-trimethyl-N-(3-nitro-4-(piperidin-1-yl)benzyl)butanamide

(66) ##STR00217##

(67) The titled compound 30 was prepared in 66% yield from 3-nitro-4-(piperidin-1-yl)benzaldehyde (234 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (193 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.61 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=8.4, 2.4 Hz), 7.16 (d, 1H, J=8.4 Hz), 4.54 (s, 2H), 3.03-3.06 (m, 7H), 1.73-1.77 (m, 4H), 1.68 (q, 2H, J=7.6 Hz), 1.57-1.62 (m, 2H), 1.28 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.19H.sub.29N.sub.3O.sub.3, 348.2; found 348.4.

Compound 31: Preparation of N-(2,3-dimethylbenzyl)-N,2,2-trimethylbutanamide

(68) ##STR00218##

(69) The titled compound 31 was prepared in 76% yield from 2,3-dimethylbenzaldehyde (134 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (134 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.05-7.09 (m, 2H), 6.93-6.95 (m, 1H), 4.65 (s, 2H), 2.97 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.92 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.16H.sub.25NO, 248.2; found 248.4.

Compound 32: Preparation of N-(3,5-dimethylbenzyl)-N,2,2-trimethylbutanamide

(70) ##STR00219##

(71) The titled compound 32 was prepared in 76% yield from 3,5-dimethylbenzaldehyde (134 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (134 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 6.89 (s, 1H), 6.82 (s, 2H), 4.57 (s, 2H), 2.96 (s, 3H), 2.29 (s, 6H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.16H.sub.25NO, 248.2; found 248.4.

Compound 33: Preparation of N-(2-fluoro-3-(trifluoromethoxy)benzyl)-N,2,2-trimethylbutanamide

(72) ##STR00220##

(73) The titled compound 33 was prepared in 76% yield from 2-fluoro-3-(trifluoromethoxy)benzaldehyde (192 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (134 mg) according to the procedure outlined for compound 13. .sup.1H NMR (CDCl.sub.3, 400 M Hz): 7.51 (t, 2H, J=7.2 Hz), 7.20 (t, 1H, J=7.6 Hz), 4.68 (s, 2H), 3.11 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.19F.sub.4NO.sub.2, 322.1; found 322.3.

Compound 34: Preparation of N,2,2-trimethyl-N-(pyridin-4-ylmethyl)butanamide

(74) ##STR00221##

(75) The titled compound 34 was prepared in 86% yield from isonicotinaldehyde (214 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (289 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 M Hz): 8.55 (brs, 2H), 7.13 (d, 2H, J=5.6 Hz), 4.59 (s, 2H), 3.05 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.20N.sub.2O, 221.2; found, 221.4.

Compound 35: Preparation of N,2,2-trimethyl-N-(pyridin-3-ylmethyl)butanamide

(76) ##STR00222##

(77) The titled compound 35 was prepared in 86% yield from nicotinaldehyde (214 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (289 mg) according to the procedure outlined for compound 13. .sup.1HNMR (CDCl.sub.3, 400 M Hz): 8.48-8.51 (m, 2H), 7.58-7.61 (m, 1H), 7.24-7.27 (m, 1H), 4.59 (s, 2H), 3.03 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.20N.sub.2O, 221.2; found, 221.4.

Compound 36: Preparation of N-((3-fluoropyridin-4-yl)methyl)-N,2,2-trimethylbutanamide

(78) ##STR00223##

(79) The titled compound 36 was prepared in 78% yield from 3-fluoroisonicotinaldehyde (125 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (134 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 M Hz): 8.41 (d, 1H, J=1.6 Hz), 8.35 (d, 1H, J=4.8 Hz), 7.18 (dd, 1H, J=6.0, 5.2 Hz), 4.65 (s, 2H), 3.12 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.19FN.sub.2O, 239.1; found 239.3.

Compound 37: Preparation of N-((2-methoxypyridin-3-yl)methyl)-N,2,2-trimethylbutanamide

(80) ##STR00224##

(81) The titled compound 37 was prepared in 72% yield from 2-methoxynicotinaldehyde (137 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (160 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 M Hz): 8.06 (dd, 1H, J=5.2, 2.0 Hz), 7.40 (d, 1H, J=7.2 Hz), 6.86 (dd, 1H, J=7.2, 5.2 Hz), 4.56 (s, 2H), 3.97 (S, 3H), 3.05 (s, 3H), 1.67 (q, 2H, J=7.6 Hz), 1.25 (s, 6H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.22N.sub.2O.sub.2, 251.2; found 251.4.

Compound 38: Preparation of N-((6-methoxypyridin-3-yl)methyl)-N,2,2-trimethylbutanamide

(82) ##STR00225##

(83) The titled compound 38 was prepared in 72% yield from 6-methoxynicotinaldehyde (137 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (160 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 M Hz): 8.01-8.02 (m, 1H), 7.53 (d, 1H, J=8.4), 6.71 (d, 1H, J=8.4), 4.51 (s, 2H), 3.92 (s, 3H), 3.00 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.22N.sub.2O.sub.2, 251.2; found 251.4.

Compound 39: Preparation of N-(cyclohexylmethyl)-N,2,2-trimethylbutanamide

(84) ##STR00226##

(85) The titled compound 39 was prepared in 62% yield from cyclohexanecarbaldehyde (112 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoyl chloride (160 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6 3.16 (d, 2H, J=6.8 Hz), 3.07 (s, 3H),1.92 (m, 1H), 1.63-1.73 (m, 8H), 1.24 (s, 6H), 1.08-1.19 (m, 4H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.27NO, 226.2; found 226.4.

Compound 40: Preparation of N,2,2-trimethyl-N-(thiophen-2-ylmethyl)butanamide

(86) ##STR00227##

(87) The titled compound 40 was prepared in 62% yield from thiophene-2-carbaldehyde (224 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (119 mg) according to the procedure outlined for compound 13. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.21 (dd, 1H, J=4.8, 1.6 Hz), 6.92-6.95 (m, 2H), 4.71 (s, 2H), 3.05 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.86 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.19NOS, 226.1; found 226.4.

Compound 41: Preparation of N,2,2-trimethyl-N-((3-methylthiophen-2-yl)methyl)butanamide

(88) ##STR00228##

(89) The titled compound 41 was prepared in 42% yield from 3-methylthiophene-2-carbaldehyde (200 mg), methanamine hydrochloride (161 mg) and 2,2-dimethylbutanoylchloride (218 mg) according to the procedure outlined for compound 13.

(90) .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.11 (d, 1H, J=5.2 Hz), 6.78 (d, 1H, J=5.2 Hz), 4.68 (s, 2H), 3.03 (s, 3H), 2.23 (s, 3H), 1.67 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.89 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.21NOS, 234.1; found 234.4.

Compound 42: Preparation of N,2,2-trimethyl-N-((5-methylthiophen-2-yl)methyl)butanamide

(91) ##STR00229##

(92) The titled compound 42 was prepared in 42% yield from 5-methylthiophene-2-carbaldehyde (200 mg), methanamine hydrochloride (161 mg) and 2,2-dimethylbutanoylchloride (218 mg) according to the procedure outlined for compound 13. .sup.1HNMR (CDCl.sub.3, 400 MHz): 6.72 (d, 1H, J=3.2 Hz), 6.56-6.57 (m, 1H), 4.62 (s, 2H), 3.03 (s, 3H), 2.43 (d, 3H, J=1.2 Hz), 1.661 (q, 2H, J=7.6 Hz), 1.269 (s, 6H), 0.877 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.21NOS, 234.1; found 234.4.

Compound 43: Preparation of N-(furan-2-ylmethyl)-N,2,2-trimethylbutanamide

(93) ##STR00230##

(94) The titled compound 43 was prepared in 22% yield from furan-2-carbaldehyde (500 mg), methanamine hydrochloride (527 mg) and 2,2-dimethylbutanoylchloride (714 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz):7.34-7.35 (m, 1H), 6.31-6.33 (m, 1H), 6.21-6.22 (m, 1H), 4.57 (s, 2H), 3.06 (s, 3H), 1.63 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.85 (t, 3H, J=7.6 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.19NO.sub.2, 210.1; found 210.3.

Compound 44: Preparation of N,2,2-trimethyl-N-((2-methylthiazol-5-yl)methyl)butanamide

(95) ##STR00231##

(96) The titled compound 44 was prepared in 23% yield from 2-methylthiazole-5-carbaldehyde (60 mg), methanamine hydrochloride (48 mg) and 2,2-dimethylbutanoylchloride (74 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.50 (s, 1H), 4.59 (s, 2H), 3.07 (s, 3H), 2.67 (s, 3H), 1.64 (q, 2H, J=7.6 Hz), 1.25 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.20N.sub.2OS, 241.1; found 241.4.

Compound 45: Preparation of N,2,2-trimethyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)butanamide

(97) ##STR00232##

(98) The titled compound 45 was prepared in 23% yield from N,1-dimethyl-1H-pyrazol-3-amine (30 mg), and 2,2-dimethylbutanoylchloride (48 mg) according to the procedure outlined for compound 13. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.26 (d, 1H, J=4.0 Hz), 6.12 (d, 1H, J=4.0 Hz), 4.57 (s, 2H), 3.85 (s, 3H), 3.01 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.21N.sub.3O, 224.2; found 224.4.

Compound 46: Preparation of N,2,2-trimethyl-N-(naphthalen-2-ylmethyl)butanamide

(99) ##STR00233##

(100) The titled compound 46 was prepared in 74% yield from 2-naphthaldehyde (312 mg) methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoylchloride (275 mg) according to the procedure outlined for compound 13

(101) 1. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.80 (m, 3H), 7.63 (m, 1H), 7.46 (m, 3H), 4.78 (s, 2H), 3.00 (s, 3H), 1.70 (q, 2H, J=7.6 Hz)), 1.30 (s, 6H), 0.93 (t, 3H, J=7.6 Hz). LC-MS (ESI).sup.[M+H]+ calcd for C.sub.18H.sub.23NO, 270.2; found 270.4.

Compound 47: Preparation of N,2,2-trimethyl-N-(quinolin-3-ylmethyl)butanamide

(102) ##STR00234##

(103) The titled compound 47 was prepared in 60% yield from quinoline-3-carbaldehyde (157 mg), methanamine hydrochloride 101 mg) and 2,2-dimethylbutanoylchloride (175 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 8.85 (d, 1H, J=4.4 Hz), 8.13 (d, 1H, J=8.4 Hz), 7.97 (d, 1H, J=8.4 Hz), 7.68-7.73 (m, 1H), 7.53-7.57 (m, 1H), 7.155 (d, 1H, J=4.4 Hz), 5.10 (s, 2H), 3.07 (s, 3H), 1.70 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.17H.sub.22N.sub.2O, 271.2; found 271.4.

Compound 48: Preparation of N,2,2-trimethyl-N-(2,4,6-trifluorobenzyl)butanamide

(104) ##STR00235##

(105) The titled compound 48 was prepared in 63% yield from 2,4,6-trifluorobenzaldehydhyde (320 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoylchloride (275 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.61-6.69 (m, 2H), 4.64 (s, 2H), 3.06 (s, 3H), 1.64 (q, 2H, J=7.6 Hz), 1.24 (s, 6H), 0.82 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO, 274.1; found 274.3.

Compound 49: Preparation of N,2,2-trimethyl-N-(2,3,4-trifluorobenzyl)butanamide

(106) ##STR00236##

(107) The titled compound 49 was prepared in 66% yield from 2,3,4-trifluorobenzaldehyde (160 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoylchloride (175 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.03-7.05 (m, 1H), 6.88-6.95 (m, 1H), 4.61 (s, 2H), 3.09 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO, 274.1; found 274.3.

Compound 50: Preparation of N-(2,6-difluoro-3-methylbenzyl)-N,2,2-trimethylbutanamide

(108) ##STR00237##

(109) The titled compound 50 was prepared in 66% yield from 2,6-difluoro-3-methylbenzaldehyde (156 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoylchloride (140 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.06 (q, 1H, J=8.4 Hz), 6.77 (t, 1H, J=8.8 Hz), 4.71 (s, 2H), 3.02 (s, 3H), 2.22 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H] calcd for C.sub.15H.sub.21F.sub.2NO, 270.2; found 270.4.

Compound 51: Preparation of N,2,2-trimethyl-N-(2,3,5,6-tetrafluorobenzyl)butanamide

(110) ##STR00238##

(111) The titled compound 51 was prepared in 66% yield from 2,3,5,6-tetrafluorobenzaldehyde (178 mg), methanamine hydrochloride (101 mg) and 2,2-dimethylbutanoylchloride (140 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.95-7.03 (m, 1H) 4.70 (s, 2H), 3.16 (s, 3H), 1.65 (q, 2H, J=7.6 Hz), 1.24 (s, 6H), 0.83 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.17F.sub.4NO, 292.1; found 292.4.

Compound 52: Preparation of 2,2-dimethyl-N-(1-phenylethyl)butanamide

(112) ##STR00239##

(113) 1-phenylethanamine (1 g, 8.26 mmoL) and Triethylamine (0.918 g, 9.09 mmoL) were dissolved in 20 mL of dry CH.sub.2Cl.sub.2. 2,2-dimethylbutanoyl chloride (1.223 g, 9.09 m moL) in 2 mL of CH.sub.2Cl.sub.2 was added slowly to the solution at 0 C. under nitrogen. The mixture was stirred at room temperature for 2 h, diluted with CH.sub.2Cl.sub.2 and water. The organic layers were washed with saturated NaHCO.sub.3, brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound 40 (1.35 g, 74.6%) as an white solid. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.26-7.34 (m, 5H), 5.77 (brs, 1H), 5.10-5.17 (m, 1H), 1.545 (q, 2H, J=8 Hz), 1.485 (d, 3H, J=4 Hz), 1.15 (s, 6H), 0.82 (t, 3H, J=8 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.21NO, 220.2; found 220.4.

Compound 53: Preparation of N,2,2-trimethyl-N-(1-phenylethyl)butanamide

(114) ##STR00240##

(115) To a solution of compound 52 (50 mg) in dry THF (1 ml) was added sodium hydride (13.7 mg) under nitrogen at 0 C. The mixture was stirred at 0 C. for 30 minutes, then iodomethane (38.9 mg) was added. The mixture was stirred at room temperature for 2 h and quenched with cold water and extracted with CH.sub.2Cl.sub.2. The combined organic layer were washed with H.sub.2O, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound 53 (8 mg, 15%) as a colorless oil. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.32-7.35 (m, 2H), 7.22-7.27 (m, 3H), 5.62-6.30 (m, 1H), 2.70 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.51 (d, 3H, J=6.0 Hz), 1.30 (s, 3H), 1.29 (s, 3H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.23NO, 234.2; found 234.4.

Compound 54: Preparation of 2,2-dimethyl-N-(1-phenylcyclopropyl)butanamide

(116) ##STR00241##

(117) The titled compound 54 was prepared in 96% yield from 1-phenylcyclopropanamine (106 mg) and 2,2-dimethylbutanoyl chloride (160 mg) according to the procedure outlined for compound 52. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.22-7.29 (m, 4H), 7.15-7.19 (m, 1H), 6.25 (brs, 1H), 1.54 (q, 2H, J=7.6 Hz), 1.24-1.29 (m, 2H), 1.18-1.22 (m, 2H), 1.16 (s, 6H), 0.81 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.21NO, 232.1; found 232.4.

Compound 55: Preparation of N,2,2-trimethyl-N-(1-phenylcyclopropyl)butanamide

(118) ##STR00242##

(119) The titled compound 55 was prepared in 30% yield from compound 42 (90 mg), sodium hydride (32 mg) and iodomethane (85.2 mg) according to the procedure outlined for compound 53. .sup.1HNMR(CDCl.sub.3, 400 MHz):7.28-7.30 (m, 2H), 7.15-7.19 (m, 3H), 3.12 (s, 3H), 1.67 (q, 2H, J=7.6 Hz), 1.30-1.32 (m, 2H), 1.26 (s, 6H), 1.24-1.25 (m, 1H), 0.81 (t, 3H, J=7.6 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.23NO, 246.1; found, 246.4.

Compound 56: Preparation of N-(2-bromo-5-fluorobenzyl)-N,2,2-trimethylbutanamide

(120) ##STR00243##

(121) The titled compound 56 was prepared in 56% yield from 2-bromo-5-fluorobenzaldehyde (500 mg), methanamine hydrochloride (249 mg) and 2,2-dimethylbutanoyl chloride (317 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz):7.48-7.52 (m, 1H), 7.04-7.10 (m, 2H), 4.80 (s, 2H), 3.15 (s, 3H), 1.71 (q, 2H, J=7.6 Hz), 1.30 (s, 6H), 0.91 (t, 3H, J=7.6 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C14H19BrFNO, 316.1; found, 316.1, 318.2.

Compound 57: Preparation of N-(2-cyano-5-fluorobenzyl)-N,2,2-trimethylbutanamide

(122) ##STR00244##

(123) A mixture of compound 56 (30 mg), sodium iodide (1.4 mg) and copper(I) cyanide (22 mg) in dry DMF (1 mL) was stirred at 180 C. for 6 h. The mixture was diluted with saturated aqueous NaHCO.sub.3 solution (2 mL) and the aqueous layer was extracted with dichloromethane (5 mL3). The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Pre-TLC to give compound 57 (18 mg, 72%). 1H-NMR (CDCl3, 400 MHz): 7.64-7.67 (m, 1H), 6.83-6.88 (m, 2H), 4.65 (s, 2H), 3.09 (s, 3H), 1.71 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.93 (t, 3H, J=7.6 Hz) MS (ES) [M+H].sup.+ calcd for C15H19FN2O, 263.1; found, 263.3.

Compound 58: Preparation of N-benzyl-2,2-dimethylbutanamide

(124) ##STR00245##

(125) The titled compound 58 was prepared in 84% yield from phenylmethanamine (107 mg) and 3,3-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 52. .sup.1H NMR (CDCl.sub.3): 7.25-7.36 (m, 5H), 5.88 (br, 1H), 4.45 (d, 2H, J=8.0 Hz), 1.58 (q, 2H, J=5.6 Hz), 1.19 (s, 6H), 0.81 (t, 3H, J=5.6 Hz).

Compound 59: Preparation of N-(2-fluorobenzyl)-N,3,3-trimethylbutanamide

(126) ##STR00246##

(127) The titled compound 59 was prepared in 34% yield from 2-fluorobenzaldehyde (124 mg), methanamine hydrochloride (101 mg) and 3,3-dimethylbutanoyl chloride (140 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.22-7.36 (m, 2H), 7.01-7.15 (m, 2H), 4.65 (s, 2H), 2.97 (s, 3H), 2.31 (s, 2H), 1.07 (s, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.20FNO, 238.2; found 238.4.

Compound 60: Preparation of N-(2-fluorobenzyl)-N-methylcyclohexanecarboxamide

(128) ##STR00247##

(129) The titled compound 60 was prepared in 66% yield from 2-fluorobenzaldehyde (124 mg), methanamine hydrochloride (101 mg) and cyclohexane carbonyl chloride (153 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz):7.23-7.28 (m, 2H), 7.01-7.11 (m, 2H), 4.63 (s, 2H), 2.97 (s, 3H), 2.51-2.56 (m, 1H), 1.52-1.79 (m, 7H), 1.24-1.31 (m, 3H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.20FNO, 250.2; found, 250.4.

Compound 61: Preparation of N-(2-fluorobenzyl)-N-methylbenzamide

(130) ##STR00248##

(131) The titled compound 61 was prepared in 56% yield from 2-fluorobenzaldehyde (124 mg), methanamine hydrochloride (101 mg) and benzoyl chloride (147 mg) according to the procedure outlined for compound 1. .sup.1HNMR (DMSO, 400 MHz): 7.20-7.42 (m, 9H), 4.70 (s, 1H), 4.50 (s, 1H), 2.84 (s, 3H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.14FNO, 244.1; found 244.3.

Compound 62: Preparation of N-(2-fluorobenzyl)-N-methylcyclopropanecarboxamide

(132) ##STR00249##

(133) The titled compound 50 was prepared in 54% yield from 2-fluorobenzaldehyde (124 mg), methanamine hydrochloride (101 mg) and cyclopropanecarbonyl chloride (147 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.25-7.27 (m, 2H), 7.03-7.14 (m, 2H), 4.76 (s, 2H), 3.11 (s, 3H), 1.69-1.83 (m, 1H), 1.01-1.05 (m, 2H), 0.69-0.86 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.14FNO, 208.1; found, 208.3.

Compound 63: Preparation of N-(3-fluorobenzyl)-N-(3-methoxypropyl)-2,2-dimethylbutanamide

(134) ##STR00250##

(135) A mixture of (2-fluorophenyl)methanamine (125 mg), potassium carbonate (414 mg) and 1-chloro-3-methoxypropane (108 mg) in DMF (5 ml) was stirred at 100 C. for 16 h. The mixture was diluted with CH.sub.2Cl.sub.2, washed with H.sub.2O, dried with Na.sub.2SO.sub.4. After removal of the solvent to give the crude N-(3-fluorobenzyl)-3-methoxypropan-1-amine (200 mg). The resulting compound was dissolve in dry THF (10 ml), and DIPEA (193 mg) was added. The mixture was cooled to 0 C., 2,2-dimethylbutanoylchloride (201 mg) was added and stirred for 4 h at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic layer were washed with brine and dried over Na.sub.2SO.sub.4. After removal of the solvent, the residue was purified by silica gel chromatography to afford the compound 63 (177 mg, 60%). .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.27-7.31 (m, 1H), 6.88-6.98 (m, 3H), 4.66 (s, 2H), 3.41 (m, 2H), 3.36 (t, 2H, J=6.0 Hz), 3.29 (s, 3H), 1.84-1.86 (m, 2H), 1.67 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.90 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.17H.sub.26FNO.sub.2, 296.2; found 296.4.

Compound 64: Preparation of N-(cyclopropylmethyl)-N-(3-fluorobenzyl)-2,2-dimethylbutanamide

(136) ##STR00251##

(137) The titled compound 64 was prepared in 54% yield from (2-fluorophenyl)methanamine (125 mg), (bromomethyl)cyclopropane (135 mg) and 2,2-dimethylbutanoylchloride (201 mg) according to the procedure outlined for compound 63. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.24-7.30 (m, 1H), 6.88-6.98 (m, 3H), 4.81 (s, 2H), 3.24 (d, 2H, J=6.4 Hz), 1.70 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.94 (t, 3H, J=7.6 Hz), 0.87-0.90 (m, 1H), 0.51 (m, 2H), 0.13 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.17H.sub.24FNO, 278.2; found 278.3.

Compound 65: Preparation of N,1-dimethyl-N-(2,3,5-trifluorobenzyl)cyclohexanecarboxamide

(138) ##STR00252##

(139) N-methyl-1-(2,3,5-trifluorophenyl)methanamine (37 mg, 0.211 mmol), which was prepared from 2,3,5-trifluorobenzaldehyde and methanamine hydrochloride according to the procedure outlined for compound 13, and 1-methylcyclohexanecarboxylic acid (30 mg, 0.211 mmoL) were dissolved in dry DMF (1 ml), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (119.7 mg, 0.315 mmoL) and N,N-Diisopropylethylamine (54.2 mg, 0.42 mmoL) were added to the solution. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 12 mg of desired compound 65 as colorless oil (yield=19.5%).sup.1H NMR: (CDCl.sub.3, 400 M Hz) (ppm) 6.80-6.82 (m, 1H), 6.72-6.76 (m, 1H), 4.65 (s, 2H), 3.10 (s, 3H), 2.06-2.11 (m, 2H), 1.36-1.54 (m, 8H), 1.27 (s, 3H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.20F.sub.3NO, 300.1; found 300.3.

Compound 66: Preparation of 3-hydroxy-N,2,2-trimethyl-N-(3,4,5-trifluorobenzyl)propanamide

(140) ##STR00253##

(141) The titled compound 66 was prepared in 34% yield from N-methyl-1-(3,4,5-trifluorophenyl)methanamine (447 mg), which was prepared from 2,3,5-trifluorobenzaldehyde and methanamine hydrochloride according to the procedure outlined for compound 13, and 3-hydroxy-2,2-dimethylpropanoic

(142) acid (300 mg) and according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.82 (m, 2H), 4.52 (s, 2H), 3.57 (s, 2H), 3.06 (s, 3H), 1.32 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found 276.3.

Compound 67: Preparation of 2-methoxy-N,2-dimethyl-N-(2,3,5-trifluorobenzyl)propanamide

(143) ##STR00254##

(144) The titled compound 55 was prepared in 14% yield from 2-methoxy-2-methylpropa-noicacid (300 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (447 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 87.01-7.04 (m, 2H), 4.64 (s, 2H), 3.42 (s, 3H), 3.37 (s, 3H), 1.62 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found 276.3.

Compound 68: Preparation of N,2,2-trimethyl-3-(methylamino)-N-(3,4,5-trifluorobenzyl) propanamide

(145) ##STR00255##

(146) A mixture of 3-chloro-N,2,2-trimethyl-N-(3,4,5-trifluorobenzyl)propanamide (60 mg) methanamine hydrochloride (27 mg), potassium carbonate (138 mg) and potassium iodide (33.2 mg) in methyl cyanide (5 mL) was refluxed for overnight. The mixture was diluted with water (2 mL), The aqueous layer was extracted with dichloromethane (5 mL3). The organic layers were combined and concentrated. The residue was purified by Pre-HPLC to give 2 mg of compound 68 as TFA salt. .sup.1H NMR: (CDCl.sub.3, 400 M Hz) 6.80-6.88 (m, 2H), 4.51 (s, 2H), 4.22 (brs, 1H), 3.00-3.16 (m, 5H), 2.82 (s, 3H), 1.51 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.19F.sub.3N.sub.2O, 289.2; found 289.4.

Compound 69: Preparation of N-methyl-N-(3,4,5-trifluorobenzyl)pivalamide

(147) ##STR00256##

(148) The titled compound 69 was prepared in 27% yield from pivalic acid (14.6 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (25 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.79-6.86 (m, 2H), 4.52 (s, 2H), 3.05 (s, 3H), 1.33 (s, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO, 260.1; found 260.3.

Compound 70: Preparation of 2,2-dimethyl-N-(2,3,5-trifluorobenzyl)butanamide

(149) ##STR00257##

(150) The titled compound 58 was prepared in 41.5% yield from (2,3,5-trifluorophenyl)methanamine (30 mg) and 2,2-dimethylbutanoyl chloride (27.6 mg) according to the procedure outlined for compound 52. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.81-6.87 (m, 2H), 6.02 (brs, 1H), 4.50 (d, 1H, J=1.2 Hz), 4.48 (d, 1H, J=1.2 Hz), 1.56 (q, 2H, J=7.6 Hz), 1.18 (s, 6H), 0.82 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO, 260.1; found 260.3.

Compound 71: Preparation of 3-methoxy-N,2,2-trimethyl-N-(3,4,5-trifluorobenzyl)propanamide

(151) ##STR00258##

(152) The titled compound 71 was prepared in 13% yield from 3-methoxy-2,2-dimethylpropanoic acid (14 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (447 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.84-6.88 (m, 2H), 4.54 (s, 2H), 3.48 (s, 2H), 3.36 (s, 3H), 3.04 (s, 3H), 1.33 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO.sub.2, 290.1; found, 290.4.

Compound 72: Preparation of 2-ethyl-N,2-dimethyl-N-(3,4,5-trifluorobenzyl)butanamide

(153) ##STR00259##

(154) The titled compound 72 was prepared in 18% yield from N-methyl-1-(3,4,5-trifluorophenyl)methanamine (20 mg) and 2-ethyl-2-methylbutanoic acid (15 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.87-6.91 (m, 2H), 4.50 (s, 2H), 3.05 (s, 3H), 1.77-1.84 (m, 2H), 1.47-1.56 (m, 2H), 1.23 (s, 3H), 0.87 (t, 6H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.20F.sub.3NO, 288.1; found 288.3.

Compound 73: Preparation of 2-ethyl-2-methyl-N-(2,3,5-trifluorobenzyl)butanamide

(155) ##STR00260##

(156) The titled compound 73 was prepared in 12% yield from (2,3,5-trifluorophenyl)methanamine (30 mg) and 2-ethyl-2-methylbutanoic acid (24.4 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.82-6.88 (m, 2H), 6.03 (brs, 1H), 4.49 (d, 2H, J=6.0 Hz), 1.61-1.69 (m, 2H), 1.39-1.48 (m, 2H), 1.12 (s, 3H), 0.80 (t, 6H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO, 274.1; found 274.3.

Compound 74: Preparation of N-ethyl-N-(2,3,5-trifluorobenzyl)cyclohexanecarboxamide

(157) ##STR00261##

(158) The titled compound 74 was prepared in 53% yield from 2,3,5-trifluorobenzaldehyde (320 mg), ethylamine hydrochloride (244 mg) and 2,2-dimethylbutanoylchloride (275 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.77-683 (m, 1H), 6.59-6.75 (m, 1H), 4.61 (s, 2H), 3.35 (q, 2H, J=7.2 Hz), 2.47-2.54 (m, 1H), 1.41-1.95 (m, 10H), 1.20 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.20F.sub.3NO, 300.1; found, 300.3.

Compound 75: Preparation of N,2,2-trimethyl-N-(2,3,5-trifluorobenzyl)butanamide

(159) ##STR00262##

(160) The titled compound 75 was prepared in 50% yield from 2,3,5-trifluorobenzaldehyde (320 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoylchloride (275 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.75-6.85 (m, 2H), 4.64 (s, 2H), 3.11 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.28 (s, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO, 274.1; found 274.3.

Compound 76: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)adamantane-1-carboxamide

(161) ##STR00263##

(162) The titled compound 76 was prepared in 16% yield from 2,3,5-trifluorobenzaldehyde (50 mg), methanamine hydrochloride (29 mg) and adamantane-1-carbonyl chloride (40 mg) according to the procedure outlined for compound 13. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.30-7.51 (m, 1H), 6.66-6.70 (m, 1H), 4.58 (s, 2H), 3.10 (s, 3H), 1.93-1.96 (m, 10H), 1.64-1.67 (m, 4H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.19H.sub.22F.sub.3NO, 338.2; found 338.4.

Compound 77: Preparation of N-(2-hydroxyethyl)-2,2-dimethyl-N-(2,3,5-trifluorobenzyl)butanamide

(163) ##STR00264##

(164) The titled compound 77 was prepared in 30% yield from 2-((2,3,5-trifluorobenzyl)amino)ethanol (50 mg) and 2,2-dimethylbutanoylchloride (33 mg) according to the procedure outlined for compound 52. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.92-6.97 (m, 1H), 6.80-6.87 (m, 1H), 4.21 (t, 2H, J=5.2 Hz), 3.92 (s, 2H), 2.89 (t, 2H, J=5.2 Hz), 1.57 (q, 2H, J=7.2 Hz), 1.16 (s, 6H), 0.83 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.20F.sub.3NO.sub.2, 304.1; found 304.3.

Compound 78: Preparation of N,2-dimethyl-N-(2,3,5-trifluorobenzyl)propane-2-sulfinamide

(165) ##STR00265##

(166) The titled compound 78 was prepared in 30% yield from N-methyl-1-(2,3,5-trifluorophenyl)methanamine (50 mg) and 2,2-dimethylbutanoylchloride (57 mg) according to the procedure outlined for compound 52. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.83-6.94 (m, 2H), 4.23-4.32 (m, 2H), 2.64 (s, 3H), 1.21 (s, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.16F.sub.3NOS, 280.1; found, 280.2.

Compound 79: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)cyclohexanesulfonamide

(167) ##STR00266##

(168) The titled compound 79 was prepared in 11% yield from N-methyl-1-(2,3,5-trifluorophenyl)methanamine (20 mg) and cyclohexanesulfonyl chloride (30 mg) according to the procedure outlined for compound 52. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.02-7.07 (m, 1H), 6.84-6.91 (m, 1H), 4.46 (s, 2H), 2.99-3.05 (m, 1H), 2.86 (s, 3H), 1.95-2.15 (m, 2H), 1.91-1.94 (m, 2H), 1.57-1.74 (m, 5H), 1.21-1.28 (m, 1H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.18F.sub.3NO.sub.2S, 322.1; found 322.3.

Compound 80: Preparation of N,1-dimethyl-N-(2,3,5-trifluorobenzyl)cyclopropanecarboxamide

(169) ##STR00267##

(170) The titled compound 80 was prepared in 35% yield from 1-methylcyclopropanecarboxylicacid (20 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (35 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.80-6.83 (m, 2H), 4.52 (s, 2H), 3.05 (s, 3H), 1.34 (s, 3H), 0.98 (t, 2H, J=4.8 Hz), 0.63 (t, 2H, J=4.8 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.14F.sub.3NO, 258.1; found 258.3.

Compound 81: Preparation of N,2,2,3,3-pentamethyl-N-(3,4,5-trifluorobenzyl)-cyclopropanecarboxamide

(171) ##STR00268##

(172) The titled compound 81 was prepared in 28.5% yield from 2,2,3,3-tetramethylcyclopropanecarboxylic acid (30 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (37 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.83-6.87 (m, 2H), 4.50 (s, 2H), 2.96 (s, 3H), 1.21 (s, 6H), 1.18 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.20F.sub.3NO, 300.1; found 300.3.

Compound 82: Preparation of N-methyl-1-phenyl-N-(2,3,5-trifluorobenzyl)cyclopropanecarboxamide

(173) ##STR00269##

(174) The titled compound 82 was prepared in 30% yield from phenylcyclopropanecarboxylic acid (50 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (55 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 87.26-7.30 (m, 1H), 7.16-7.26 (m, 3H), 6.74-6.94 (m, 3H), 4.65 (s, 2H), 2.85 (s, 3H), 1.43-1.46 (m, 2H), 1.23 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.18H.sub.16F.sub.3NO, 320.1; found 320.3.

Compound 83: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)cyclobutanecarboxamide

(175) ##STR00270##

(176) The titled compound 83 was prepared in 29.2% yield from cyclobutanecarboxylic acid (20 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (35 mg) according to the procedure outlined for compound 65. .sup.1HNMR: (CDCl.sub.3, 400 M Hz): 6.76-6.86 (m, 2H), 4.61 (s, 2H), 3.29-3.33 (m, 1H), 2.89 (s, 3H), 2.32-2.41 (m, 2H), 2.17-2.22 (m, 2H), 1.86-1.99 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.14F.sub.3NO, 258.2; found 258.4.

Compound 84: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)-1-(trifluoromethyl)cyclobutanecarboxamide

(177) ##STR00271##

(178) The titled compound 84 was prepared in 25.9% yield from 1-(trifluoromethyl)cyclobutanecarboxylic acid (30 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (31 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.80-6.89 (m, 1H), 6.74-6.77 (m, 1H), 4.66 (s, 2H), 2.92 (s, 3H), 2.68-2.77 (m, 2H), 2.52-2.58 (m, 2H), 2.08-2.16 (m, 1H), 1.83-1.87 (m, 1H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.13F.sub.6NO, 326.1; found 326.4.

Compound 85: Preparation of N-methyl-N-(3,4,5-trifluorobenzyl)cyclopentanecarboxamide

(179) ##STR00272##

(180) The titled compound 85 was prepared in 25.2% yield from cyclopentanecarboxylic acid (30 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (46 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.28-6.86 (m, 2H), 4.50 (s, 2H), 2.99 (s, 3H), 2.93-2.97 (m, 1H), 1.73-1.89 (m, 6H), 1.57-1.62 (m, 2H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.16F.sub.3NO, 272.1; found 272.3.

Compound 86: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)-1-(trifluoromethyl)cyclopentanecarboxamide

(181) ##STR00273##

(182) The titled compound 86 was prepared in 26.9% yield from 1-(trifluoromethyl)cyclopentanecarboxylic acid (30 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (29 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.79-6.85 (m, 1H), 6.65-6.69 (m, 1H), 4.65 (s, 2H), 3.07 (s, 3H), 2.38-2.44 (m, 2H), 2.15-2.21 (m, 2H), 1.59-1.74 (m, 4H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.15F.sub.6NO, 340.1; found, 340.3.

Compound 87: Preparation of N-methyl-1-phenyl-N-(2,3,5-trifluorobenzyl)cyclopentanecarboxamide

(183) ##STR00274##

(184) The titled compound 87 was prepared in 29.5% yield from 1-phenylcyclopentanecarboxylic acid (50 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (47 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 7.19-7.31 (m, 5H), 6.74-6.77 (m, 2H), 4.60 (s, 2H), 2.54 (s, 3H), 2.37-2.43 (m, 2H), 2.02-2.05 (m, 2H), 1.66-1.77 (m, 4H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.20H.sub.20F.sub.3NO, 348.1; found 348.3.

Compound 88: Preparation of 1-ethyl-N-methyl-N-(3,4,5-trifluorobenzyl)cyclobutanecarboxamide

(185) ##STR00275##

(186) The titled compound 88 was prepared in 19.7% yield from 1-ethylcyclobutanecarboxylic acid (18 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (25 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.74-6.94 (m, 2H), 4.46 (s, 2H), 2.82 (s, 3H), 2.46-2.55 (m, 2H), 1.74-1.98 (m, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.18F.sub.3NO, 286.1; found 286.4.

Compound 89: Preparation of 1-ethyl-N-methyl-N-(3,4,5-trifluorobenzyl)cyclopentanecarboxamide

(187) ##STR00276##

(188) The titled compound 89 was prepared in 18.7% yield from 1-ethylcyclopentanecarboxylic acid (20 mg) and N-methyl-1-(3,4,5-trifluorophenyl)methanamine (25 mg) according to the procedure outlined for compound 65. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.82-6.90 (m, 2H), 4.50 (s, 2H), 2.99 (s, 3H), 2.18-2.27 (m, 2H), 1.66 (q, 2H, J=7.6 Hz), 1.57-1.62 (m, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.20F.sub.3NO, 300.2; found 300.4.

Compound 90: Preparation of N-benzyl-N,2,2-trimethylbutanamide

(189) ##STR00277##

(190) The titled compound 90 was prepared in 72% yield from N-(2-fluorobenzyl)-2,2-dimethylbutanamide (1.312 g) and iodomethane (1 g) according to the procedure outlined for compound 10. .sup.1H NMR (CDCl.sub.3): 7.21-7.33 (m, 5H), 4.64 (s, 2H), 2.99 (s, 3H), 1.68 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.90 (t, 3H, J=7.6 Hz).

Compound 91: Preparation of N-(3,4-difluorobenzyl)-N,2,2-trimethylbutanamide

(191) ##STR00278##

(192) The titled compound 91 was prepared in 45% yield from compound 8 (71.7 mg) and iodomethane (84.5 mg) according to the procedure outlined for compound 10.

(193) .sup.1H NMR (CDCl.sub.3): 7.03-7.14 (m, 2H), 6.94-6.98 (m, 1H), 4.55 (s, 2H), 3.02 (s, 3H), 1.69 (q, 2H, J=7.6 Hz), 1.29 (s, 6H), 0.89 (t, 3H, J=7.6 Hz).

Compound 92: Preparation of N-benzyl-N-hydroxy-2,2-dimethylbutanamide

(194) ##STR00279##

(195) n-benzylhydroxylamine hydrochloride (100 mg) was dissolved in 2 ml of THF/H.sub.2O (1:1) and 0.45 ml of saturated aqueous NaHCO.sub.3. The solution was cooled to 0 C. and 2,2-dimethylbutanoylchloride (81 mg) was added and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc and the combined organic layer washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification by silica gel chromatography to give compound 80 (60 mg, 43.3%) as an white solid. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.34-37 (m, 2H), 7.31-7.33 (m, 3H), 4.89 (s, 2H), 1.69 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.86 (t, 6H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.19NO.sub.2, 222.1; found 222.4.

Compound 93: Preparation of N-hydroxy-2,2-dimethyl-N-(2,3,5-trifluorobenzyl)butanamide

(196) ##STR00280##

(197) Reagent and conditions; (a) tert-butyl (tert-butoxycarbonyl)oxycarbamate, 1N NaOH, TBAB, DCM; (b) TFA, DCM; (c) 2,2-dimethylbutanoyl chloride, aq. NaHCO.sub.3, THF, H.sub.2O.

(198) Tert-butyl (tert-butoxycarbonyl)oxycarbamate (104 mg) and 1-(bromomethyl)-2,3,5-trifluorobenzene (100 mg) were dissolved in CH.sub.2Cl.sub.2 (10 ml). The mixture was added 1M NaOH (4.5 ml) and tetrabutylammonium bromide (7 mg), and stirred at room temperature for overnight. The resulting mixture was washed with water and dried with Na.sub.2SO.sub.4, concentrated in vacuo and purification by silica gel chromatography to give tert-butyl (tert-butoxycarbonyl)oxy(2,3,5-trifluorobenzyl)-

(199) carbamate (150 mg, 89%). .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.95-6.98 (m, 1H), 6.81-6.89 (m, 1H), 4.82 (s, 2H), 1.50 (s, 9H), 1.49 (s, 9H).

(200) The above intermediate was dissolved in CH.sub.2Cl.sub.2 (2.5 ml), TFA (0.8 ml) was added at 0 C. The mixture was stirred at room temperature for 4 h and concentrated to give N-(2,3,5-trifluorobenzyl)hydroxylamine (100 mg) as a TFA salt, which was used without further purification.

(201) The above intermediate was dissolved in THF (3 ml) and water (3 ml) and 1 ml of saturated aqueous NaHCO.sub.3 was added. The mixture was stirred at room temperature for 30 min, then cooled to 0 C., 2,2-dimethylbutanoylchloride (54 mg) was added and stirred for overnight. The mixture was extracted with EtOAc, washed with brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo. Purification by silica gel chromatography to give compound 93 (80 mg, total yield 65%). .sup.1HNMR (CDCl.sub.3, 400 MHz): 9.80 (s, 1H), 7.41-7.48 (m, 1H), 6.91-6.96 (m, 1H), 4.74 (s, 2H), 1.64 (q, 2H, J=7.6 Hz), 1.13 (s, 6H), 0.72 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found, 276.2.

Compound 94: Preparation of N-(4-fluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide

(202) ##STR00281##

(203) The titled compound 94 was prepared in 71% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (247 mg), 1-(bromomethyl)-4-fluorobenzene (200 mg) and 2,2-dimethylbutanoylchloride (135 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.27-7.31 (m, 2H), 7.02-7.06 (m, 2H), 4.85 (s, 2H), 1.68 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.18FNO.sub.2, 240.1; found 240.2.

Compound 95: Preparation of N-(3,4-difluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide

(204) ##STR00282##

(205) The titled compound 95 was prepared in 71% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (225 mg), 4-(bromomethyl)-1,2-difluorobenzene (200 mg) and 2,2-dimethylbutanoylchloride (135 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.10-7.17 (m, 2H), 7.02-7.06 (m, 1H), 4.81 (s, 2H), 1.68 (q, 2H, J=7.6 Hz), 1.25 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.17F.sub.2NO.sub.2, 258.1; found 258.2.

Compound 96: Preparation of N-(2,4-difluorobenzyl)-N-hydroxy-2,2-dimethylbutanamide

(206) ##STR00283##

(207) The titled compound 96 was prepared in 65% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (225 mg), 1-(bromomethyl)-2,4-difluorobenzene (200 mg) and 2,2-dimethylbutanoylchloride (135 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 77.32-7.38 (m, 1H), 6.80-6.90 (m, 2H), 4.90 (s, 2H), 1.68 (q, 2 H, J=7.6 Hz), 1.25 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.17F.sub.2NO.sub.2, 258.1; found 258.2.

Compound 97: Preparation of N-hydroxy-2,2-dimethyl-N-(2,3,4-trifluorobenzyl)butanamide

(208) ##STR00284##

(209) The titled compound 97 was prepared in 65% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (104 mg), 1-(bromomethyl)-2,3,4-trifluorobenzene (100 mg) and 2,2-dimethylbutanoylchloride (54 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.08-7.14 (m, 1H), 6.93-7.00 (m, 1H), 4.92 (s, 2H), 1.68 (q, 2H, J=7.6 Hz), 1.25 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found 276.2.

Compound 98: Preparation of N-hydroxy-2,2-dimethyl-N-(2,4,5-trifluorobenzyl)butanamide

(210) ##STR00285##

(211) The titled compound 98 was prepared in 65% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (104 mg), 1-(bromomethyl)-2,4,5-trifluorobenzene (100 mg) and 2,2-dimethylbutanoylchloride (54 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.19-7.24 (m, 1H), 6.91-6.98 (m, 1H), 4.88 (s, 2H), 1.68 (q, 2H, J=7.6 Hz), 1.25 (s, 6H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found 276.2.

Compound 99: Preparation of N-hydroxy-2,2-dimethyl-N-(3,4,5-trifluorobenzyl)butanamide

(212) ##STR00286##

(213) The titled compound 99 was prepared in 65% yield from tert-butyl (tert-butoxycarbonyl)oxycarbamate (104 mg), 5-(bromomethyl)-1,2,3-trifluorobenzene (100 mg) and 2,2-dimethylbutanoylchloride (54 mg) according to the procedure outlined for compound 93. .sup.1HNMR(CDCl.sub.3, 400 MHz): 6.92-7.00 (m, 2H), 4.79 (s, 2H), 1.68 (q, 2H, J=7.6 Hz), 1.26 (s, 6H), 0.85 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.16F.sub.3NO.sub.2, 276.1; found, 276.2.

Compound 100: Preparation of (S)-methyl 3-(2,2-dimethylbutanamido)-3-phenylpropanoate

(214) ##STR00287##

(215) (S)-3-amino-3-phenylpropanoic acid (1 g) was dissolved in methanol (10 ml), 1 ml of thionyl chloride was added at 0 C. The mixture was refluxed for 4 h. The solvent was evaporated to dryness and the resulting solid was washed with petroleum ether. The crude product and triethylamine (0.7 ml) were dissolved in 15 ml of CH.sub.2Cl.sub.2, 2,2-dimethylbutanoylchloride (1 g) was added slowly at 0 C. under nitrogen. The mixture was stirred at room temperature for 4 h. After removal of solvent and purified by silica gel column chromatography to give compound 100 (110 mg, 32%). .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.31-7.35 (m, 2H), 7.23-7.28 (m, 3H), 5.40-5.45 (m, 1H), 3.62 (s, 3H), 2.87 (m, 2H), 1.57 (q, 2H, J=7.6 Hz), 1.19 (s, 3H), 1.18 (s, 3H), 0.83 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.23NO.sub.3, 278.2; found 278.4.

Compound 101: Preparation of (S)-2,2-dimethyl-N-(3-(methylamino)-3-oxo-1-phenylpropyl)butanamide

(216) ##STR00288##

(217) Compound 100 (840 mg) was dissolved in 30 ml of methanol, 1M NaOH (40 ml) was added. The mixture was stirred at room temperature for 5 h. The solvent was removed and acidified with 1N HCl. The aqueous phase was extracted with CH.sub.2Cl.sub.2. The combined organic layer was wash with water, dried with Na.sub.2SO.sub.4. Filtered and evaporated to dryness to give (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (780 mg, 98%) as a brown oil. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.31-7.34 (m, 2H), 7.24-7.28 (m, 3H), 6.75 (d, 1H, J=8.4 Hz), 5.40-5.45 (m, 1H), 2.83-2.93 (m, 2H), 1.55 (q, 2H, J=7.6 Hz), 1.16 (s, 1H), 1.15 (s, 1H), 0.81 (t, 3H, J=7.6 Hz).

(218) The titled compound 101 was prepared in 55% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and methanamine hydrochloride (9.2 mg) according to the procedure for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.83 (brs, 1H), 7.26-7.33 (m, 3H), 7.21-7.25 (m, 2H), 5.92 (brs, 1H), 5.26-5.31 (m, 1H), 3.67-3.72 (m, 1H), 3.12-3.19 (m, 1H), 2.71 (d, 3H, J=4.8 Hz), 1.58 (m, 2H), 1.20 (s, 3H), 1.19 (s, 3H), 0.82 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.21NO.sub.3, 277.2; found 277.4.

Compound 102: Preparation of (S)N-(3-((2-(2-methoxyethoxy)ethyl)amino)-3-oxo-1-phenylpropyl)-2,2-dimethylbutanamide

(219) ##STR00289##

(220) The titled compound 102 was prepared in 51% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and 2-(2-methoxyethoxy)ethanamine (16.3 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.98-8.01 (brs, 1H), 7.27-7.33 (m, 4H), 7.21-7.25 (m, 1H), 6.41-6.45 (brs, 1H), 5.27-5.32 (m, 1H), 3.67-3.74 (m, 1H), 3.40-3.56 (m, 5H), 3.36 (s, 3H), 3.13-3.19 (m, 2H), 2.78-2.83 (m, 1H), 2.68-2.73 (m, 1H), 1.54-1.62 (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H), 0.83 (t, 3H, J=7.2 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.20H.sub.32N.sub.2O.sub.4, 365.2; found 365.4.

Compound 103: Preparation of (S)N-(3-(ethylamino)-3-oxo-1-phenylpropyl)-2,2-dimethylbutanamide

(221) ##STR00290##

(222) The titled compound 103 was prepared in 39% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and ethylamine hydrochloride (11 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): .sup.1H-NMR (CDCl3) 7.87-7.89 (brs, 1H), 7.27-7.32 (m, 4H), 7.23-7.25 (m, 1H), 5.74 (brs, 1H), 5.28-5.32 (m, 1H), 3.12-3.24 (m, 2H), 2.757 (dd, 1H, J=4.8, 14.4 Hz), 2.582 (dd, 1H, J=5.6, 14.4 Hz), 1.56-1.62 (qd, 2H, J=7.2, 1.6 Hz), 1.21 (s, 3H), 1.21 (s, 3H), 1.006 (t, 3H, J=7.2 Hz), 0.823 (t, 3H, J=7.2 Hz) LC-MS (ESI) [M+H].sup.+ calcd for C.sub.17H.sub.26N.sub.2O.sub.2, 291; found 291.2.

Compound 104: Preparation of (S)N-(3-(cyclohexylamino)-3-oxo-1-phenylpropyl)-2,2-dimethylbutanamide

(223) ##STR00291##

(224) The titled compound 104 was prepared in 21% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and cyclohexanamine (14 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.95 (brs, 1H), 7.27-7.31 (m, 3H), 7.20-7.24 (m, 2H), 5.41 (brs, 1H), 5.28-5.32 (m, 1H), 3.62-3.71 (m, 1H), 2.73 (dd, 1H, J=4.8, 14.4 Hz), 2.50 (dd, 1H, J=4.8, 14.4 Hz), 1.79-1.82 (m, 2H), 1.56-1.67 (m, 6H), 1.26-1.36 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H), 1.01-1.13 (m, 2H), 0.82 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.21H.sub.32N.sub.2O.sub.2, 345.2; found 345.4.

Compound 105: Preparation of (S)-2,2-dimethyl-N-(3-oxo-1-phenyl-3-(piperidin-1-yl)propyl)butanamide

(225) ##STR00292##

(226) The titled compound 105 was prepared in 29% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and piperidine (14 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.99 (brs, 1H), 7.27-7.32 (m, 4H), 7.19-7.23 (m, 1H), 5.32 (m, 1H), 3.56-3.60 (m, 1H), 3.32-3.39 (m, 1H), 3.17-3.24 (m, 2H), 3.033 (dd, 1H, J=5.6, 14.4 Hz), 2.679 (dd, 1H, J=4.8, 14.4 Hz), 1.55-1.61 (m, 2H), 1.50-1.54 (m, 2H), 1.36-1.48 (m, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.04-1.10 (m, 1H), 0.83 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.20H.sub.30N.sub.2O.sub.2, 331.2, found 331.4.

Compound 106: Preparation of (S)-2,2-dimethyl-N-(3-oxo-1-phenyl-3-(phenylamino)propyl)butanamide

(227) ##STR00293##

(228) The titled compound 106 was prepared in 28% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and aniline (13 mg) according to the procedure outlined for compound 101. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.65 (brs, 1H), 7.27-7.40 (m, 9H), 7.106 (t, 1H, J=7.2 Hz), 5.41-5.45 (m, 1H), 2.83-2.99 (m, 2H), 1.578 (q, 2H, J=7.6 Hz), 1.19 (s, 6H), 0.81 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.21H.sub.26N.sub.2O.sub.2, 339.2; found, 339.4.

Compound 107: Preparation of (S)N-(3-(benzylamino)-3-oxo-1-phenylpropyl)-2,2-dimethylbutanamide

(229) ##STR00294##

(230) The titled compound 107 was prepared in 28% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and phenylmethanamine (15 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.91 (brs, 1H), 7.28-7.39 (m, 8H), 7.02-7.04 (m, 2H), 6.29 (brs, 1H), 5.33-5.36 (m, 1H), 4.39 (d, 2H, J=5.2 Hz), 2.84-2.91 (m, 1H), 2.71-2.76 (m, 1H), 1.59 (qd, 2H, J=1.2, 7.6 Hz), 1.21 (s, 3H), 1.20 (s, 3H), 0.83 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.22H.sub.28N.sub.2O.sub.2, 353.2; found, 353.4.

Compound 108: Preparation of (S)-2,2-dimethyl-N-(3-oxo-3-(phenethylamino)-1-phenylpropyl)butanamide

(231) ##STR00295##

(232) The titled compound 108 was prepared in 31% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and phenylmethanamine (16 mg) according to the procedure outlined for compound 101. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.96-7.98 (brs, 1H), 7.27-7.34 (m, 4H), 7.17-7.25 (m, 4H), 6.94-6.97 (m, 2H), 5.59 (brs, 1H), 5.28-5.32 (m, 1H), 3.46-3.55 (m, 1H), 3.25-3.33 (m, 1H), 2.67-2.75 (m, 2H), 2.49-2.61 (m, 2H), 1.58 (qd, 2H, J=2.0, 7.6 Hz), 1.22 (s, 3H), 1.21 (s, 3H), 0.84 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.23H.sub.30N.sub.2O.sub.2, 367.2; found, 367.4.

Compound 109: Preparation of (R)N-(2-hydroxy-1-phenylethyl)-2,2-dimethylbutanamide

(233) ##STR00296##

(234) (R)-2-amino-2-phenylethanol (50 mg, 0.365 mmoL) and NaHCO.sub.3 (91.9 mg, 1.094 mmol) were dissolved in 2 mL of THF/H.sub.2O (v/v=1/1). 2,2-dimethylbutanoylchloride

(235) (43 mg, 0.398 mmoL) was added slowly to the solution at 0 C. under nitrogen. The mixture was stirred at room temperature for 16 h, and extracted with EtOAc (15 mL3). The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4. Filtered and evaporated to dryness. The residue was purified by column chromatography to give compound 109 as white solid (45 mg, 59.2%). .sup.1H NMR: (CDCl.sub.3, 400 M Hz): (ppm) 7.35-7.39 (m, 2H), 7.28-7.32 (m, 3H), 6.26 (brs, 1H), 5.05-5.09 (m, 1H), 3.87-3.94 (m, 2H), 2.70 (brs, 1H), 1.59 (q, 2H, J=7.6 Hz), 1.20 (s, 3H), 1.19 (s, 3H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.2iNO.sub.2, 236.2; found 236.3.

Compound 110: Preparation of N-(2-hydroxy-1-phenylethyl)-2,2-dimethylbutanamide

(236) ##STR00297##

(237) The titled compound 110 was prepared in 78.3% yield from 2-amino-2-phenylethanol (50 mg) and 2,2-dimethylbutanoyl chloride (54 mg) according to the procedure outlined for compound 109. .sup.1H NMR: (CDCl.sub.3, 400 M Hz) 7.36-7.40 (m, 2H), 7.28-7.33 (m, 3H), 6.27 (brs, 1H), 5.07 (dd, 1H, J=5.6, 10.8 Hz), 3.88-3.92 (m, 2H), 2.72 (brs, 1H), 1.58 (q, 2H, J=7.6 Hz), 1.20 (s, 3H), 1.19 (s, 3H), 0.87 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.23NO.sub.2, 236.2; found 236.3.

Compound 111: Preparation of N-(2-hydroxy-1-phenylethyl)-N,2,2-trimethylbutanamide

(238) ##STR00298##

(239) The titled compound 111 was prepared in 9.8% yield from 2-(methylamino)-2-phenylethanol (50 mg) and 2,2-dimethylbutanoyl chloride (48 mg) according to the procedure outlined for compound 109. .sup.1H NMR: (MeOD, 400 M Hz) 7.43-7.44 (m, 3H), 7.28-7.38 (m, 2 H), 4.29-4.38 (m, 2H), 5.88 (m, 1H), 2.43 (s, 3H), 1.528 (q, 2H, J=7.6 Hz), 1.11 (s, 6H), 0.75 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.23NO.sub.2, 250.2; found 250.3.

Compound 112: Preparation of N-(2-methoxy-1-phenylethyl)-N,2,2-trimethylbutanamide

(240) ##STR00299##

(241) N-(2-hydroxy-1-phenylethyl)-2,2-dimethylbutanamide (40 mg, 0.17 mmoL) was dissolved in 2 mL of dry THF. NaH (20.4 mg, 0.51 mmoL, 60% in material oil) was added in portions to the solution at 0 C. under nitrogen. After stirring at 0 C. for 0.5 h, iodomethane (72.5 mg, 0.51 mmoL) was added. The mixture was stirred at room temperature for 16 h, quenched with water (1 ml) and extracted with EtOAc. The combined organic layers were evaporated to dryness and the residue was purified by column chromatography to give compound 112 (20 mg, 44.7%) as colorless oil. .sup.1H NMR: (CDCl.sub.3, 400 M Hz) 7.31-7.35 (m, 2H), 7.22-7.28 (m, 3H), 5.70-6.20 (m, 1H), 3.81-3.90 (m, 2H), 3.41 (s, 3H), 2.84 (s, 3H), 1.63-1.73 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), 0.91 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.25NO.sub.2, 264.2; found, 264.4.

Compound 113: Preparation of 3-cyclohexyl-1-(2-fluorobenzyl)-1-methylurea

(242) ##STR00300##

(243) To a solution of 1-(2-fluorophenyl)-N-methylmethanamine (97 mg) in THF (10 ml) was added N,N-Diisopropylethylamine (135 mg), then isocyanatocyclohexane (131 mg) in THF (1 ml) was added. The mixture was stirred for overnight and diluted with water. The aqueous layer was extracted with CH.sub.2Cl.sub.2 and the combined organic layers were washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography to give compound 113 (65 mg, 35%). .sup.1HNMR: (CDCl.sub.3, 400 M Hz): 87.22-7.34 (m, 2H), 7.02-7.14 (m, 2H), 4.53 (s, 2H), 3.59-3.71 (m, 1H), 2.90 (s, 3H), 1.91-1.97 (m, 2H), 1.57-1.71 (m, 3H), 1.31-1.42 (m, 2H), 1.03-1.18 (m, 3H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.21FN.sub.2O, 265.2; found 265.4.

Compound 114: Preparation of 1-(2-fluorobenzyl)-3-isopropyl-1-methylurea

(244) ##STR00301##

(245) The titled compound 117 was prepared in 30% yield from 2-isocyanatopropane (92 mg) and 1-(2-fluorophenyl)-N-methylmethanamine (97 mg) according to the procedure outlined for compound 113. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 87.22-7.32 (m, 2H), 7.02-7.14 (m, 2H), 4.53 (s, 2H), 3.96-4.03 (m, 1H), 2.89 (s, 3H), 1.15 (d, 6H, J=6.4 Hz), LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.17FN.sub.2O, 225.1; found 225.2.

Compound 115: Preparation of 1-ethyl-3-isopropyl-3-methyl-1-(2,3,5-trifluorobenzyl)urea

(246) ##STR00302##

(247) To a solution of triphosgene (154 mg) in dichloromethane (4 ml) was added N-methylpropan-2-amine (40 mg) at 0 C. under nitrogen The mixture was stirred at 0 C. for 4 h. Then the solvent was removed, and a solution of N-(2,3,5-trifluorobenzyl)-ethanamine (60 mg) in dichloromethane (2 ml) was added. The mixture was stirred at 35 C. for overnight, diluted with water. The aqueous layer was extracted with EtOAc (5 mL3). The combined organic layers were washed with saturated NaHCO.sub.3 and brine, dried with Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by column chromatography to give compound 115 (4 mg, 2.5%) as a yellow oil. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.86-6.89 (m, 1H), 6.76-6.81 (m, 1H), 4.38 (s, 2H), 4.07 (m, 1H), 3.09-3.14 (q, 2H, J=7.2 Hz), 2.70 (s, 3H), 1.13-1.17 (m, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.19F.sub.3N.sub.2O, 289.1; found 289.2.

Compound 116: Preparation of 2-ethyl-N-methyl-N-(2,3,5-trifluorobenzyl)piperidine-1-carboxamide

(248) ##STR00303##

(249) The titled compound 119 was prepared in 14.9% yield from triphosgene (77.1 mg), 2-ethylpiperidine (29.4 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.79-6.88 (m, 2H), 4.45 (d, 1H, J=15.6 Hz), 4.29 (d, 1H, J=15.6 Hz), 3.72-3.74 (m, 1H), 3.43-3.48 (m, 1H), 2.94-3.01 (m, 1H), 2.77 (s, 3H), 1.57-1.70 (m, 8H), 0.98 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.21F.sub.3N.sub.2O, 315.2; found 315.3.

Compound 117: Preparation of N,2-dimethyl-N-(2,3,5-trifluorobenzyl)piperidine-1-carboxamide

(250) ##STR00304##

(251) The titled compound 120 was prepared in 15.6% yield from triphosgene (77.1 mg), 2-methylpiperidine (25.71 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.78-6.84 (m, 2H), 4.43 (d, 1H, J=16 Hz), 4.34 (d, 1H, J=16 Hz), 3.90-3.93 (m, 1H), 3.32-3.36 (m, 1H), 2.95-3.02 (m, 1H), 2.76 (s, 3H), 1.44-1.68 (m, 6H), 1.18 (d, 3H, J=4 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.19F.sub.3N.sub.2O, 301.1; found 301.3.

Compound 118: Preparation of N,3-dimethyl-N-(2,3,5-trifluorobenzyl)piperidine-1-carboxamide

(252) ##STR00305##

(253) The titled compound 121 was prepared in 9.7% yield from triphosgene (84.8 mg), 2-methylpiperidine (28.3 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 MHz): 7.05-7.07 (m, 1H), 6.89-6.91 (m, 1H), 4.42-4.84 (m, 2H), 2.80 (s, 3H), 3.49-3.53 (m, 2H), 2.75-2.77 (m, 2H), 1.77-1.79 (m, 1H), 1.57-1.67 (m, 4H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.19F.sub.3N.sub.2O, 301.1; found 301.3.

Compound 119: Preparation of 1,1-diisopropyl-3-methyl-3-(2,3,5-trifluorobenzyl)urea

(254) ##STR00306##

(255) The titled compound 119 was prepared in 19.3% yield from triphosgene (84.8 mg), diisopropylamine (26.86 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.79-6.82 (m, 2H), 4.30 (s, 2H), 3.58-3.62 (m, 2H), 2.68 (s, 3H), 1.26 (d, 12H, J=6.4 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.21F.sub.3N.sub.2O, 303.2; found 303.4.

Compound 120: Preparation of isopropyl-1,3-dimethyl-3-(2,3,5-trifluorobenzyl)urea

(256) ##STR00307##

(257) The titled compound 120 was prepared in 20.8% yield from triphosgene (84.8 mg), N-methylpropan-2-amine (20.86 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.80-6.87 (m, 2H), 4.38 (s, 2H), 4.00-4.11 (m, 1H), 2.75 (s, 3H), 2.67 (s, 3H), 1.10 (d, 6H, J=6.4 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.17F.sub.3N.sub.2O, 275.1; found 275.2.

Compound 121: Preparation of N,2,6-trimethyl-N-(2,3,5-trifluorobenzyl)piperidine-1-carboxamide

(258) ##STR00308##

(259) The titled compound 121 was prepared in 14.5% yield from triphosgene (84.8 mg), 2,6-dimethylpiperidine (32.28 mg) and N-methyl-1-(2,3,5-trifluorophenyl)methanamine (30 mg) according to the procedure outlined for compound 115. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.80-6.90 (m, 2H), 4.61 (s, 2H), 3.18-3.23 (m, 2H), 2.97 (s, 3H), 1.70-1.75 (m, 1H), 1.59-1.65 (m, 2H), 1.32-1.45 (m, 1H), 1.22-1.39 (m, 2H), 1.12 (d, 6H, J=6.4 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.21F.sub.3N.sub.2O, 315.2; found 315.4.

Compound 122: Preparation of (R)-2,2-dimethyl-N-(2-(methylamino)-2-oxo-1-phenylethyl)butanamide

(260) ##STR00309##

(261) The titled compound 122 was prepared in 35% yield from (R)-2-(2,2-dimethylbutanamido)-2-phenylacetic acid (30 mg), which was prepared from (R)-2-amino-2-phenylacetic acid according to the procedure outlined for compound 101, and methanamine hydrochloride (10 mg) according to the procedure outlined for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.28-7.38 (m, 5H), 7.14 (brs, 1H), 6.38 (brs, 1H), 5.52 (d, J=6.8 Hz, 1H), 2.77 (d, J=4.8 Hz, 3H), 1.51-1.60 (m, 2H), 1.18 (s, 3H), 1.17 (s, 3H), 0.78 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.22N.sub.2O.sub.2, 263.2; found, 263.3.

Compound 123: Preparation of (R)N-(2-(dimethylamino)-2-oxo-1-phenylethyl)-2,2-dimethylbutanamide

(262) ##STR00310##

(263) The titled compound 186 was prepared in 35% yield from (R)-2-(2,2-dimethylbutanamido)-2-phenylacetic acid (30 mg) and dimethylamine (6.48 mg) according to the procedure outlined for compound 65. .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.28-7.41 (m, 5H), 5.80 (d, 1H, J=6.8 Hz), 2.99 (s, 3H), 2.89 (s, 3H), 1.45-1.55 (m, 2H), 1.13 (s, 3H), 1.12 (s, 3H), 0.70 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.16H.sub.24N.sub.2O.sub.2, 277.2; found, 277.4.

Compound 124: Preparation of (R)N-(2-(benzylamino)-2-oxo-1-phenylethyl)-2,2-dimethylbutanamide

(264) ##STR00311##

(265) The titled compound 124 was prepared in 37% yield from (R)-2-(2,2-dimethylbutanamido)-2-phenylacetic acid (30 mg) and phenylmethanamine (15.4 mg) according to the procedure outlined for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.28-7.38 (m, 5H), 7.23-7.26 (m, 2H), 7.07-7.12 (m, 3H), 6.14 (brs, 1H), 5.49 (d, 1H, J=6.4 Hz), 4.42 (d, 2H, J=5.2 Hz), 1.49-1.55 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 0.76 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.21H.sub.26N.sub.2O.sub.2, 339.2; found, 339.4.

Compound 125: Preparation of (R)-2,2-dimethyl-N-(2-oxo-2-(phenethylamino)-1-phenylethyl)butanamide

(266) ##STR00312##

(267) The titled compound 188 was prepared in 38% yield from (R)-2-(2,2-dimethylbutanamido)-2-phenylacetic acid (30 mg) and 2-phenylethanamine (17.4 mg) according to the procedure outlined for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.28-7.35 (m, 5H), 7.17-7.23 (m, 3H), 7.11-7.12 (brs, 1H), 6.92-6.94 (m, 2H), 5.57 (brs, 1H), 5.25-5.27 (d, 1H, J=6.0 Hz), 3.57-3.65 (m, 1H), 3.32-3.40 (m, 1H), 2.63-2.77 (m, 2H), 1.50-1.56 (qd, 2H, J=7.6, 2.0 Hz), 1.16 (s, 3H), 1.15 (s, 3H), 0.76 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.22H.sub.28N.sub.2O.sub.2, 353.2; found, 353.4.

Compound 126: Preparation of (S)-2,2-dimethyl-N-(3-oxo-3-((2-phenoxyethyl)amino)-1-phenylpropyl)butanamide

(268) ##STR00313##

(269) The titled compound 126 was prepared in 42% yield from (S)-3-(2,2-dimethylbutanamido)-3-phenylpropanoic acid (30 mg) and 2-phenoxyethanamine (19 mg) according to the procedure outlined for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.79-7.81 (brs, 1H), 7.27-7.31 (m, 2H), 7.19-7.26 (m, 4H), 7.09-7.13 (m, 1H), 6.95-7.00 (m, 1H), 6.78-6.81 (m, 2H), 5.94 (brs, 1H), 5.31-5.35 (m, 1H), 3.90-3.94 (m, 1H), 3.79-3.84 (m, 1H), 3.50-3.61 (m, 2H), 2.77 (dd, 1H, J=4.8, 14.4 Hz), 2.62 (dd, 1H, J=4.8, 14.4 Hz), 1.56-1.63 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H), 0.83 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.23H.sub.30N.sub.2O.sub.3, 383.2, found, 383.4.

Compound 127: Preparation of (R)-2,2-dimethyl-N-(2-oxo-2-((2-phenoxyethyl)amino)-1-phenylethyl)butanamide

(270) ##STR00314##

(271) The titled compound 127 was prepared in 40% yield from (R)-2-(2,2-dimethylbutanamido)-2-phenylacetic acid (30 mg) and 2-phenoxyethanamine (20 mg) according to the procedure outlined for compound 65. .sup.1HNMR(CDCl.sub.3, 400 MHz): 7.27-7.36 (m, 5H), 7.23-7.25 (m, 1H), 6.92-7.00 (m, 2H), 6.77-6.80 (m, 2H), 6.10 (brs, 1H), 5.41 (d, 1H, J=6.4 Hz), 3.94-4.03 (m, 2H), 3.57-3.71 (m, 2H), 1.51-1.57 (m, 2H), 1.17 (s, 3H), 1.16 (s, 3H), 0.77 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.22H.sub.28N.sub.2O.sub.3, 369.2; found, 369.4.

Compound 128: Preparation of N-((4,5-dimethylthiophen-2-yl)methyl)-N,2,2-trimethylbutanamide

(272) ##STR00315##

(273) The titled compound 128 was prepared in 36% yield from 1-(4,5-dimethylthiophen-2-yl)-N-methylmethanamine (60 mg), which was prepared from 4,5-dimethylthiophene-2-carbaldehyde and methanamine hydrochloride according to the procedure outlined for compound 13, and 2,2-dimethylbutanoyl chloride (57 mg) according to the procedure outlined for compound 52. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 6.61 (s, 1H), 4.58 (s, 2H), 3.03 (s, 3H), 2.28 (s, 3H), 2.07 (s, 3H), 1.66 (q, 2H, J=7.6 Hz), 1.27 (s, 6H), 0.88 (t, 3H, J=7.6 Hz). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.23NOS 254.2; found 254.3.

Compound 129: Preparation of 2,6-dichloro-N-methyl-N-(3,4,5-trifluorobenzyl)benzamide

(274) ##STR00316##

(275) The titled compound 129 was prepared in 77% yield from N-methyl-1-(3,4,5-trifluorophenyl)methanamine (30 mg) and 2,6-dichlorobenzoyl chloride (39.5 mg) according to the procedure outlined for compound 52. .sup.1H NMR: (CDCl.sub.3, 400 M Hz): 7.33-7.36 (m, 2H), 7.26-7.29 (m, 1H), 7.04-7.07 (m, 2H), 4.72 (s, 2H), 2.77 (s, 3H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.15H.sub.10C.sub.12F.sub.3NO, 348.0; found, 348.2.

Compound 130-135 and 151

(276) Compound 130-135 are prepared according to the method of scheme 1

(277) ##STR00317##

(278) Scheme 1: Reagent and conditions: (a): NaOH, Dimethylsulfate, DCM/H.sub.2O

Compound 136-147

(279) Compounds 136-147 are prepared according to the method of scheme 2

(280) ##STR00318##

(281) Scheme 2: Reagent and conditions: (a): NH.sub.2OH*HCl; Na.sub.2CO.sub.3; (b): Na(CN)BH.sub.3; (c) 2,2-dimethylbutanoyl chloride or 2,2-dimethylbut-3-enoyl chloride, NaHCO3, THF/H2O, 0 C. 30 min, rt, 16 h.

Compound 148 and 149

(282) Compound 148 and 149 are prepared according to the method of scheme 3

(283) ##STR00319##

(284) Scheme 3: Reagent and conditions: (a): NaHCO3, ethyl carbonochloridate, THF/DCM (b) LiAlH.sub.4, THF, rt, 16 h (c): 2,2-dimethylbutanoyl chloride NaHCO3, THF/H2O, 0 C. 30 min, rt, 16 h,

Compound 150

(285) Compound 150 is prepared according to the method of scheme 4

(286) ##STR00320##

(287) Scheme 4: Reagent and conditions: (a): NaHCO3, ethyl carbonochloridate, THF/DCM, 0 C. 30 rt, 16 h.

Compound S1: Preparation of N-(2,3,5-trifluorobenzyl)pivalamide

(288) ##STR00321##

(289) (2,3,5-trifluorophenyl)methanamine (42 mg, 0.263 mmol) and triethylamine (53.2 mg, 0.526 mmol) were dissolved in 2 mL of dry CH.sub.2Cl.sub.2. Pivaloyl chloride (38 mg, 0.316 mmol) was added slowly to the solution at 0 C. under nitrogen. The mixture was stirred at room temperature for 2 h, diluted with CH.sub.2Cl.sub.2 and water. The organic layer were washed with saturated NaHCO.sub.3 solution, brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound 51 (49 mg, 74%) as an light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.86-6.77 (m, 2H), 4.47 (d, J=4.9 Hz, 2H), 1.21 (s, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.12H.sub.15F.sub.3NO, 246.11; found, 246.17.

Compound S2: Preparation of N-methyl-N-(2,3,5-trifluorobenzyl)pivalamide

(290) ##STR00322##

(291) Compound S1 (70 mg) was dissolved in 2 mL of dry THF, 17 mg of NaH (60%) was added at 0 C. under N2 and stirred for 2 h. Iodomethane (0.026 mL) was added and the mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was quenched with cold water and extracted with DCM, the combined organic layers was washed with water, brine, dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by pre-TLC to give the product S2 (35 mg, 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.82-6.71 (m, 2H), 4.65 (s, 2H), 3.11 (s, 3H), 1.33 (s, 9H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.13H.sub.17F.sub.3NO, 260.13; found, 260.19.

Compound 3: Preparation of N-acetoxy-N-benzyl-2,2-dimethylbutanamide

(292) ##STR00323##

(293) n-benzylhydroxylamine hydrochloride (100 mg) was dissolved in 2 mL of THF/H.sub.2O (1:1) and 0.45 mL of saturated aqueous NaHCO.sub.3. The solution was cooled to 0 C. and 2,2-dimethylbutanoylchloride (81 mg) was added and the mixture was stirred at rt for 16 h. The mixture was extracted with EtOAc and the combined organic layer washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Purification by silica gel chromatography to give N-benzyl-N-hydroxy-2,2-dimethylbutanamide (60 mg, 43.3%) as an white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.34 (m, 2H), 7.33-7.31 (m, 3H), 4.89 (s, 2H), 1.69 (q, J=7.6 Hz, 2H), 1.26 (s, 6H), 0.86 (t, J=7.6 Hz, 6H).

(294) N-benzyl-N-hydroxy-2,2-dimethylbutanamide (800 mg) and TEA (2.5 mL) were dissolved in 20 mL of DCM. Acetyl chloride (0.283 mL) was added slowly to the mixture at 0 C. and the mixture was stirred at room temperature for 16 h, concentrated and the residue was purified by chromatography to give product S3 (260 mg, 27.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.33-7.23 (m, 5H), 4.89 (s, 2H), 2.09 (s, 3H), 1.53 (q, J=7.5 Hz, 2H), 1.16 (s, 6H), 0.80 (t, J=7.5 Hz, 3H).

Compound S4: Preparation of N-benzyl-N-methoxy-2,2-dimethylbutanamide

(295) ##STR00324##

(296) N-benzyl-N-hydroxy-2,2-dimethylbutanamide (800 mg), iodomethane (565.2 mg) and KOH (179.4 mg) were added in 30 mL of ethanol. The mixture was stirred at 50 C. for 5 h and evaporated to dryness. The residue was diluted with CH.sub.2Cl.sub.2 and water. The organic layer were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give compound S4 (210 mg, 28.2%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.34-7.22 (m, 5H), 4.79 (s, 2H), 3.64 (s, 3H), 1.63 (q, J=7.5 Hz, 2H), 1.20 (s, 6H), 0.79 (t, J=7.5 Hz, 3H).

Compound S5: Preparation of 3,3-difluoro-N,2,2-trimethyl-N-(2,3,5-trifluorobenzyl)butanamide

(297) ##STR00325##

(298) A mixture of K.sub.2CO.sub.3 (324 mg, 2.35 mmol) and methanamine hydrochloride (316 mg, 4.69 mmol) in 10 mL of MeOH was stirred at rt for 30 min. Then 2,3,5-trifluorobenzaldehyde (500 mg, 3.125 mmol) was added to the mixture and stirred at rt for 2 h. The mixture was cooled to 0 C., and NaBH.sub.4 (178.2 mg, 4.69 mmol) was added in portions. The mixture was stirred at 0 C. for 1 h and warmed to room temperature and stirred for 12 h. The solid was filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was dissolved in EtOAc and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, concentrated to give N-methyl-1-(2,3,5-trifluorophenyl)methanamine (260 mg), which used for next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.94-6.87 (m, 1H), 6.86-6.76 (m, 1H), 3.81 (d, J=1.4 Hz, 2H), 2.44 (s, 3H).

(299) To a solution of N-methyl-1-(2,3,5-trifluorophenyl)methanamine (44 mg) and 3,3-difluoro-2,2-dimethylbutanoic acid (38 mg) in dry DMF (1 mL) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (142 mg) and DIEA (0.08 mL). The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layer was washed with saturated brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by pre-TLC to give compound S5 (36 mg, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.88-6.78 (m, 1H), 6.71 (m, 1H), 4.67 (s, 2H), 3.15 (s, 3H), 1.66 (t, J=19.4 Hz, 3H), 1.46 (s, 6H). LC-MS (ESI) [M+H].sup.+ calcd for C.sub.14H.sub.17F.sub.5NO, 310.12; found, 310.21.

Compound S6: Preparation of N-benzyl-3,3-difluoro-N-hydroxy-2,2-dimethylbutanamide

(300) ##STR00326##

(301) To a solution of n-benzylhydroxylamine hydrochloride (36.8 mg) and 3,3-difluoro-2,2-dimethylbutanoic acid (35 mg) in dry DMF (1 mL) was added 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg) and DIEA (0.16 mL). The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with CH.sub.2Cl.sub.2. The organic layer were washed with saturated brine, dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by pre-TLC to give compound S6 (10 mg, 17%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.34-7.25 (m, 5H), 4.64 (s, 2H), 1.73 (t, J=19.8 Hz, 3H), 1.38 (s, 6H).

Compound S7: Preparation of N-(4-fluorobenzyl)-N,2,2-trimethylbutanamide

(302) ##STR00327##

(303) A mixture of K.sub.2CO.sub.3 (207 mg, 1.5 mmol) and methanamine hydrochloride (202 mg, 3.0 mmol) in 5 mL of MeOH was stirred at rt for 30 min. Then 4-fluorobenzaldehyde (248 mg, 2.0 mmol) was added to the mixture and stirred at rt for 1 h. The mixture was cooled to 0 C., and NaBH.sub.4 (113.5 mg, 3.0 mmol) was added in portions. The mixture was stirred at 0 C. for 1 h and warmed to room temperature and stirred for 2 h. The solid was filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was dissolved in EtOAc and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4. The residue was dissolved in 10 mL of dry THF. DIEA (264 mg, 2.05 mmol) was added, 2,2-dimethylbutanoyl chloride (275 mg, 2.05 mmol) was added slowly to the solution at 0 C. under nitrogen, then stirred at room temperature for 2 h. 15 mL of water was added to the solution and extracted with EtOAc (10 mL3). The combined organic was washed with 1M HCl, brine, dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/2) to give the 189 mg of S7 as a brown solid (total yield=40%). .sup.1H NMR (400 M Hz, CDCl.sub.3) 7.21-7.12 (m, 2H), 6.98-6.93 (m, 2H), 4.54 (s, 2H), 2.95 (s, 3H), 1.64 (q, J=7.5 Hz, 2H), 1.24 (s, 6H), 0.84 (t, J=7.5 Hz, 3H). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.21F.sub.2NO, 256.16; found, 256.18.

Compound S8: Preparation of N-(2,3-difluorobenzyl)-N,2,2-trimethylbutanamide

(304) ##STR00328##

(305) Compound S8 was prepared in 56% yield from 2,3-difluorobenzaldehyde (284 mg), methanamine hydrochloride (202 mg) and 2,2-dimethylbutanoyl chloride (275 mg) according to the procedure outlined for compound 7. .sup.1H NMR (400 M Hz, CDCl.sub.3) 7.11-6.94 (m, 3H), 4.66 (s, 2H), 3.06 (s, 3H), 1.66 (q, J=7.5 Hz, 2H), 1.25 (s, 6H), 0.85 (t, J=7.5 Hz, 3H). LC-MS (ESI) [M+H].sup.+ calcd for: C.sub.14H.sub.20F.sub.2NO, 256.15; found, 256.18.

Compound S9-S20

(306) Compound S9-S20 are prepared according to the procedure outlined in scheme 1

(307) ##STR00329##

(308) 3. Kinase Assay of RIPK1

(309) Materials:

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

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

(312) Results:

(313) pIC50 of hRIP1 kinase assay correlated with our pIC50 of cell necrosis assay. Exemplary data are shown below:

(314) TABLE-US-00013 RIP1 Cell viability hRIP1 kinase assay, IC50(nM) or # CMPD ID assay, EC50 (nM) % inhibition at 2uM 14 TC001004 3277 66% inhibition at 2uM 16 TC001014 150.9/70.59 IC50 = 52 nM 75 TC001035 0.247/10.21 IC50 = 33 nM 92 TC001165 28.36 IC50 = 13.2 nM 99 TC001186 45.7 IC50 = 29.6 nM

(315) 4. Necrosis Assay

(316) Methods:

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

(318) Dose-dependent inhibition of necrosis by the compounds in HT-29 cells were determined by measuring ATP levels as described above. Compound necrosis activity data are reported below:

(319) TABLE-US-00014 # EC50 # EC50 # EC50 1 1-10 uM 52 1-100 uM 103 1-100 uM 2 1-10 uM 53 1-100 uM 104 1-100 uM 3 1-10 uM 54 1-100 uM 105 1-100 uM 4 1-10 uM 55 1-100 uM 106 1-100 uM 5 1-10 uM 56 1-10 uM 107 1-100 uM 6 1-10 uM 57 1-10 uM 108 1-100 uM 7 1-10 uM 58 1-1000 nM 109 1-100 uM 8 1-10 uM 59 1-10 uM 110 1-100 uM 9 1-10 uM 60 1-10 uM 111 1-100 uM 10 1-10 uM 61 1-100 uM 112 1-100 uM 11 1-10 uM 62 1-100 uM 113 1-100 uM 12 1-10 uM 63 1-100 uM 114 1-100 uM 13 1-1000 nM 64 1-100 uM 115 1-100 uM 14 1-10 uM 65 1-1000 nM 116 1-100 uM 15 1-100 uM 66 1-100 uM 117 1-10 uM 16 1-1000 nM 67 1-10 uM 118 1-100 uM 17 1-1000 nM 68 1-100 uM 119 1-100 uM 18 1-1000 nM 69 1-10 uM 120 1-10 uM 19 1-10 uM 70 1-1000 nM 121 1-1000 nM 20 1-100 uM 71 1-100 uM 122 1-100 uM 21 1-100 uM 72 1-10 uM 123 1-100 uM 22 1-100 uM 73 1-10 uM 124 1-100 uM 23 1-100 uM 74 1-100 uM 125 1-100 uM 24 1-1000 nM 75 1-1000 nM 126 1-100 uM 25 1-1000 nM 76 1-100 uM 127 1-100 uM 26 1-1000 nM 77 1-1000 nM 128 1-1000 nM 27 1-1000 nM 78 1-100 uM 129 1-100 uM 28 1-1000 nM 79 1-100 uM 130 1-100 uM 29 1-10 uM 80 1-100 uM 131 1-100 uM 30 1-100 uM 81 1-100 uM 132 1-100 uM 31 1-100 uM 82 1-100 uM 133 1-100 uM 32 1-100 uM 83 1-10 uM 134 1-100 uM 33 1-100 uM 84 1-1000 nM 135 1-100 uM 34 1-100 uM 85 1-100 uM 136 1-100 uM 35 1-10 uM 86 1-100 uM 137 1-100 uM 36 1-100 uM 87 1-100 uM 138 1-100 uM 37 1-100 uM 88 1-100 uM 139 1-100 uM 38 1-100 uM 89 1-10 uM 140 1-100 uM 39 1-1000 nM 90 1-1000 nM 141 1-100 uM 40 1-1000 nM 91 1-1000 nM 142 1-100 uM 41 1-10 uM 92 1-1000 nM 143 1-100 uM 42 1-1000 nM 93 1-1000 nM 144 1-100 uM 43 1-1000 nM 94 1-1000 nM 145 1-100 uM 44 1-10 uM 95 1-1000 nM 146 1-100 uM 45 1-100 uM 96 1-1000 nM 147 1-100 uM 46 1-100 uM 97 1-1000 nM 148 1-100 uM 47 1-100 uM 98 1-1000 nM 149 1-100 uM 48 1-10 uM 99 1-1000 nM 150 1-100 uM 49 1-1000 nM 100 1-100 uM 151 1-100 uM 50 1-10 uM 101 1-100 uM S1 1-10 uM 51 1-10 uM 102 1-100 uM S2 1-1000 nM S3 1-1000 nM S4 1-1000 nM S5 1-1000 nM S6 1-1000 nM S7 1-10 uM S8 1-1000 nM S9 1-100 uM S10 1-100 uM S11 1-100 uM S12 1-100 uM S13 1-100 uM S14 1-100 uM S15 1-100 uM S16 1-100 uM S17 1-100 uM S18 1-100 uM S19 1-100 uM S20 1-100 uM