Inhibitors of AkT activity

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) 1,1-dimethylethyl (2-{[(4,5-dibromo-2-furanyl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol), PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol) in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H) + .

b) 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (2-{[(4,5-dibromo-2-furanyl)carbonyl]amino}-3-phenylpropyl)carbamate (0.30 g, 0.60 mmol) in dioxane/H 2 O (5:1, 8.6 mL) was added K 2 CO 3 (0.25 g, 1.8 mmol), tetrakistriphenylphosphine Pd(0) (70 mg, 0.06 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (0.12 g, 0.60 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was poured onto H 2 O (100 mL) and extracted with DCM. The organics were dried (Na 2 SO 4 ), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (0.20 g, 66%) as a white solid: LC-MS (ES) m/z=504.

c) N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

1,1-Dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate (0.20 g, 0.40 mmol) was dissolved in DCM (10 mL) and treated with TFA (5 mL). After 2 h, the solution was concentrated, and purified on reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 95-5%) affording the TFA salt of the title compound (0.16 g, 91%) as a white powder: LC-MS (ES) m/z=405 (M+H) + , 1 H NMR (d 4 -MeOH, 400 MHz) δ 7.59 (s, 1H), 7.33 (m, 3H), 7.30 (m, 2H), 6.85 (s, 1H), 4.57 (m, 1H), 4.03 (s, 3H), 3.25 (m, 1H), 3.14 (m, 1H), and 2.98 (m, 2H).

Preparation of N-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl)carbonyl]amino}-2-phenylethyl)carbamate

To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol), PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9 mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol) [prepared in Preparation 1]. After 16 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fraction were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (4 g, 62%) as a white solid: LC-MS (ES) m/z=426 (M+H) + .

b) 1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate

To a solution of 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl)carbonyl]amino}-2-phenylethyl)carbamate (1 g, 2.35 mmol) in DMF (9 mL) were added KOAc (693 mg, 7.05 mmol), bis(pinocolato)diboron (1.2 g, 4.71 mmol) and Pd(dppf)Cl 2 (169 mg, 0.212 mmol). The reaction contents were heated to 80° C. in a sealed tube for 18 hours and were then partitioned between 6N NaOH and DCM. The pH of the aqueous fraction was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated to a solid under vacuum and used directly in the next reaction: LC-MS (ES) m/z=473 (M+H) + boronic ester, 391(M+H) + boronic acid.

c) 1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate

To a solution of 1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate (200 mg, 0.42 mmol) in dioxane/H 2 O (5:1, 8.6 mL) was added K 2 CO 3 (234 mg, 1.69 mmol), tetrakistriphenylphosphine Pd(0) (24 mg, 0.02 mmol), and 5-iodo-1-methyl-1H-pyrazole (97 mg, 0.47 mmol) [prepared according to Effenberger, F.; et al J. Org. Chem. 1984, 49, 24, 4687]. The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was poured onto H 2 O (100 mL) and extracted with DCM. The organics were dried (Na 2 SO 4 ), concentrated under vacuum, and purified on silica gel (1% MeOH in DCM) to give the title compound (56 mg, 31%) as a yellow solid: LC-MS (ES) m/z=427.

d) N-(2-amino-1-phenylethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate (56 mg, 0.131 mmol) was dissolved in MeOH (2 mL) and treated with excess 4M HCl in dioxane (656 μL, 2.62 mmol). After 4 h, the solution was concentrated affording the title compound (46 mg, quant.) as a yellow solid: LC-MS (ES) m/z 327 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 9.46 (d, J=8.2 Hz, 1H), 8.27 (bs, 1H), 8.20 (d, J=4.0 Hz, 1H), 7.48-7.75 (m, 3H), 7.37-7.40 (m, 2H), 7.31-7.33 (m, 1H), 6.58 (d, J=1.9 Hz, 1H), 5.21-5.30 (m, 1H), 3.97 (s, 3H), 3.36-3.41 (m, 1H), 3.19-3.25 (m, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an tan solid according to Example 2, except substituting 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (1.65 g, 7.97 mmol) [prepared in Preparation 2] for 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate: LC-MS (ES) m/z 341 (M+H) + , 1 H NMR (d 6 -DMSO, 400 MHz) δ 8.74 (d, J=8.5 Hz, 1H), 8.05 (bs, 1H), 7.89 (d, J=3.9 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.43 (d, J=3.9 Hz, 1H), 7.26-7.29 (m, 3H), 7.20-7.22 (m, 1H), 6.56 (d, J=2.0 Hz, 1H), 4.31-4.42 (m, 1H), 2.98-3.01 (m, 2H), 2.91-2.93 (m, 2H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 2, except substituting 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) for 5-bromo-2-thiophenecarboxylic acid and 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (1.2 g, 4.83 mmol) [prepared in Preparation 2] for 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate: LC-MS (ES) m/z 441 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 8.98 (bs, 1H), 8.29 (s, 1H), 8.17 (bs, 2H), 7.98 (s, 1H), 7.46 (s, 1H), 7.27-7.29 (m, 3H), 7.19 (s, 1H), 6.46 (s, 1H), 4.35-4.37 (m, 1H), 3.51 (s, 3H), 2.75-3.12 (m, 4H).

Preparation of N-(2-amino-1-phenylethyl)-4-{[(2Z)-1-methyl-2-(2-propen-1-ylidene)hydrazino]methyl}-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 2, except substituting 4-bromo-2-thiophenecarboxylic acid (650 mg, 3.14 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 427 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 9.65 (d, J=7.3 Hz, 1H), 8.58 (s, 1H), 8.31 (br s, 2H), 7.99 (s, 1H), 7.42-7.51 (m, 2H), 7.72-7.80 (m, 2H), 7.20-7.31 (m, 1H), 6.51 (s, 1H), 3.52 (s, 1H), 5.25-5.35 (m, 1H), 3.51 (s, 3H), 3.32-3.48 (m, 1H), 3.15-3.21 (m, 1H).

Preparation of N-(2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 5-bromo-2-thiophenecarboxylic acid (100 mg, 0.48 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (267 mg, 1.93 mmol), tetrakistriphenylphosphine Pd(0) (28 mg, 24 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (94 mg, 0.48 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (−100 mg, quant.): LC-MS (ES) m/z=209 (M+H) + .

b) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H) + .

c) N-(2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86 μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound.

The neutral compound from above was dissolved in MeOH (2 mL), treated with excess 4M HCl in dioxane (500 μL) and concentrated affording the HCl salt of the title compound: LC-MS (ES) m/z=409 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 8.97 (d, J=9.0 Hz, 1H), 8.17 (bs, 1H), 8.00 (d, 3.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.55-7.61 (m, 2H), 7.42-7.47 (m 2H), 6.56 (d, J=2.0 Hz, 1H), 4.47-4.51 (m, 1H), 4.18 (s, 3H), 3.09-3.11 (m, 4H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 1, except substituting 4,5-dibromo thiophenecarboxylic acid (376 mg, 1.32 mmol) for 4,5-dibromo furancarboxylic acid: LC-MS (ES) m/z=419 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 8.92 (d, J=8.6 Hz, 1H), 8.03-8.06 (m, 2H), 7.56 (d, J=1.9 Hz, 1H), 7.26-7.32 (m, 3H), 7.21-7.23 (m, 1H), 6.55 (d, J=1.9 Hz, 1H), 4.32-4.42 (m, 1H), 3.77 (s, 3H), 3.00-3.01 (m, 2H), 2.89-2.91 (m, 2H).

Preparation of N-(2-amino-1-phenylethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 1, except substituting 4,5-dibromo thiophenecarboxylic acid (2.2 g, 7.69 mmol) for 4,5-dibromo furancarboxylic acid and 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (1.1 g, 4.66 mmol) for 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate: LC-MS (ES) m/z=406 (M+H) + , 1 H NMR (d6-DMSO, 400 MHz) δ 9.47 (d, J=7.9 Hz, 1H), 8.26 (s, 1H), 8.17 (bs, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.38-7.46 (m, 3H), 7.30-7.34 (m, 1H), 6.56 (d, J=1.6 Hz, 1H), 5.28-5.37 (m, 1H), 3.81 (s, 3H), 3.35-3.41 (m, 1H), 3.21-3.28 (m, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 5-bromo-2-furancarboxylic acid (58 mg, 0.3 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z=393 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ 7.62 (br s, 1H), 7.57 (m, 1H), 7.51 (m, 3H), 7.22 (m, 1H), 6.91 (m, 1H), 6.76 (m, 1H), 4.6 (m, 1H), 4.07 (m, 3H) and 3.15 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 6, except substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (306 mg, 0.80 mmol) for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z=409 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.81-2.88 (m, 1H) 2.93 (td, J=9.03, 4.93 Hz, 2H) 3.09 (dd, J=13.89, 5.31 Hz, 1H) 4.00 (s, 3H) 4.28-4.35 (m, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.32 (d, J=4.04 Hz, 1H) 7.45-7.52 (m, 3H) 7.54-7.58 (m, 1H) 7.60 (s, 1H) 7.70 (d, J=4.04 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (237 mg, 0.83 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z=488 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δppm 2.97-3.10 (m, 4H) 3.78 (s, 3H) 4.42-4.54 (m, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.45 (t, J=7.58 Hz, 1H) 7.50-7.54 (m, 1H) 7.56-7.63 (m, 2H) 7.71 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 8.76 (d, J=9.09 Hz, 1H)

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (237 mg, 0.83 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (206 mg, 0.535 mmol) for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z=488 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ ppm 2.97-3.07 (m, 1H) 3.10-3.21 (m, 2H) 3.27 (d, J=3.54 Hz, 1H) 3.82 (s, 3H) 4.50-4.59 (m, 1H) 6.51 (d, J=2.02 Hz, 1H) 7.50-7.60 (m, 4H) 7.62 (s, 1H) 7.71 (s, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 5-bromo-2-furancarboxylic acid (44 mg, 0.23 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (87 mg, 0.25 mmol) for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z=393 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ 7.63 (br s, 1H), 7.57 (m, 1H), 7.51 (m, 3H), 7.22 (m, 1H), 6.91 (m, 1H), 6.77 (m, 1H), 4.6 (m, 1H), 4.07 (m, 3H) and 3.14 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-furancarboxylic acid (82 mg, 0.3 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (115 mg, 0.3 mmol) for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z=472 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ 7.61 (m, 2H), 7.53 (m, 3H), 7.30 (m, 1H), 6.84 (m, 1H), 4.59 (m, 1H), 4.03 (s, 3H), 3.28 (m, 1H), 3.17 (m, 2H) and 3.01 (m, 1H)

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-furancarboxylic acid (82 mg, 0.3 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z=472 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ 7.71 (m, 1H), 7.60 (m, 1H), 7.53 (m, 2H), 7.44 (m, 1H), 7.33 (m, 1H), 6.88 (m, 1H), 4.7 (m, 1H), 4.06 (s, 3H), 3.25 (m, 3H) and 3.09 (m, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl[2-({[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (0.35 g, 0.67 mmol) [from Example 7] in dioxane/H 2 O (5:1, 25:5 mL) was added K 2 CO 3 (0.28 mg, 2.0 mmol), tetrakistriphenylphosphine Pd(0) (77 mg, 0.06 mmol), and trimethylboroxine (0.17 mL, 1.2 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (0.10 g, 33%) as a white solid: LC-MS (ES) m/z=455 (M+H) + .

b) N-[2-amino-1-(phenylmethyl)ethyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (0.10 g, 0.22 mmol) was dissolved in MeOH (10 mL) and THF (5 mL) and treated with 4 M HCl in dioxane (5 mL). After 4 h, the solution was concentrated affording the HCl salt of the title compound (68 mg, 91%) as a white powder: LC-MS (ES) m/z=355 (M+H) + , 1 H NMR (d 4 -MeOH, 400 MHz) δ 7.79 (s, 1H), 7.68 (s, 1H), 7.31 (m, 4H), 7.25 (m, 1H), 6.56 (s, 1H), 4.54 (m, 1H), 3.87 (s, 3H), 3.69 (s, 2H), 3.34 (m, 2H), 3.03 (d, J=7.6 Hz, 2H) and 2.21 (s, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 16, except substituting 3-furan boronic acid (0.13 g, 1.2 mmole) for trimethylboroxine: LC-MS (ES) m/z=472 (M+H) + , 1 H NMR (CD 3 OD, 400 MHz) δ 8.13 (s, 1H), 7.81 (s, 1H), 7.53 (m, 2H), 7.34 (m, 4H), 7.26 (m, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 4.57 (m, 1H), 3.68 (s, 2H), 3.63 (s, 3H), 3.24 (m, 2H) and 3.07 (m, 2H)

Preparation of N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-chloro-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (2.0 g, 12.3 mmol) in dry MeOH (75 mL) was added H 2 SO 4 (1 mL). The reaction mixture was heated to 50° C. for 20 h and was then concentrated under vacuum. The residue was dissolved in DCM and washed several times with saturated NaHCO3 solution. The organic fraction was dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification 21.3 g, quant.): LC-MS (ES) m/z=177 (M+H) + .

b) methyl 5-chloro-4-iodo-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (5.0 g, 28.0 mmol) in acetic acid (150 mL) was added ZnCl 2 (38 g, 280 mmoles) and benzyltrimethylammonium dichloroiodate (20.5 g, 58.8 mmole) [ Bull. Chem. Soc. Jpn. 64, 2566-2568 (1991)]. The reaction mixture was heated to 70° C. for 48 h and was then concentrated under vacuum. The residue was extracted with hexanes (2×200 mL) and the hexane solution washed with saturated NaHCO 3 solution. The organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 4:1) to give the title compound (3.8 g, 45%) as a light yellow solid: LC-MS (ES) m/z=302 (M+H) + .

c) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-chloro-4-iodo-2-thiophenecarboxylate (1.75 g, 5.8 mmol) in dioxane/H 2 O (50:5 mL) was added K 2 CO 3 (3.4 g, 24.9 mmol), tetrakistriphenylphosphine Pd(0) (0.96 g, 0.83 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (3.4 g, 16.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 15 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 4:1) to give the title compound (0.35 g, 24%) as a yellow oil: LC-MS (ES) m/z=257 (M+H) + .

d) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.30 g, 1.17 mmole) in THF (10 mL) and MeOH (10 mL) was added 6N NaOH (5 mL). The reaction solution was heated to 50° C. for 2 hrs. The reaction solution was concentrated under vacuum, made acidic (pH ˜2) with 3N HCl, and extracted with DCM. The organic solution was dried (Na 2 SO 4 ) and concentrated to a solid (0.22 g) which was used without further purification. LC-MS (ES) m/z=243 (M+H) + .

e) 5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21 g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine (0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg, 0.96 mmol) [prepared according to Preparation 5]. After 16 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica) affording the title compound (200 mg, 46%) as a white solid: LC-MS (ES) m/z=505 (M+H) + .

f) N-[(1S)-2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (200 mg, 0.40 mmol) in MeOH/THF (10 mL, 1:1) at RT was added hydrazine hydrate (0.20 mL, 4.0 mmol). After stirring for 24 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound as a light yellow solid.

The neutral compound from above was dissolved in DCM (2 mL), treated with excess 4M HCl in dioxane (1 mL) and concentrated affording the HCl salt (102 mg) of the title compound: LC-MS (ES) m/z=375 (M+H) + , 7.78 (s, 1H), 7.63 (s, 1H), 7.31 (m, 4H), 7.26 (m, 1H), 6.55 (s, 1H), 4.54 (m, 1H), 3.91 (s, 3H), 3.24 (m, 2H) and 3.03 (m, 2H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl 4,5-dibromo-3-hydroxy-2-thiophenecarboxylate (500 mg, 1.59 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (339 mg, 1.75 mmol), Pd(PPh 3 ) 4 (92 mg, 79.4 μmol) and K 2 CO 3 (876 mg, 6.35 mmol) in dioxane (6.6 mL) and H 2 O (1.3 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (75 mg, 15%) as a brown residue: LCMS (ES) m/z=318 (M+H) + .

b) methyl 4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (175 mg, 0.554 mmol), MeOH (26 μL, 0.609 mmol), PPh 3 (189 mg, 0.720 mmol) in THF (6 mL) at 25° C. was added DEAD (113 μL, 0.720 mmol) in one portion. After 30 min, the reaction was concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (135 mg, 74%) as a white solid: LC-MS (ES) m/z=332 (M+H) + .

c) 1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

i) A solution of methyl 4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.410 mmol) in 6N NaOH (4 mL) and THF (4 mL) was stirred in a sealed tube at 80° C. After 2 h, the solution was acidified to pH 3 using 1N HCl then extracted several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=318 (M+H) + .

ii) To a solution of the crude acid, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (88 mg, 0.351 mmol) [from Preparation 2], diisopropylethyl amine (305 μL, 1.76 mmol) in DCM (3.5 mL) was added PyBrop (196 mg, 0.422 mmol) in one portion. After 12 h, additional diisopropylethyl amine (305 μL, 1.76 mmol) and PyBrop (196 mg, 0.422 mmol) were added. After 2 h, the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=550 (M+H) + .

d) N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of 1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound as the HCl salt: LC-MS (ES) m/z 450 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.07 (br. s., 3H) 7.85 (d, J=8.84 Hz, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.32 (d, J=7.07 Hz, 2H) 7.26-7.29 (m, 2H) 7.20-7.24 (m, 1H) 6.54 (d, J=2.02 Hz, 1H) 4.50-4.55 (m, 1H) 3.79 (d, J=6.82 Hz, 3H) 3.74 (d, J=6.57 Hz, 1H) 3.17 (s, 1H) 2.98-3.10 (m, 4H).

Preparation of N-[3-amino-1-(phenylmethyl)propyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1 g, 3.5 mmol) in dioxane/H 2 O (5:1, 18 mL) was added K 2 CO 3 (1.9 g, 13.98 mmol), tetrakistriphenylphosphine Pd(0) (201 mg, 0.175 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (678 mg, 3.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (˜1 g, quant.): LC-MS (ES) m/z=288 (M+H) + .

b) 1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate

To a solution of 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (250 mg, 0.874 mmol), PyBrOP (489 mg, 8.74 mmol) and diisopropylethyl amine (762 μL, 4.37 mmol) in DCM (8 mL) at 25° C. was added 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate (230 mg, 0.874 mmol) [prepared according to Preparation 8]. After 16 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica) affording the title compound (130 mg, 29%) as a white solid: LC-MS (ES) m/z=533 (M+H) + .

c) N-[3-amino-1-(phenylmethyl)propyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of 1,1-dimethylethyl[3-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-4-phenylbutyl]carbamate (130 mg, 0.24 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (40 mg, 40%) as the HCl salt: LC-MS (ES) m/z 433 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.68 (d, J=8.59 Hz, 1H) 7.97 (s, 1H) 7.77 (br s, 3H) 7.57 (d, J=2.02 Hz, 1H) 7.28 (d, J=2.27 Hz, 3H) 7.25-7.32 (m, 2H) 6.55 (d, J=2.02 Hz, 1H) 4.17-4.24 (m, 1H) 3.78 (s, 3H) 2.77-2.89 (m, 4H) 1.85-1.92 (m, 1H) 1.81 (td, J=9.54, 4.93 Hz, 1H).

Preparation of 4-bromo-N-[2-(methylamino)-1-phenylethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to the procedure of Example 1, except substituting 1,1-dimethylethyl (2-amino-2-phenylethyl)methylcarbamate (1 g, 4.02 mmol) [Prepared according to the procedure of Preparation 1] for 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate and substituting 4,5-dibromo-2-thiophenecarboxylic acid (1.89 g, 6.6 mmol) for 4,5-dibromo-2-furancarboxylic acid: LCMS (ES) m/z 420 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.64 (d, J=8.34 Hz, 1H) 8.91 (br. s., 1H) 8.33 (s, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.42-7.50 (m, 2H) 7.38-7.42 (m, 2H) 7.34 (d, J=7.07 Hz, 1H) 6.56 (d, J=2.02 Hz, 1H) 5.37-5.44 (m, 1H) 3.79 (s, 3H) 3.47-3.54 (m, 1H) 3.33 (td, J=8.46, 3.79 Hz, 1H) 2.63 (t, J=5.31 Hz, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 1, except substituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (81 mg, 0.368 mmol) [from Preparation 10] for 4,5-dibromo-2-furancarboxylic acid: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.84 (d, J=8.34 Hz, 1H) 8.15 (br. s., 3H) 8.00 (s, 1H) 7.52 (d, J=1.77 Hz, 1H) 7.24-7.31 (m, 4H) 7.17-7.23 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 4.35 (d, J=3.03 Hz, 1H) 3.78 (s, 3H) 3.03 (dd, J=6.82, 2.53 Hz, 1H) 2.93-2.99 (m, 2H) 2.90 (d, J=6.06 Hz, 1H) 2.38 (s, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 1, except substituting 4-bromo-5-chloro-2-thiophenecarboxylic acid (250 mg, 1.04 mmol) [from Preparation 11] for 4,5-dibromo-2-furancarboxylic acid: LC-MS (ES) m/z 375 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.09 (d, J=8.59 Hz, 1H) 8.14 (s, 3H) 8.10 (br. s., 1H) 7.55 (d, J=1.77 Hz, 1H) 7.25-7.32 (m, 4H) 7.21 (dd, J=6.19, 2.40 Hz, 1H) 6.48 (d, J=2.02 Hz, 1H) 4.35 (d, J=8.59 Hz, 1H) 3.84 (s, 3H) 2.99 (d, J=10.86 Hz, 1H) 2.89-2.96 (m, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) in dioxane/H 2 O (5:1, 16 mL) was added K 2 CO 3 (2.7 g, 19 mmol), tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (−1 g, quant.): LCMS (ES) m/z=209 (M+H) + .

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (600 mg, 2.88 mmol) and N-chlorosuccinimide (384 mg, 2.88 mmol) in THF (14 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H 2 O-DCM, the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (698 mg, quant.): LCMS (ES) m/z=243 (M+H) + .

c) 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (350 mg, 1.45 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (362 mg, 1.45 mmol) [from Preparation 2] and diisopropylethyl amine (1.3 mL, 7.23 mmol) in DCM (7 mL) was added PyBrop (809 mg, 1.74 mmol) in one portion. After 1 h, the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=476 (M+H) + .

d) N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (90 mg, 17%-2 steps) as the HCl salt: LCMS (ES) m/z 476 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.75 (d, J=8.08 Hz, 1H) 8.10 (d, J=1.52 Hz, 2H) 8.08 (s, 3H) 7.68 (s, 1H) 7.26-7.32 (m, 4H) 7.22 (dd, J=6.06, 2.53 Hz, 1H) 4.39 (br. s., 1H) 3.87 (s, 3H) 2.91 (d, J=7.33 Hz, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-5-chloro-2-thiophenecarboxylic acid (1.3 g, 5.42 mmol), PyBrOP (3 g, 6.5 mmol) and diisopropylethyl amine (4.7 mL, 27.1 mmol) in DCM (54 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (2.0 g, 5.42 mmol) [prepared in Preparation 6]. After 1 h, the solution was partitioned between H 2 O and washed with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and used directly: LCMS (ES) m/z=572 (M+H) + .

b) 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

To a solution of 4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (crude from part a) in THF-MeOH (1:1, 20 mL) was added hydrazine (1.59 mL, 54.2 mmol). After 12 h, the solution was filtered and the filtrate concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH 4 OH)) affording the free base which was dissolved in THF (25 mL) and treated with Boc 2 O (1.2 g, 5.31 mmol). After 30 min the solution was concentrated affording a white powder of the title compound (800 mg, 27%-3 steps): LCMS (ES) m/z=542 (M+H) + .

c) 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

To a solution of 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (750 mg, 1.38 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (762 mg, 5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol) were added. After 12 h, the solution was poured onto H 2 O (100 mL) and extracted with DCM. The organics were dried (Na 2 SO 4 ), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS (ES) m/z=544.

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (194 mg, 0.357 mmol) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (2-5% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (134 mg, 85%) as the HCl salt: LCMS (ES) m/z 444 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.10 (d, J=9.09 Hz, 1H) 8.11 (s, 1H) 8.10 (bs, 3H) 7.70 (d, J=8.08 Hz, 1H) 7.57 (d, J=2.02 Hz, 2H) 7.43 (s, 1H) 6.49 (d, J=2.02 Hz, 1H) 4.47 (br. s., 1H) 3.85 (s, 3H) 3.06 (d, J=8.34 Hz, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

The title compound was prepared as white solid according to the procedure of Example 24, except substituting 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (288 mg, 0.826 mmol) [from Preparation 6] for 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate: LCMS (ES) m/z 444 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (150 mg, 0.262 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (123 uL, 2.62 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (30 mg, 26%) as the HCl salt: LCMS (ES) m/z 444 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.69 (s, 1H) 8.11 (d, J=1.26 Hz, 1H) 8.03 (d, J=1.26 Hz, 1H) 7.93 (bs, 3H) 7.69 (s, 2H) 7.53-7.59 (m, 2H) 7.44 (d, J=4.80 Hz, 1H) 4.49 (br. s., 1H) 3.87 (s, 3H) 2.99-3.12 (m, 4H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 24, except substituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol) [from Preparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting NBS (325 mg, 2.43 mmol) for NCS: LCMS (ES) m/z 434 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.65 (br. s., 1H) 8.01 (br. s., 3H) 7.80 (s, 1H) 7.70 (s, 1H) 7.25-7.32 (m, 4H) 7.21 (td, J=6.19, 2.78 Hz, 1H) 4.31-4.35 (m, 1H) 3.71 (s, 3H) 2.86-2.92 (m, 4H) 2.33 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 26, except substituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol) [from Preparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting NBS (325 mg, 2.43 mmol) for NCS: LCMS (ES) m/z 502 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.81 (br. s., 1H) 8.05 (br. s., 3H) 7.83-7.90 (m, 1H) 7.67-7.74 (m, 2H) 7.53-7.60 (m, 2H) 7.39-7.47 (m, 1H) 4.48 (d, J=5.05 Hz, 1H) 3.68-3.76 (m, 3H) 3.01-3.08 (m, 4H) 2.33 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 26, except substituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol) [from Preparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LCMS (ES) m/z 457 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.76 (br. s., 1H) 8.03 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 2H) 7.53-7.60 (m, 2H) 7.39-7.47 (m, 1H) 4.46 (d, J=9.35 Hz, 1H) 3.72 (s, 3H) 3.03-3.10 (m, 4H) 2.34 (s, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 24, except substituting 4-bromo-5-methyl-2-thiophenecarboxylic acid (1 g, 4.52 mmol) [from Preparation 9] for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LCMS (ES) m/z 389 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.67 (br. s., 1H) 8.01 (br. s., 3H) 7.82 (s, 1H) 7.70 (s, 1H) 7.25-7.32 (m, 4H) 7.19-7.23 (m, 1H) 4.31-4.38 (m, 1H) 3.71 (s, 3H) 2.97 (br. s., 2H) 2.89 (t, J=6.19 Hz, 2H) 2.34 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (110 mg, 0.202 mmol) [prepared in Example 25] and N-chlorosuccinimide (35 mg, 0.263 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=578 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (43 mg, 44%-2 steps) as the HCl salt: LCMS (ES) m/z 478 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.10 (d, J=8.84 Hz, 1H) 8.06 (s, 4H) 7.75 (s, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.54-7.61 (m, 2H) 7.43 (t, J=7.45 Hz, 1H) 4.47 (t, J=8.84 Hz, 1H) 3.78 (s, 3H) 2.98-3.12 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

a) 1,1-dimethylethyl {(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate

A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (121 mg, 0.22 mmol) [prepared in Example 25] and N-bromosuccinimide (52 mg, 0.290 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=622 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl {(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (42 mg, 44%-2 steps) as the HCl salt: LCMS (ES) m/z 522 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.13 (d, J=9.09 Hz, 1H) 8.17 (br. s., 1H) 8.05 (s, 3H) 7.75 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.54-7.61 (m, 2H) 7.43 (t, J=7.58 Hz, 1H) 4.46 (d, J=9.60 Hz, 1H) 3.78 (s, 3H) 2.99-3.13 (m, 4H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

The title compound was prepare as an orange oil according to Example 24, except substituting N-bromosuccinimide (1 g, 5.77 mmol) for N-chlorosuccinimide: LCMS (ES) m/z 288 (M+H) + .

b) 4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (688 mg, 2.41 mmol) in dioxane/H 2 O (5:1, 12 mL) was added K 2 CO 3 (1.3 g, 9.6 mmol), tetrakistriphenylphosphine Pd(0) (139 mg, 0.120 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (293 mg, 2.41 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (139 mg, 0.120 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (293 mg, 2.41 mmol) were added. After 12 h, the solution was poured onto H 2 O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na 2 SO 4 ) and concentrated affording the title compound white was used directly without further purification: LC-MS (ES) m/z=284 (M+H) + .

c) 1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (341 mg, 1.2 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (300 mg, 1.2 mmol) [from Preparation 2], diisopropylethyl amine (1 mL, 6.01 mmol) in DCM (6 mL) was added PyBrop (673 mg, 1.44 mmol) in one portion. After 1 h, the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=517 (M+H) + .

d) N-[2-amino-1-(phenylmethyl)ethyl]-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of 1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (105 mg, 21%-3 steps) as the HCl salt: LCMS (ES) m/z 417 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.82 (d, J=8.34 Hz, 1H) 8.14 (br. s., 3H) 7.96 (s, 1H) 7.90 (d, J=1.26 Hz, 1H) 7.82 (s, 1H) 7.29 (s, 1H) 7.25 (t, J=8.46 Hz, 9H) 4.34 (dd, J=7.45, 5.68 Hz, 1H) 3.75 (s, 3H) 2.94-3.00 (m, 2H) 2.89 (dd, J=6.82, 5.31 Hz, 2H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 33, except substituting 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (420 mg, 1.2 mmol) [from Preparation 6] for 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate: LCMS (ES) m/z 615 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (crude from part a) in THF-MeOH (1:1, 10 mL) was added hydrazine (384 uL, 12 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (40 mg, 7%) as the HCl salt: LCMS (ES) m/z 485 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.78 (d, J=9.09 Hz, 1H) 8.05 (br. s., 3H) 7.91 (dd, J=9.09, 1.26 Hz, 2H) 7.83 (s, 1H) 7.69 (d, J=7.33 Hz, 1H) 7.50-7.53 (m, 1H) 7.43 (d, J=7.58 Hz, 1H) 7.47 (t, J=6.82 Hz, 1H) 7.23-7.30 (m, 4H) 7.22 (s, 1H) 4.47 (br. s., 1H) 3.75 (s, 3H) 3.01 (d, J=8.08 Hz, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

a) methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1 g, 4.25 mmol) in dioxane/H 2 O (5:1, 20 mL) was added K 2 CO 3 (2.3 g, 17 mmol), bis(tri-t-butylphosphine)palladium(0) (108 mg, 0.213 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.52 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification: LCMS (ES) m/z=237 (M+H) + .

b) 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude from part a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h, the solution was poured onto H 2 O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na 2 SO 4 ) and concentrated affording the title compound as a white solid which was used directly without further purification: LCMS (ES) m/z=223 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 27, except substituting 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (424 mg, 1.92 mmol) for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LCMS (ES) m/z 457 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.84 (d, J=8.84 Hz, 1H) 8.05 (br. s., 3H) 7.84 (s, 1H) 7.74 (s, 1H) 7.71 (d, J=8.08 Hz, 1H) 7.56-7.63 (m, 2H) 7.44 (t, J=7.20 Hz, 1H) 4.47-4.54 (m, 1H) 3.70 (s, 3H) 2.93-3.12 (m, 4H) 2.10 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

a) methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (1 g, 4.25 mmol) in dioxane/H 2 O (5:1, 20 mL) was added K 2 CO 3 (2.3 g, 17 mmol), bis(tri-t-butylphosphine)palladium(0) (108 mg, 0.213 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.52 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.24 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification: LCMS (ES) m/z=237 (M+H) + .

b) 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude from part a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h, the solution was poured onto H 2 O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na 2 SO 4 ) and concentrated affording the title compound white was used directly without further purification: LCMS (ES) m/z=223 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-methyl-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 26, except substituting 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (424 mg, 1.92 mmol) for 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting N-bromosuccinimide (376 mg, 2.11 mmol) for N-chlorosuccinimide: LCMS (ES) m/z 502 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.84 (d, J=9.09 Hz, 1H) 8.05 (br. s., 3H) 7.83 (s, 1H) 7.67-7.74 (m, 2H) 7.60 (q, J=7.83 Hz, 2H) 7.40-7.47 (m, 1H) 4.50 (d, J=4.04 Hz, 1H) 3.71 (s, 3H) 2.98-3.12 (m, 4H) 2.09 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-bromo-2-thiophenecarboxylate

To a solution of 4-bromo-2-thiophenecarboxylic acid (4 g, 19 mmol) in MeOH (100 mL) was added H 2 SO 4 (5 mL) dropwise at 25° C. The solution was stirred for 12 h at 50° C. and was poured into ice-H 2 O and the pH was adjusted to 11 with aqueous NaOH. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly (4.27 g, quant.): LCMS (ES) m/z 222 (M+H) + .

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (1 g, 4.52 mmol) in dioxane/H 2 O (5:1, 16 mL) was added K 2 CO 3 (2.7 g, 19 mmol), bis(tri-t-butylphosphine)palladium(0) (116 mg, 0.226 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.88 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 1 h, the reaction was partitioned between H 2 O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z 223 (M+H) + .

c) methyl 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (330 mg, 1.49 mmol) and Selectfluor® (793 mg, 2.23 mmol) in THF (7 mL) and H 2 O (500 uL) was stirred in a sealed tube at 70° C. After 1 h, additional selectfluor (793 mg, 2.23 mmol) was added and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H 2 O-DCM, the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na 2 SO 4 ), concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (126 mg, 33%) as a white solid: LCMS (ES) m/z=241 (M+H) + .

d) 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (126 mg, 0.53 mmol) in THF (1 mL) and 6N NaOH (1 mL) was heated to 70° C. After 1 h, the solution was poured onto H 2 O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na 2 SO 4 ) and concentrated affording the title compound white was used directly without further purification: LCMS (ES) m/z=227 (M+H) + .

e) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (84 mg, 0.372 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (130 mg, 0.372 mmol) [from Preparation 6], diisopropylethyl amine (323 uL, 1.86 mmol) in DCM (4 mL) was added PyBrop (208 mg, 0.446 mmol) in one portion. After 1 h, the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 0.5% MeOH-DCM) affording the title compound (135 mg, 65%) as a white solid: LCMS (ES) m/z=557 (M+H) + .

f) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (135 mg, 0.242 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (75 uL, 2.42 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (3% MeOH in DCM (1% NH 4 OH)). The title compound was further purified via Gilson reverse phase chromatography using 5-95% mobile phase gradient affording the TFA-salt of the title compound which was neutralized through a silica plug ((5% MeOH in DCM (1% NH 4 OH)) then transferred to the HCl salt using excess 4M HCl in dioxane (40 mg, 26%): LCMS (ES) m/z 427 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 8.88 (d, J=8.84 Hz, 1H) 8.13 (s, 1H) 8.06 (bs, 3H) 7.70 (d, J=7.83 Hz, 1H) 7.55-7.62 (m, 3H) 7.54 (br. s., 1H) 7.41 (d, J=2.53 Hz, 1H) 4.49 (d, J=5.05 Hz, 1H) 3.92 (s, 3H) 2.99-3.11 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 37, except substituting methyl 4-bromo-5-methyl-2-thiophenecarboxylate (1 g, 4.26 mmol) [from Preparation 11] for methyl 4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z 441 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J=9.60 Hz, 1H) 8.03 (br s, 3H) 7.91 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.62 (d, J=4.55 Hz, 1H) 7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H) 4.47 (br. s., 1H) 3.74 (s, 3H) 3.06 (br. s., 4H) 2.36 (s, 3H).

Preparation of N-[1-(aminomethyl)-3-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate (0.44 g, 1.7 mmol) [from Preparation 4] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z=435 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 1.92-2.22 (m, 2H) 2.71-2.82 (m, 2H) 3.02-3.11 (m, 1H) 3.12-3.24 (m, 1H) 3.88 (s, 3H) 4.30 (s, 1H) 6.59 (d, J=1.77 Hz, 1H) 7.17 (t, J=7.07 Hz, 1H) 7.22-7.29 (m, 4H) 7.67 (d, J=1.77 Hz, 1H) 7.85 (s, 1H).

Preparation of N-[1-(aminomethyl)-3-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (223 mg, 1.07 mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate (0.51 g, 1.9 mmol) [from Preparation 4] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 1.87-1.99 (m, 2H) 2.69-2.91 (m, 4H) 4.00-4.07 (m, 3H) 4.08-4.16 (m, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.15 (t, J=6.95 Hz, 1H) 7.20-7.28 (m, 4H) 7.35 (d, J=3.79 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.79 (d, J=3.79 Hz, 1H).

Preparation of 4-bromo-N-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl (3-amino-3-phenylpropyl)methylcarbamate (289 mg, 1.09 mmol) [from Preparation 12] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 435 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.12-2.23 (m, 2H) 2.45-2.52 (m, 3H) 2.64-2.74 (m, 1H) 2.76 (dd, J=8.72, 5.94 Hz, 1H) 3.77-3.88 (m, 3H) 5.10-5.20 (m, 1H) 6.52 (d, J=2.02 Hz, 1H) 7.30 (d, J=6.82 Hz, 1H) 7.35-7.45 (m, 4H) 7.57 (d, J=1.77 Hz, 1H) 7.89 (s, 1H).

Preparation of N-[3-(methylamino)-1-phenylpropyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl (3-amino-3-phenylpropyl)methylcarbamate (430 mg, 1.63 mmol) [from Preparation 12] for 1,1-dimethylethyl (2-amino-4-phenylbutyl)carbamate and substituting 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (224 mg, 1.08 mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.18-2.28 (m, 2H) 2.55 (s, 3H) 2.77-2.85 (m, 1H) 2.87 (dd, J=8.84, 5.81 Hz, 1H) 4.01 (s, 3H) 5.19 (dd, J=8.59, 6.57 Hz, 1H) 6.55 (d, J=2.02 Hz, 1H) 7.31 (d, J=7.07 Hz, 1H) 7.34-7.41 (m, 3H) 7.44-7.47 (m, 2H) 7.50 (d, J=2.02 Hz, 1H) 7.85 (d, J=4.04 Hz, 1H).

Preparation of 4-bromo-N-[2-(methylamino)-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl (2-amino-3-phenylpropyl)methylcarbamate (0.26 g, 1.09 mmol) [from Preparation 12] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 435 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.60 (s, 3H) 2.90-3.01 (m, 2H) 3.06 (d, J=6.57 Hz, 2H) 3.83 (s, 3H) 4.48-4.58 (m, 1H) 6.52 (d, J=1.77 Hz, 1H) 7.17-7.27 (m, 1H) 7.27-7.33 (m, 4H) 7.57 (d, J=2.02 Hz, 1H) 7.77 (s, 1H).

Preparation of N-((1S)-2-amino-1-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 6, except substituting 2-{(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.22 g, 0.62 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl. The reaction mixture was absorbed onto silica and purified via column chromatography to yield the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 489 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.04-3.30 (m, 4H) 3.81-3.85 (m, 3H) 4.59 (dd, J=6.32, 3.28 Hz, 1H) 6.52 (d, J=2.02 Hz, 1H) 7.50 (d, J=8.08 Hz, 2H) 7.58 (d, J=2.02 Hz, 1H) 7.64 (d, J=8.08 Hz, 2H) 7.73 (s, 1H).

Preparation of N-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (194 mg, 0.68 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (0.20 g, 0.58 mmol) [prepared according to preparation 16] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 448 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 1.40 (s, 3H) 1.47 (s, 3H) 2.85-2.92 (m, 1H) 3.01 (d, J=11.37 Hz, 1H) 3.83-3.86 (m, 3H) 4.74 (dd, J=11.37, 2.27 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.28 (t, J=7.33 Hz, 1H) 7.41 (t, J=7.71 Hz, 3H) 7.52 (d, J=7.58 Hz, 2H) 7.59 (d, J=2.02 Hz, 1H) 7.89 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (135 mg, 0.47 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (153 mg, 0.44 mmol) [prepared according to the procedure of Preparation 6] for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 491 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.03 (dd, J=13.89, 9.35 Hz, 1H) 3.14-3.21 (m, 1H) 3.21-3.29 (m, 2H) 3.84 (s, 3H) 4.62-4.70 (m, 1H) 6.53 (d, J=2.02 Hz, 1H) 7.28-7.32 (m, 1H) 7.33-7.37 (m, 1H) 7.51 (d, J=2.02 Hz, 1H) 7.58 (d, J=2.02 Hz, 1H) 7.73-7.76 (m, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a pale yellow solid according to the procedure of Example 30, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (2.84 g, 9.9 mmol) for 4-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 457 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.95-3.07 (m, 4H) 3.75 (s, 3H) 4.44 (dd, J=6.44, 4.93 Hz, 1H) 7.18-7.24 (m, 1H) 7.27-7.32 (m, 4H) 7.59 (s, 1H) 7.86 (s, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

a) 4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic acid

NBS (6.3 g, 35.4 mmol) was added in portions over 15 minutes to a stirred solution of 1-methyl-1H-pyrrole-2-carboxylic acid (2.1 g, 16.78 mmol) in DMF (30 mL) at 0° C. Upon complete addition the mixture was slowly brought to 70° C. After 1 h, the solution was partitioned between H 2 O—CHCl 3 , the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with CHCl 3 . The combined organic fractions were dried (Na 2 SO 4 ) and concentrated under vacuum to yield a 3:4 mixture of 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid and 4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic acid (3.4 g) which was used directly without further purification: LCMS (ES) m/z=206/286 (M+H) + .

b) 1,1-dimethylethyl (2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid and 4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylic acid (1.3 g), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (1.2 g, 4.8 mmol) [from Preparation 2] and PyBrop (2.6 g, 5.6 mmol) in CHCl 3 (30 mL) was added diisopropylethyl amine (2.8 mL, 16.1 mmol). The reaction mixture was stirred overnight, adsorbed onto silica and purified via column chromatography [1:3 EtOAc/hexanes] to give a 1:1 mixture of 1,1-dimethylethyl (2-{[(5-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate and 1,1-dimethylethyl (2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate (800 mg): LCMS (ES) m/z=438/518 (M+H) + .

c) 1,1-dimethylethyl[2-({[4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of a 1:1 mixture of 1,1-dimethylethyl (2-{[(5-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate and 1,1-dimethylethyl (2-{[(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate (307 mg) in dioxane/H 2 O (5:1, 5.6 mL) was added Cs 2 CO 3 (800 mg, 2.5 mmol), tetrakistriphenylphosphine Pd(0) (44 mg, 0.04 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (157 mg, 0.75 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h after which additional tetrakistriphenylphosphine Pd(0) (20 mg, 0.02 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (177 mg, 0.85 mmol) were added. After 12 h, the reaction mixture was adsorbed onto silica and purified via column chromatography to give two isomers: the title compound 1,1-dimethylethyl[2-({[4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (17 mg, 0.033 mmol) and 1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (20 mg, 0.05 mmol).

d) N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

1,1-dimethylethyl[3-{[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate (0.045 g, 0.09 mmol) dissolved in CHCl 3 (4 mL) and MeOH (1 mL) was treated with 4 M HCl in dioxane (2 mL). After stirring for 18 h at RT, the reaction solution was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound as a white solid.

The neutral compound from above was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O (150 μL) and concentrated affording the HCl salt of the title compound: LC-MS (ES) m/z 418 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.76-2.98 (m, 4H) 3.57 (d, J=2.78 Hz, 3H) 3.71 (d, J=1.26 Hz, 3H) 4.28 (ddd, J=8.27, 5.12, 2.78 Hz, 1H) 6.44 (dd, J=7.58, 2.02 Hz, 1H) 6.85 (s, 1H) 7.18-7.24 (m, 1H) 7.27-7.32 (m, 4H) 7.61 (d, J=2.02 Hz, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (20 mg, 0.05 mmol) [prepared in Example 48] in CHCl 3 (4 mL) and MeOH (1 mL) was treated with 4 M HCl in dioxane (2 mL). After stirring for 18 h at RT, the reaction solution was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound.

The above compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O (150 μL ) and concentrated affording the HCl salt of the title compound: LC-MS (ES) m/z 338 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.74-2.81 (m, 1H) 2.83-2.90 (m, 2H) 2.92-2.98 (m, 1H) 3.63 (s, 3H) 3.76 (s, 3H) 4.29 (ddd, J=8.02, 5.12, 2.53 Hz, 1H) 6.27 (d, J=4.04 Hz, 1H) 6.39 (d, J=2.02 Hz, 1H) 6.80 (d, J=4.04 Hz, 1H) 7.20 (td, J=5.87, 2.65 Hz, 1H) 7.26-7.31 (m, 4H) 7.57 (d, J=2.02 Hz, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

a) 1,1-dimethylethyl (2-{[(4-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate

To a 50 mL round-bottomed flask was added 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (610 mg, 3.0 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (748 mg, 2.99 mmol) [prepared according to the procedure of Preparation 2] and PyBrop (1.71 g, 3.67 mmol) in Chloroform (15 mL). DIEA (1.8 mL, 10.3 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (Hex/EtOAc) affording the title compound (335 mg, 26%): LC-MS (ES) m/z=438 (M+H) + .

b) 1,1-dimethylethyl[2-({[1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (2-{[(4-bromo-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-phenylpropyl)carbamate (313 mg, 0.717 mmol) in dioxane/H 2 O (4:1, 6.25 mL) was added Cs 2 CO 3 (840 mg, 2.6 mmol), tetrakistriphenylphosphine Pd(0) (62 mg, 0.05 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (202 mg, 1.04 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between H 2 O and CHCl 3 . The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum, adsorbed onto silica gel and purified via column chromatography (35% EtOAc/Hex) affording the title compound (285 mg, 91%): LC-MS (ES) m/z=438 (M+H) + .

c) N-[2-amino-1-(phenylmethyl)ethyl]-1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxamide

HCl in Dioxane (4M, 2 mL) was added to a solution of 1,1-dimethylethyl[2-({[1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (285 mg, 0.65 mmol) in CHCl3/MeOH (10:1, 10 mL) affording the title compound as a white solid (71 mg, 0.21 mmol, 32%): LC-MS (ES) m/z 338 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.77-2.93 (m, 4H) 3.86 (s, 3H) 3.92 (s, 3H) 4.29 (ddd, J=8.15, 4.74, 2.02 Hz, 1H) 6.30 (d, J=2.02 Hz, 1H) 6.94 (d, J=1.77 Hz, 1H) 7.14 (d, J=1.77 Hz, 1H) 7.19 (td, J=5.56, 3.03 Hz, 1H) 7.25-7.30 (m, 4H) 7.41 (d, J=1.77 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (232 mg, 1.11 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 409 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.09-3.30 (m, 4H) 3.97-4.00 (m, 3H) 4.62-4.72 (m, 1H) 6.48 (d, J=2.02 Hz, 1H) 7.43 (ddd, J=8.08, 4.42, 4.17 Hz, 1H) 7.51-7.56 (m, 3H) 7.72 (d, J=7.83 Hz, 1H) 7.89-7.93 (m, 2H).

Preparation of N-[2-(methylamino)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl (2-amino-3-phenylpropyl)methylcarbamate (0.32 g, 1.2 mmol) [from Preparation 13] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate and substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (220 mg, 1.06 mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.41 (s, 3H) 2.81 (td, J=11.81, 7.96 Hz, 2H) 2.87-2.97 (m, 2H) 3.96 (s, 3H) 4.43-4.52 (m, 1H) 6.45 (d, J=1.52 Hz, 1H) 7.16-7.23 (m, 1H) 7.25-7.30 (m, 4H) 7.50 (d, J=1.52 Hz, 1H) 7.85 (d, J=13.14 Hz, 2H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 2-[2-(methylamino)-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.7 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl and substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.72 mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.86 (s, 3H) 2.97 (dd, J=14.02, 8.72 Hz, 2H) 3.12-3.23 (m, 2H) 3.70 (m, 1H) 3.97 (s, 3H) 6.47 (d, J=2.02 Hz, 1H) 7.30-7.35 (m, 1H) 7.37-7.43 (m, 5H) 7.51 (d, J=2.02 Hz, 1H) 7.88 (d, J=1.52 Hz, 1H) 7.94 (d, J=1.52 Hz, 1H).

Preparation of N-[1-(aminomethyl)-2-methyl-2-phenylpropyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (129 mg, 0.62 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (0.20 g, 0.58 mmol) [prepared according to the procedure of Preparation 14] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 369 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 1.36 (s, 3H) 1.41 (s, 3H) 2.61 (d, J=6.82 Hz, 2H) 3.99 (s, 3H) 4.49 (t, J=6.95 Hz, 1H) 6.49 (d, J=1.77 Hz, 1H) 7.23 (t, J=7.33 Hz, 1H) 7.36 (t, J=7.71 Hz, 2H) 7.47-7.52 (m, 3H) 7.89 (d, J=1.26 Hz, 1H) 8.00 (d, J=1.52 Hz, 1H)).

Preparation of N-{(1S)-2-amino-1-[(2,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (99 mg, 0.48 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (155 mg, 0.44 mmol) [prepared according to procedure of Preparation 6] for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 411 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.05-3.28 (m, 4H) 3.97 (s, 3H) 4.63-4.72 (m, 1H) 6.47 (d, J=2.02 Hz, 1H) 7.26-7.29 (m, 1H) 7.34-7.37 (m, 1H) 7.49 (d, J=2.27 Hz, 1H) 7.51 (d, J=2.02 Hz, 1H) 7.86 (d, J=1.52 Hz, 1H) 7.90 (d, J=1.52 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.93 mmol) [prepared according to the procedure of Preparation 9], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.60 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (340 mg, 0.73 mmol) in Chloroform (15 mL). DIEA (0.81 mL, 4.65 mmol) was added and the mixture stirred overnight at room temperature. Upon completion, the reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (112 mg, 0.203 mmol, 22%): LC-MS (ES) m/z=553 (M+H) +

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (112 mg, 0.203 mmol) in Tetrahydrofuran (THF) (6 mL) and Methanol (1 mL). Hydrazine (40 μL, 1.3 mmol) was added and the mixture stirred overnight at room temperature. Upon completion, the mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (43 mg, 0.102 mmol, 50% yield): LC-MS (ES) m/z 423 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.38 (s, 3H) 3.01 (m, 1H) 3.08 (d, J=6.57 Hz, 3H) 3.76-3.83 (m, 3H) 4.47 (m, 1H) 6.37 (d, J=2.02 Hz, 1H) 7.41 (t, J=7.58 Hz, 1H) 7.50-7.57 (m, 2H) 7.57-7.63 (m, 1H) 7.68 (d, J=7.58 Hz, 1H) 8.04 (d, J=9.09 Hz, 1H) 8.15 (s, 3H) 8.96 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 1.07 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (357 mg, 1.2 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 359 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.96-3.06 (m, 4H) 3.92-3.98 (m, 3H) 4.40 (dd, J=8.08, 5.56 Hz, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.02 (td, J=8.46, 2.02 Hz, 1H) 7.14 (t, J=8.08 Hz, 2H) 7.26-7.35 (m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.16-8.27 (m, 3H) 8.34 (d, J=1.26 Hz, 1H) 9.08 (d, J=8.34 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.66 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (196 mg, 0.66 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl. The reaction mixture was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 359 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.80-3.03 (m, 4H) 3.89-3.97 (m, 3H) 4.30-4.40 (m, 1H) 6.45 (d, J=1.77 Hz, 1H) 7.12 (t, J=8.84 Hz, 2H) 7.29 (dd, J=8.34, 5.56 Hz, 2H) 7.48 (d, J=1.77 Hz, 1H) 7.92 (br. s, 3H) 7.96 (d, J=1.26 Hz, 1H) 8.02 (d, J=1.26 Hz, 1H) 8.58 (d, J=8.84 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (189 mg, 0.91 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (297 mg, 0.85 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 409 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.06 (d, J=7.07 Hz, 4H) 3.91-3.98 (m, 3H) 4.35-4.45 (m, 1H) 6.46 (d, J=1.77 Hz, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.49-7.57 (m, 2H) 7.58-7.63 (m, 1H) 7.69 (s, 1H) 7.98 (d, J=1.52 Hz, 1H) 8.23 (s, 3H) 8.32 (d, J=1.26 Hz, 1H) 9.11 (d, J=8.84 Hz, 1H).

Preparation of N-((1S)-2-amino-{[4-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg, 0.9 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid and substituting 2-{(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (278 mg, 0.80 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 409 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.04 (m, 4H) 3.96 (s, 3H) 4.42 (s, 1H) 6.44-6.49 (m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.52 (d, J=7.83 Hz, 2H) 7.66 (d, J=8.08 Hz, 2H) 8.01 (s, 1H) 8.05-8.32 (br. m, 3H) 8.34 (m, 1H) 8.9-9.2 (br. s, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl[2-({[5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl[3-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)propyl]carbamate (154 mg, 0.32 mmol) [prepared according to the procedure of Example 3] in Dioxane/H 2 O (5:1, 3.1 mL) was added Cs 2 CO 3 (415 mg, 1.27 mmol), tetrakistriphenylphosphine Pd(0) (29 mg, 0.03 mmol), and 5-iodo-1-methyl-1H-1,2,4-triazole (95 mg, 0.46 mmol) [prepared according to the procedure of Preparation 15]. The reaction mixture was heated to 85° C. in a sealed tube for 12 hours. The reaction was partitioned between H 2 O and CHCl 3 , the organic layer dried with Na 2 SO 4 , absorbed onto silica and purified via column chromatography (35-50% EtOAc/Hexanes) affording the title compound as a yellow solid (61 mg, 28%): LC-MS (ES) m/z=521.

b) N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thiophenecarboxamide

HCl in Dioxane (4M, 1 mL) was added to a solution of 1,1-dimethylethyl[2-({[5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (61 mg, 0.12 mmol) in CHCl 3 /MeOH (10:1, 10 mL) and the mixture stirred overnight. Upon completion, the mixture was adsorbed onto silica gel and purified via chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH). The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound as a white solid (30 mg, 0.09 mmol, 77%): LC-MS (ES) m/z 341 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.79-2.91 (m, 3H) 2.94 (t, J=5.56 Hz, 1H) 4.10 (s, 3H) 4.25-4.34 (m, 1H) 7.18 (ddd, J=8.27, 5.75, 3.16 Hz, 1H) 7.24-7.29 (m, 4H) 7.63 (d, J=4.04 Hz, 1H) 7.75 (d, J=4.04 Hz, 1H) 7.95 (s, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl[2-({[5-(1-methyl-1H-imidazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl[2-phenyl-2-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]carbonyl}amino)ethyl]carbamate (72 mg, 0.15 mmol) [prepared according to the procedure of Example 3] in dioxane/H 2 O (5:1, 1.4 mL) was added Cs 2 CO 3 (200 mg, 0.61 mmol), tetrakistriphenylphosphine Pd(0) (8.5 mg, 0.01 mmol), and 5-bromo-1-methyl-1H-imidazole (64 mg, 0.40 mmol). The reaction mixture was heated to 85° C. in a sealed tube for 12 h. Upon completion, the reaction mixture was partitioned between H 2 O (25 mL) and CHCl 3 . The organics were dried (Na 2 SO 4 ), concentrated under vacuum, adsorbed onto silica gel and purified via column chromatography (35-50% EtOAc/Hexanes) to give the title compound (19.6 mg, 31%) as a yellow solid: LC-MS (ES) m/z=441.

b) N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-imidazol-5-yl)-2-thiophenecarboxamide

HCl in Dioxane (4M, 1 mL) was added to a solution of 1,1-dimethylethyl[2-({[5-(1-methyl-1H-imidazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (19.6 mg, 0.04 mmol) in CHCl 3 /MeOH (10:1, 5 mL). Upon completion of the reaction, the mixture was adsorbed onto silica gel and purified via chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound as a white solid (19 mg, 0.05 mmol, quant.): LC-MS (ES) m/z 341 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 2.77-2.83 (m, 1H) 2.85-2.91 (m, 2H) 2.93-2.99 (m, 1H) 3.82 (s, 3H) 4.30 (ddd, J=8.08, 4.80, 1.77 Hz, 1H) 7.15-7.31 (m, 7H) 7.69 (d, J=4.04 Hz, 1H) 7.76 (s, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (253 mg, 0.69 mmol) for 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. The reaction mixture was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH 4 OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H 2 O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 569 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.14-3.30 (m, 4H) 3.82 (s, 3H) 4.73 (dd, J=9.47, 4.67 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.44-7.50 (m, 1H) 7.56-7.62 (m, 3H) 7.74 (d, J=7.83 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.50 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 488 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.15 (s, 2H) 3.23 (s, 2H) 3.84 (s, 3H) 4.65 (s, 1H) 6.52-6.57 (m, 1H) 7.46 (s, 1H) 7.52-7.61 (m, 3H) 7.72 (s, 1H) 7.81 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl (157 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 455 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.11 (s, 1H) 3.22 (s, 1H) 3.27 (s, 2H) 3.85 (s, 3H) 4.70 (s, 1H) 6.57 (s, 1H) 7.26 (s, 2H) 7.41 (s, 2H) 7.66 (s, 1H) 7.88 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl (149 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 438 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.00 (s, 1H) 3.09 (s, 1H) 3.15 (dd, J=3.41, 1.64 Hz, 2H) 3.83 (s, 4H) 4.58 (s, 1H) 6.52 (d, J=2.02 Hz, 1H) 7.08-7.17 (m, 3H) 7.27-7.37 (m, 3H) 7.59 (d, J=2.02 Hz, 1H) 7.74 (d, J=3.54 Hz, 1H).

Preparation of N-[(1S)-2-amino-1-(1H-indol-3-ylmethyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-thiophenecarboxylic acid (143 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(1H-indol-3-yl)propyl]-1H-isoindole-1,3(2H)-dione-dione-HCl (160 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 459 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.15 (dt, J=10.42, 6.79 Hz, 3H) 3.27 (dd, J=4.04, 2.27 Hz, 1H) 3.84 (s, 3H) 4.63 (d, J=6.82 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.05 (t, J=7.45 Hz, 1H) 7.13 (t, J=7.07 Hz, 1H) 7.19 (s, 1H) 7.37 (d, J=8.08 Hz, 1H) 7.64-7.73 (m, 2H) 7.77 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(2-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 6, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl (157 mg, 0.5 mmol) [prepared according to Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 375 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.11-3.20 (m, 1H) 3.22-3.31 (m, 3H) 4.23 (s, 3H) 4.75 (s, 1H) 6.96 (s, 1H) 7.18-7.26 (m, 2H) 7.38 (d, J=6.06 Hz, 1H) 7.46 (d, J=4.55 Hz, 1H) 8.22 (s, 2H) 8.32 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 6, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(2-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl (149 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 359 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.06-3.17 (m, 2H) 3.25-3.31 (m, 2H) 4.18 (s, 3H) 4.59-4.67 (m, 1H) 6.88 (s, 1H) 7.05-7.12 (m, 2H) 7.23-7.30 (m, 1H) 7.36-7.42 (m, 1H) 8.12 (d, J=1.01 Hz, 1H) 8.17 (s, 1H) 8.21 (s, 1H).

Preparation of N-[2-amino-1-(1-naphthalenyl)ethyl]-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate (143 mg, 0.5 mmol) [from Preparation 16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 456 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.60 (s, 1H) 3.72 (s, 1H) 3.84 (s, 3H) 6.33 (d, J=10.11 Hz, 1H) 6.55 (s, 1H) 7.55-7.61 (m, 3H) 7.64 (d, J=8.34 Hz, 1H) 7.74 (s, 1H) 7.92-7.99 (m, 2H) 8.09 (s, 1H) 8.26 (s, 1H).

Preparation of N-[2-amino-1-(1-naphthalenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 4,5-dibromo-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl[2-amino-2-(1-naphthalenyl)ethyl]carbamate (143 mg, 0.5 mmol) [from Preparation 16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 377 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.62 (d, J=4.04 Hz, 1H) 3.67-3.78 (m, 1H) 4.08-4.10 (m, 3H) 6.35 (s, 1H) 6.73 (d, J=2.27 Hz, 1H) 7.55-7.60 (m, 2H) 7.62-7.67 (m, 1H) 7.76 (d, J=7.33 Hz, 1H) 7.88 (d, J=2.53 Hz, 1H) 7.93-7.99 (m, 2H) 8.10 (d, J=1.52 Hz, 1H) 8.23-8.27 (m, 2H).

Preparation of N-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 4,5-dibromo-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl {2-amino-2-[2-(trifluoromethyl)phenyl]ethyl}carbamate (152 mg, 0.5 mmol) [prepared according to the procedure of Preparation 16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 395 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.36-3.39 (m, 1H) 3.46-3.53 (m, 1H) 3.98 (s, 3H) 5.86-5.91 (m, 1H) 6.48 (s, 1H) 7.51 (d, J=2.02 Hz, 1H) 7.60 (s, 1H) 7.76 (s, 1H) 7.83 (d, J=8.08 Hz, 2H) 7.94 (s, 1H) 8.05 (s, 1H).

Preparation of N-{2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl {2-amino-2-[2-(trifluoromethyl)phenyl]ethyl}carbamate (152 mg, 0.5 mmol) [prepared according to the procedure of Preparation 16] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 474 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.37 (s, 1H) 3.65 (s, 1H) 3.89-4.00 (m, 3H) 5.88 (s, 1H) 6.76 (d, J=2.27 Hz, 1H) 7.58 (s, 1H) 7.77 (d, J=9.60 Hz, 2H) 7.91-8.03 (m, 2H) 8.26 (d, J=2.27 Hz, 1H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 24, except substituting NBS (194 mg, 1.09 mmol) for NCS: LC-MS (ES) m/z 418 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.03 (d, J=7.33 Hz, 2H) 3.23 (s, 2H) 3.90 (s, 3H) 4.56 (d, J=1.77 Hz, 1H) 7.20-7.27 (m, 1H) 7.28-7.34 (m, 4H) 7.58 (s, 1H) 7.96 (s, 2H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 25, except substituting NBS (67 mg, 0.5 mmol) for NCS: LC-MS (ES) m/z 488 (M+H) + , 1 H NMR (400 MHz, MeOD) δ ppm 3.10-3.19 (m, 1H) 3.20-3.28 (m, 3H) 3.91 (s, 3H) 4.66 (dd, J=8.59, 3.03 Hz, 1H) 7.39-7.47 (m, 1H) 7.51-7.58 (m, 2H) 7.59 (s, 1H) 7.72 (d, J=8.08 Hz, 1H) 7.98 (s, 2H).

Preparation of N-{(1S)-2-amino-1-[(3,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a light yellow solid according to the procedure of Example 6, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione-HCl (158 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 395 (M+H) + , 1 H NMR (400 MHz, DMSO) δ ppm 2.94-3.06 (m, 4H) 3.95 (s, 3H) 4.40 (d, J=6.06 Hz, 1H) 6.46 (d, J=1.77 Hz, 1H) 7.00-7.10 (m, 3H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.10 (s, 2H) 8.21 (s, 1H) 8.92 (d, J=8.0 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to the procedure of Example 6, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(3-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (157 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 395 (M+H) + , 1 H NMR (400 MHz, DMSO) δ ppm 2.92-3.04 (m, 4H) 3.92-3.98 (m, 3H) 4.36 (d, J=5.56 Hz, 1H) 6.47 (s, 1H) 7.19-7.29 (m, 2H) 7.29-7.35 (m, 1H) 7.37-7.42 (m, 1H) 7.47 (s, 1H) 8.17 (s, 3H) 8.85-9.07 (m, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-chlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to the procedure of Example 6, except substituting 4-bromo-2-thiophenecarboxylic acid (104 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid and substituting 2-[(2S)-2-amino-3-(4-chlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (157 mg, 0.5 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl: LC-MS (ES) m/z 395 (M+H) + , 1 H NMR (400 MHz, DMSO) δ ppm 2.92-2.97 (m, 2H) 2.99-3.04 (m, 2H) 4.01 (s, 3H) 4.32-4.42 (m, 1H) 6.43-6.50 (m, 1H) 7.27-7.37 (m, 4H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.21 (s, 3H) 8.94-9.10 (m, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 4,5-dibromo-2-furancarboxylic acid (135 mg, 0.5 mmol) for 5-bromo-2-thiophenecarboxylic acid: LC-MS (ES) m/z 472 (M+H) + , 1 H NMR (400 MHz, DMSO) δ ppm 3.11 (d, J=9.85 Hz, 1H) 3.21-3.31 (m, 3H) 4.06 (s, 3H) 4.70 (s, 1H) 6.87 (d, J=2.02 Hz, 1H) 7.33 (s, 1H) 7.41-7.48 (m, 1H) 7.50-7.57 (m, 2H) 7.60 (d, J=2.02 Hz, 1H) 7.71 (d, J=7.83 Hz, 1H).

Preparation of N-(3-amino-1-phenylpropyl)-4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 1,1-dimethylethyl[3-(methylamino)-3-phenylpropyl]carbamate (125 mg, 0.5 mmoles) [from Preparation 3] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z 420 (M+H) + , 1 H NMR (400 MHz, DMSO) δ ppm 2.25-2.37 (m, 2H) 2.96 (d, J=8.08 Hz, 1H) 3.04-3.13 (m, 1H) 3.84 (s, 3H) 5.22 (t, J=7.58 Hz, 1H) 6.53 (d, J=1.52 Hz, 1H) 7.35 (d, J=6.57 Hz, 1H) 7.44 (dt, J=15.09, 7.48 Hz, 4H) 7.58.

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a suspension of NaH (60% in mineral oil, 2.2 g, 55 mmol) in THF (50 mL) was added pyrazole (3.4 g, 50 mmol) in THF (10 mL) at room temperature. After 30 min, to above suspension was added EtI (7.75 g, 50 mmol) dropwise. After the reaction was complete (20 h), the suspension was filtered, and the resulting solution was used directly with further purification.

At 0° C., to above solution of 4-methylpyrazole (˜50 mmol) was added n-BuLi (2.5M in hexane, 22 mL, 55 mmol). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [ J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.2 g, 55 mmol). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH 4 Cl solution and extracted with DCM. The organics were dried over Na 2 SO 4 and concentrated under vacuum to afford a tan solid (9.8 g, 89%) which was used without further purification. LCMS (ES) m/z 141 (M+H) + for [RB(OH) 2 ]; 1 H NMR (CDCl 3 , 400 MHz) δ ppm 7.52 (d, J=2 Hz, 1H), 6.36 (d, J=2 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H), 1.36 (s, 12H)

b) 1,1-dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (100 mg, 0.23 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (100 mg, 0.72 mmol), tetrakistriphenylphosphine Pd(0) (30 mg, 26 μmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.29 mmol). The reaction mixture was heated to 70° C. in a sealed tube. After 12 h, the reaction mixture was concentrated under vacuum and purified on silica (hex/EtOAc, 40-60%) to afford the title compound (0.074 g, 71%) as a light yellow solid: LC-MS (ES) m/z 455 (M+H) + .

c) N-[2-amino-1-(phenylmethyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-Dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (74 mg, 0.16 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 1 h, the solution was concentrated and neutralized through silica using 4% MeOH in DCM (1% NH 4 OH). The title compound was further purified using reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 40-10%) affording the bis-TFA salt of the title compound (47 mg, 50%) as a white solid: LCMS (ES) m/z 355 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.71 (d, J=3.8 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.34-7.22 (m, 6H), 6.51 (d. J=1.8 Hz, 1H), 4.55 (m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.22 (dd, J=3.5, 13.1 Hz, 1H), 3.13 (dd, J=10.1, 13.1 Hz, 1H), 3.00 (m, 2H), and 1.42 (t, J=7.1 Hz, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-3,4-dibromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 1, except substituting 1,1-dimethylethyl (3-phenyl-2-{[(3,4,5-tribromo-2-thienyl)carbonyl]amino}propyl)carbamate (120 mg, 0.20 mmol) for 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate: LC-MS (ES) m/z 499 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.59 (d, J=2.0 Hz, 1H), 7.37-7.24 (m, 5H), 6.53 (d, J=2.0 Hz, 1H), 4.62 (m, 1H), 3.27 (d, J=13.1, 4.3 Hz, 1H), 3.21 (dd, J=13.1, 9.4 Hz, 1H), 3.09 (dd, J=14.2, 6.1 Hz, 1H), 3.02 (dd, J=13.9, 9.1 Hz, 1H), and 1.96 (s, 3H).

N-[2-amino-1-(phenylmethyl)ethyl]-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-[2-amino-1-(phenylmethyl)ethyl]-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 1, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64.0 mg, 0.23 mmol) [from Preparation 17] for 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate, and substituting 1,1-dimethylethyl (2-{[(5-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (110 mg, 0.25 mmol) for 1,1-dimethylethyl (2-{[(5-bromo-3-thienyl)carbonyl]amino}-2-phenylethyl)carbamate: LC-MS (ES) m/z 355 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.75 (d, J=3.8 Hz, 1H), 7.40 (br s, 1H), 7.32-7.23 (m, 5H), 7.21 (d, J=3.8 Hz, 1H), 4.56 (m, 1H), 3.86 (s, 3H), 3.23 (dd, J=13.1, 3.8 Hz, 1H), 3.15 (dd, J=12.9, 10.1 Hz, 1H), 3.01 (m, 2H) and 2.10 (s, 3H).

N-[2-amino-1-(phenylmethyl)ethyl]-4-bromo-5-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 1, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg, 0.23 mmol) [from Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and substituting 1,1-dimethylethyl (2-{[(4,5-dibromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (150 mg, 0.29 mmol) for 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate: LC-MS (ES) m/z 434 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.77 (s, 1H), 7.43 (s, 1H), 7.35-7.23 (m, 5H), 4.55 (m, 1H), 3.72 (s, 3H), 3.23 (dd, J=3.5 Hz, 1H), 3.13 (dd, J=10.6, 13.1 Hz, 1H), 3.02-2.95 (m, 2H), and 1.99 (s, 3H).

N-[2-amino-1-(phenylmethyl)ethyl]-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 1, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 1.0 mmol) [from Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and substituting 1,1-dimethylethyl (2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (150 mg, 0.34 mmol) for 1,1-dimethylethyl[2-({[4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-furanyl]carbonyl}amino)-3-phenylpropyl]carbamate: LC-MS (ES) m/z=355 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 8.14-8.13 (m, 3H), 7.35-7.20 (m, 5H), 4.58 (m, 1H), 4.07 (s, 3H), 3.36-3.22 (m, 2H), 3.12-3.01 (m, 2H), and 2.21 (s, 3H).

N-[2-amino-1-(phenylmethyl)ethyl]-N-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 1,1-dimethylethyl {2-[[(4-bromo-2-thienyl)carbonyl](hydroxy)amino]-3-phenylpropyl}carbamate

To a solution of 4-bromo-2-thiophenecarboxylic acid (1.0 g, 4.83 mmol) in DCM (10 mL) was added PyBrop (3.4 g, 7.24 mmol) and Hunig's base (2 mL, 12.6 mmol). After 15 min, 1,1-dimethylethyl[2-(hydroxyamino)-3-phenylpropyl]carbamate (641 mg, 2.41 mmol) was added to the reaction mixture in DCM (2 mL) and stirred for 2 h at RT. The reaction solution was concentrated to give crude 1,1-dimethylethyl[2-([(4-bromo-2-thienyl)carbonyl]{[(4-bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamate. LC-MS (ES) m/z=645 (M+H) + .

To a solution of 1,1-dimethylethyl[2-([(4-bromo-2-thienyl)carbonyl]{[(4-bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamate in MeOH (5 mL) was added K 2 CO 3 (1.0 g, 7.3 mmol). The mixture was stirred at RT for 2 h. The mixture was concentrated under vacuum and purified on silica gel (EtOAc/Hexane, 30%) to give the title compound (410 mg, 37% for two steps) as an off white solid: LC-MS (ES) m/z=456 (M+H) + .

b) 1,1-dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl {2-[[(4-bromo-2-thienyl)carbonyl](hydroxy)amino]-3-phenylpropyl}carbamate (100 mg, 0.22 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (91 mg, 0.66 mmol), tetrakistriphenylphosphine Pd(0) (23 mg, 0.022 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68 mg, 0.33 mmol). The reaction mixture was heated to 75° C. in a sealed tube. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 20-40%) to afford the title compound (87 mg, 87%): LC-MS (ES) m/z=456 (M+H) + .

c) N-[2-amino-1-(phenylmethyl)ethyl]-N-hydroxy-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-Dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (84 mg, 0.19 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). The reaction was stirred over 1 h, and concentrated, and purified by reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 40-10%), and concentrated to afford the bis-TFA salt of the title compound (51.2 mg, 64.8%). LC-MS (ES) m/z 357 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 8.03 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 7.34-7.18 (m, 5H), 5.16 (m, 1H), 3.95 (s, 3H), 3.38 (dd, J=13.1, 10.6 Hz, 1H), 3.17-3.11 (m, 2H), and 2.95 (dd, J=13.6, 6.6 Hz, 1H)

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-2-thiophenecarboxylic acid (80 mg, 0.39 mmol) in DCM (2 mL) at 25° C. was added bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (218 mg, 0.47 mmol) in one portion, followed by addition of DIPEA (0.2 mL, 1.14 mmol). After stirring for 10 min, diamine 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (165 mg, 0.43 mmol) was added to above solution. After 2 h, the solution was concentrated and purified via column chromatography (silica, 10% MeOH in CH 3 Cl) affording the title compound (206 mg, 99%) as a white solid: LC-MS (ES) m/z 538 (M+H) + .

b) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (200 mg, 0.37 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (0.17 g, 1.23 mmol), tetrakistriphenylphosphine Pd(0) (42 mg, 0.036 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (413 mg, 1.86 mmol) [from Preparation 17]. The reaction mixture was heated to 80° C. in a sealed tube for 2 h. The reaction solution was concentrated under vacuum, and purified on silica gel (10-50% EtOAc/Hex) to give the title compound (192 mg, 94%) as a white solid: LC-MS (ES) m/z 553 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(1,4-Dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (110 mg, 0.198 mmol) was dissolved in MeOH (2 mL) and was treated with NH 2 NH 2 (0.5 mL, 15.93 mmol). The reaction was stirred over 10 h, concentrated and the residue in DCM (2 mL) was treated with TFA (1.0 mL). After stirring for 2 h, the solvent was removed and the residue was purified by reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 40-10%), and concentrated to afford the bis-TFA salt of the title compound. The bis-TFA salt was neutralized through a silica plug (90:9:1 CHCl 3 /MeOH/NH 4 OH) affording the free base of the title compound. The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (62 mg, 34.6%) as the HCl salt: LC-MS (ES) m/z 423 (M+H) + , 1 H NMR (d4-MeOD, 400 MHz) δ ppm 8.27 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.70 (d, 7.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.51 (dd, J=7.3, 7.3 Hz, 1H), 7.41 (dd, J=7.6, 7.3 Hz, 1H), 4.69 (m, 1H), 4.12 (s, 3H), 3.41-3.19 (m, 4H), and 2.24 (s, 3H).

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a white solid according to the procedure of Example 87, except substituting 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104 mg, 0.47 mmol) for 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (ES) m/z=423 (M+H) + , 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 8.35-8.31 (m, 2H), 8.21 (br s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.51 (dd, J=7.3, 7.3 Hz, 1H), 7.42 (dd J=7.6, 7.3 Hz, 1H), 7.00 (m, 1H), 4.70-4.61 (m, 3H), 3.40-3.17 (m, 4H), and 1.57 (t, J=6.8 Hz, 3H).

N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-methyl-2-thiophenecarboxylic acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (2.07 g, 10 mmol) in DMF (5 mL) was added NCS (2.7 g, 15 mmol) in one portion. The reaction mixture was stirred at 50° C. for 10 h, and then cooled to room temperature. The desired product precipitated after water (5 mL) was added. The white solid was filtered and dried under high vacuum to give 1.9 g (79%). LC-MS (ES) m/z=242 (M+H) + ,

b) 1,1-dimethylethyl (2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate

To a solution of 5-chloro-4-methyl-2-thiophenecarboxylic acid (242 mg, 1.0 mmol) and diisopropylethyl amine (2.5 mL, 14.60 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 30 min, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (250 mg, 1.0 mmol) was added at one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 10-40% EtOAc in Hexane) affording the title compound (460 mg, 97%) as a white solid: LC-MS (ES) m/z=474 (M+H) + .

c) 1,1-dimethylethyl[2-({[5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

To a solution of 1,1-dimethylethyl (2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (100 mg, 0.21 mmol) in THF (5 mL) was added Na 2 CO 3 (2N, 0.3 mL, 0.6 mmol), Pd(dppf)Cl 2 (20 mg, 24 μmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92 mg, 0.42 mmol). The reaction mixture was heated to 80° C. in a sealed tube under N 2 . After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (hex/EtOAc, 20-50%) to afford the title compound (74 mg, 72%) as a light yellow solid: LC-MS (ES) m/z 489 (M+H) + .

d) N-[2-amino-1-(phenylmethyl)ethyl]-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

1,1-dimethylethyl[2-({[5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (61 mg, 0.12 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 0.5 h, the solution was concentrated and neutralized through silica using 4% MeOH in DCM (1% NH 4 OH). The title compound was further purified using reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 40-10%) affording the bis-TFA salt of the title compound (41 mg, 53%) as a white solid. LC-MS (ES) m/z=389 (M+H) + . 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.61 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.33-7.21 (m, 5H), 6.41 (d, J=2.0 Hz, 1H), 4.52 (m, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.22 (dd, J=12.9, 3.5 Hz, 1H), 3.12 (dd, J=12.6, 10.1 Hz, 1H), 2.98 (m, 2H), and 1.35 (t, J=7.1 Hz, 3H).

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as an off-white solid according to the procedure of Example 89(c), except substituting 4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (150 mg, 0.26 mmol) for 1,1-dimethylethyl (2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate: LC-MS (ES) m/z 587 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (110 mg, 0.19 mmol) in MeOH/THF (5 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified by reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 40-10%) to afford the bis-TFA salt of the title compound. The bis-TFA salt was dissolved in water, and neutralized by ammonium hydroxide. The mixture was extracted with DCM (5 mL×3), dried over Na 2 SO 4 , and concentrated to give a free base of the title compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (26 mg, 26%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H) + . 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 8.28 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53 (dd, J=7.3, 7.6 Hz, 1H), 7.43 (dd, J=7.6, 7.6 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.66 (m, 1H), 4.43 (q, J=7.3 Hz, 2H), 3.37-3.16 (m, 4H), and 1.50 (t, J=7.3 Hz, 3H).

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (260 mg, 0.46 mmol) in THF (5 mL) was added Na 2 CO 3 (2N, 0.7 mL, 1.4 mmol), Pd(dppf)Cl 2 (40 mg, 48 μmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (303 mg, 1.38 mmol). The reaction mixture was heated to 75° C. in a sealed tube under N 2 . After 8 h, the reaction mixture was concentrated under vacuum and purified on silica (10:1 CHCl 3 /MeOH) to afford the title compound (196 mg, 73.4%): LC-MS (ES) m/z=587 (M+H) + .

b) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified on silica (50% MeOH in CHCl 3 (0.5% NH 4 OH) to give a free base of the tile compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (107 mg, 51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H) + . 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m, 1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.52 mmol) in dioxane/H 2 O (5:1, 6 mL) was added K 2 CO 3 (1.86 g, 13.5 mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.23 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 5.85 mmol). The reaction mixture was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (hex/EtOAc, 20-40%) to afford methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.7 g, 66%) as a light yellow solid: LC-MS (ES) m/z=237 (M+H) + .

To a solution of the above compound (0.5 g, 2.11 mmol) in THF (10 mL) was added NCS (0.364 g, 2.74 mmol). The reaction mixture was heated to 70° C. under nitrogen. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (Hexanes/EtOAc, 10-20%) to afford the title compound (0.45 g, 78%) as a light yellow solid: LC-MS (ES) m/z 271 (M+H) + .

(b) 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.3 g, 1.1 mmol) in THF/H 2 O (5 mL/0.5 mL) was added KOH (0.2 g, 3.4 mmol). The reaction mixture was heated to 50° C. for 4 h and then concentrated and diluted with H 2 O (2 mL). The pH was adjusted to 3 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (260 mg) which was used directly without further purification. LC-MS (ES) m/z=256 (M+H) + .

To a solution of 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.26 g, 1.0 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.35 g, 1.1 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.6 g, 1.2 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/hexane) affording the title compound (0.54 g, 91%) as a white solid: LC-MS (ES) m/z=588 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (350 mg, 0.60 mmol) was dissolved in MeOH (5 mL) and treated with NH 2 NH 2 (0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, and concentrated. The residue was purified by column chromatography (silica, 2-5% MeOH in CHCl 3 (0.5% NH 4 OH) affording the free base of the title compound, which was treated with HCl(aq) in MeOH to give title compound (0.16 g, 51%) as a off white solid: LC-MS (ES) m/z=457 (M+H) + . 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.97-7.94 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.56-7.51 (m, 2H), 7.43 (dd, J=7.6, 7.6 Hz, 1H), 4.67 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.36-3.12 (m, 4H), and 1.38 (t, J=7.1 Hz, 3H).

N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.45 g, 1.9 mmol) [see example 92(a)] in THF (5 mL) was added NBS (0.33 g, 2.5 mmol). The reaction mixture was heated to 70° C. under nitrogen. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/hexanes, 10-30%) to afford the title compound (0.47 g, 78%). LC-MS (ES) m/z=316 (M+H) + .

b) 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.2 g, 0.63 mmol) in THF/H 2 O (5 mL/1 mL) was added KOH (0.15 g, 2.4 mmol). The reaction mixture was heated to 50° C. for 10 h and then concentrated and diluted with H 2 O (2 mL). The pH was adjusted to 6 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, which was used directly without further purification. LC-MS (ES) m/z=302 (M+H) + .

To a solution of 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid 156 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.18 g, 0.52 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.29 g, 0.62 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-60% EtOAc/hexane) affording the title compound (0.281 g, 86%). LC-MS (ES) m/z=632 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (250 mg, 0.39 mmol) was dissolved in MeOH (5 mL) and treated with NH 2 NH 2 (0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, and concentrated. The residue was purified by column chromatography [silica, 2-10% MeOH in CHCl 3 (0.5% NH 4 OH)]affording the free base of the title compound, which was treated with HCl(aq) in MeOH to give the title compound (144 mg, 51%) as an off white solid: LC-MS (ES) m/z 502 (M+H) + . 1 H NMR (d 4 -MeOD, 400 MHz) δ ppm 7.93-7.87 (m, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.57-7.51 (m, 2H), 7.43 (t, J=6.6 Hz, 1H), 4.67 (m, 1H), 4.25 (q, J=7.3 Hz, 2H), 3.37-3.11 (m, 4H), and 1.37 (t, J=7.1 Hz, 3H).

Preparation of N-[2-amino-1-(phenylmethyl)ethyl]-3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

Methyl 4-bromo-3-(methyloxy)-2-thiophenecarboxylate (250 mg, 0.10 mmol) [prepared according to Corral, C.; El-Ashmawy, M. B.; Lissavetzky, J.; Basilio, A.; Giraldez, A.; Eur. J. Med. Chem. Chim. Ther. 22; 1987; 251-254.], 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (250 mg, 1.20 mmol), Pd(PPh 3 ) 4 (58 mg, 49.8 μmol) and K 2 CO 3 (550 mg, 3.98 mmol) in dioxane (5 mL) and H 2 O (1 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (215 mg, 86%) as a brown residue: LCMS (ES) m/z=253 (M+H) + .

b) 1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate

i) A solution of methyl 3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (215 mg, 0.853 mmol) in 6N NaOH (4 mL) and THF (4 mL) was stirred in a sealed tube at 70° C. After 2 h, the solution was acidified to pH 3 using 1N HCl then extracted several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=239 (M+H) + .

ii) To a solution of the crude acid, 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (210 mg, 0.844 mmol) [from Preparation 2] and diisopropylethyl amine (735 μL, 4.22 mmol) in DCM (8 mL) was added PyBrop (472 mg, 1.01 mmol) in one portion. After 1 h, the reaction contents were partitioned between H 2 O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly: LCMS (ES) m/z=471 (M+H) + .

c) N-[2-amino-1-(phenylmethyl)ethyl]-3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

A solution of 1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part b) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH 4 OH)) affording the free base of the title compound.

The free base, as a solution in MeOH, was then treated with excess 4M HCl in dioxane affording the title compound (270 mg, 86%-2 steps) as the HCl salt: LCMS (ES) m/z 371 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.06 (br. s., 3H) 7.91 (s, 1H) 7.72 (d, J=8.59 Hz, 1H) 7.52 (d, J=1.77 Hz, 1H) 7.25-7.31 (m, 4H) 7.18-7.23 (m, 1H) 6.39 (d, J=2.02 Hz, 1H) 4.52 (br. s., 1H) 3.78 (s, 3H) 3.41 (s, 3H) 2.97-3.05 (m, 4H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-chloro-2-thiophenecarboxylate

To a solution of 5-chloro-2-thiophenecarboxylic acid (20 g, 123 mmoles) in MeOH (200 mL) was added conc. H 2 SO 4 (5 mL). After heating to 55° C. for 12 h, the reaction solution was concentrated and diluted with DCM (250 mL). The DCM solution was washed with aqueous NaHCO 3 , then H 2 O and dried over Na 2 SO 4 . Concentration under vacuum gave the title compound as a yellow oil (21.5 g, 99%): LCMS (ES) m/z 178 (M+H) + .

b) methyl 4-bromo-5-chloro-2-thiophenecarboxylate

To a 1 L round bottom flask was added aluminum chloride (11.32 g, 85 mmol) and methyl 5-chloro-2-thiophenecarboxylate (10 g, 56.6 mmol) dissolved in CHCl 3 (250 mL). Br 2 (4.08 ml, 79 mmol) was added dropwise over 10 minutes. After stirring for 6 h at 25° C., the light orange reaction solution was washed with sat NaHCO 3 . The organic layer was dried Na 2 SO 4 , filtered and concentrated. The residue was purified on silica gel [hexanes/EtOAc, 9:1] to give the product [12 g, 80%] as a white solid. LCMS (ES) m/z 256 (M+H) + .

c) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 300 mL sealed flask was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.14 g, 39.1 mmol), potassium carbonate (12.98 g, 94 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1,4-dioxane (50 ml) and H 2 O (6 ml). After stirring for 90 min at 75° C., the reaction solution was diluted with DCM (100 mL) and washed with H 2 O. The organic layer was dried Na 2 SO 4 , filtered and concentrated. The reaction residue was purified on silica gel [hexanes/EtOAc, 2:1] to give the product [5.7 g, 70%] as a tan solid: LCMS (ES) m/z 258 (M+H) + .

d) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a 250 mL round-bottomed flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (4.4 g, 17.14 mmol) and sodium hydroxide (28.6 ml, 171 mmol) in tetrahydrofuran (THF) (50 ml) and MeOH (50 mL). The reaction solution was stirred at RT for 12 h and then made acidic (pH ˜2) with 2.5 M HCl and extracted with DCM. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated to an off-white solid (4.2 g, 94%) which was used directly without further purification: LCMS (ES) m/z 243 (M+H) + .

e) 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 500 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (4.2 g, 17.31 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (6.37 g, 19.04 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (4.53 ml, 26.0 mmol) and Pybrop (12.05 g, 26.0 mmol) in dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H 2 O (2×100 mL) and the organic layer was dried Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [7.8 g, 86%] as a white solid: LCMS (ES) m/z 524 (M+H) + .

f) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 250 mL round-bottomed flask was added 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (7.8 g, 14.91 mmol) and hydrazine (14.50 ml, 298 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated. The crude product was purified on a silica gel column [CHCl 3 /MeOH/NH 4 OH, 90:9:1] to give the title compound as a white solid. The free base product was treated with 4M HCl in dioxane (15 mL). After 5 min, the solution was concentrated and dried under vacuum to afford the product (6.8 g, 95%) as an HCl salt: LCMS (ES) m/z 467 (M+H) + , 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.97 (s, 2H), 7.31 (s, 1H), 7.14 (m, 2H), 6.98 (m, 1H), 6.75 (s, 1H), 4.54 (m, 1H), 3.98 (s, 3H), 3.24 (m, 2H), 3.04 (m, 2H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a 500 mL flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (5 g, 19.48 mmol) [from Example 95] and NCS (3.12 g, 23.37 mmol) in tetrahydrofuran (THF) (100 ml) (50 mL). After stirring for 4 h at 70° C., the yellow reaction solution was treated with 6M NaOH (32 mL, 195 mmole) and stirred an additional 2 hours. The reaction solution was diluted with H 2 O (50 mL) and DCM (200 mL). The organic layer was separated and the aqueous layer made acidic with 6N HCl. The acidic aqueous solution was extracted with DCM (3×200 mL), dried over Na 2 SO 4 , and concentrated to give the crude product [2.6 g, 48%] as a tan solid: LCMS (ES) m/z 277 (M+H) + .

b) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 500 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6 g, 21.65 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (7.25 g, 21.65 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (5.67 ml, 32.5 mmol) and Pybrop (15.08 g, 32.5 mmol) in Dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H 2 O (2×100 mL) and the organic layer was dried Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [9.0 g, 74%] as a white solid: LCMS (ES) m/z 558 (M+H) + .

c) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 250 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (9 g, 16.15 mmol) and hydrazine (15.69 ml, 323 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated, and the crude product was purified on a silica gel column [CHCl 3 /MeOH/NH 4 OH, 90:9:1] to give the title compound as a white solid.

The free base product was treated with 4M HCl in dioxane (15 mL). After 5 min, the product solution was concentrated and dried under vacuum to afford the product (6.5 g, 91%) as an HCl salt: LCMS (ES) m/z 428 (M+H) + , 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.75 (s, 1H), 7.60 (s, 1H), 7.32 (m, 1H) 7.14 (m, 2H), 6.98 (m, 1H), 4.54 (m, 1H), 3.78 (s, 3H), 3.24 (m, 2H), 3.02 (m, 2H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 0.974 mmol) [prepared according to the procedure in Example 95] in acetonitrile (4.864 ml) and H 2 O (486 μl) was added selectfluor (449 mg, 1.27 mmol). The resulting solution was stirred at 70° C. in a sealed tube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) was added in one portion. After stirring 12 h, the solution was partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM-THF and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) affording methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274, 276 (M, M+H).

b) 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol) in 6N sodium hydroxide (0.39 ml, 2.37 mmol) and tetrahydrofuran (2 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (54 mg, 0.17 mmol, 72% yield) as a yellow oil; LCMS (ES) m/e 261, 263 (M, M+2) + .

c) 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (53 mg, 0.203 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (78 mg, 0.203 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.18 ml, 1.02 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (95 mg, 0.203 mmol) in one portion. The solution stirred at 25° C. over 12 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (106 mg, 0.129 mmol, 63.5% yield) as a clear oil; LCMS (ES) m/e 591, 593 (M, M+H) + .

d) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (106 mg, 0.179 mmol) in tetrahydrofuran (1.095 ml) and methanol (1.095 ml) at 25° C. was added hydrazine (0.056 ml, 1.79 mmol) dropwise. After 48 h, the solution was concentrated, dry loaded (silica, 5% MeOH in DCM (1% NH 4 OH)) and purified initially by column chromatography. The residue was then further purified via gilson reverse phase chromatography using 2%-95% mobile phase affording the TFA salt of the title compound. This compound was neutralized through a plug of silica (5% MeOH in DCM (1% NH 4 OH)) concentrated and transferred to the HCl salt adding excess 4M HCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (17 mg, 0.029 mmol, 16.16% yield) as a white solid: LCMS (ES) m/z=461, 463 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H) 8.11 (s, 1H) 7.71 (br. s., 3H) 7.66-7.70 (m, 2H) 7.54-7.61 (m, 2H) 7.41-7.44 (m, 1H) 4.47 (br. s., 1H) 3.79 (s, 3H) 3.07-3.16 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-bromo-5-ethyl-2-thiophenecarboxylate

To a solution of 4-bromo-5-ethyl-2-thiophenecarboxylic acid (1 g, 4.25 mmol) in methanol (21.27 ml) was added sulfuric acid (0.23 mL, 4.25 mmol). The resulting solution was stirred at 50° C. for 48 h. H 2 O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to 12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification providing methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (1.060 g, 4.25 mmol, 100% yield): LCMS (ES) m/e 248, 250 (M, M+2) + .

b) methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg, 1.204 mmol), potassium carbonate (832 mg, 6.02 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (326 mg, 1.565 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (301 mg, 1.204 mmol, 100° A yield) as a brown oil: LCMS (ES) m/e 251 (M+H) + .

c) 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.198 mmol) in 6N sodium hydroxide (2.397 ml, 1.198 mmol) and tetrahydrofuran (5.992 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol, 100% yield) as a yellow oil; LCMS (ES) m/z=236 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (461 mg, 1.2 mmol) [prepared according to Preparation 6] and diisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317 mmol) in one portion. The solution was stirred at 25° C. over 12 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol) in tetrahydrofuran (2.144 ml) and methanol (2.14 ml) at 25° C. was added hydrazine (0.269 ml, 8.58 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded and purified via column chromatography (silica, 5% MeOH in DCM (1% NH 4 OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (250 mg, 0.491 mmol, 57.2% yield)-2HCl as a white solid: LCMS (ES) m/z=437 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=8.84 Hz, 1H) 8.08 (br. s., 3H) 7.93 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.51-7.61 (m, 3H) 7.39-7.46 (m, 1H) 6.34 (d, J=2.02 Hz, 1H) 4.48 (br. s., 1H) 3.77 (s, 3H) 2.99-3.11 (m, 4H) 2.74 (q, J=7.49 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2 g, 8.51 mmol) [prepared in Preparation 10], potassium carbonate (5.88 g, 42.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.124 g, 10.21 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.217 g, 0.425 mmol) in 1,4-Dioxane (35.4 ml) and H 2 O (7.09 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate. This reaction was run in several batches (1 g, 3×2 g) which were combined for workup and purification affording the title compound (5.5 g, 78% combined yield) as a viscous yellow oil: LCMS (ES) m/e 236 (M+H) + .

b) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (580 mg, 2.45 mmol) and n-bromosuccinimide (437 mg, 2.45 mmol) in tetrahydrofuran (12.300 ml) was stirred in a sealed tube for 1 h at 70° C. The solution was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated then purified via column chromatography (silica, 20% EtOAc in hexanes) yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (600 mg, 1.90 mmol, 78° A yield) as a yellow oil: LCMS (ES) m/e 314, 316 (M, M+H) + .

c) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (420 mg, 1.33 mmol), potassium carbonate (921 mg, 6.66 mmol), PdCl 2 (dppf) (98 mg, 0.13 mmol) and trimethylboroxine (0.371 ml, 2.67 mmol) in N,N-dimethylformamide (6.663 ml) was stirred at 110° C. in a sealed tube for 2 h. This reaction was run in two batches (100 mg and 420 mg) which were combined and partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240 mg, 58%) as a yellow oil: LCMS (ES) m/e 251 (M+H) + .

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240 mg, 0.96 mmol) in 6N sodium hydroxide (3.20 ml, 19.18 mmol) and tetrahydrofuran (4.79 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (217 mg, 0.92 mmol, 96% yield) as a yellow oil: LCMS (ES) m/e 236 (M+H) + .

e) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a solution of methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.918 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (353 mg, 0.92 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.800 ml, 4.59 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (472 mg, 1.01 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide (373 mg, 0.66 mmol, 71.7% yield) as a yellow foam: LCMS (ES) m/e 567 (M+H) + .

f) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide (373 mg, 0.66 mmol) in tetrahydrofuran (1.65 ml) and methanol (1.65 ml) at 25° C. was added hydrazine (0.21 ml, 6.58 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (253 mg, 0.497 mmol, 75% yield) as a yellow solid: LCMS (ES) m/z=437 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J=8.59 Hz, 1H) 8.09 (br. s., 3H) 7.82 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.58 (t, J=8.08 Hz, 1H) 7.43 (t, J=7.33 Hz, 1H) 7.38 (s, 1H) 4.47 (br. s., 1H) 3.64 (s, 3H) 2.99-3.07 (m, 4H) 2.27 (s, 3H) 1.89 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-chlorosuccinimide (160 mg, 1.2 mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (1 ml, 5.99 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (325 mg, 1.20 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2) + .

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (284 mg, 0.74 mmol) [prepared according to Preparation 6] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414 mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603 (M, M+2) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.53 mmol) in tetrahydrofuran (1.314 ml) and methanol (1.3 ml) at 25° C. was added hydrazine (0.16 ml, 5.26 mmol) dropwise. After 12 h, the solution was concentrated, purified via column chromatography (silica, 5% MeOH in DCM (1% NH 4 OH)) and converted to the HCl salt by adding excess 2M HCl in Et 2 O (2 ml) to the residue in MeOH (5 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide (163 mg, 0.30 mmol, 57% yield) as a white solid: LCMS (ES) m/z=471, 473 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (br. s., 1H) 8.04 (bs, 3H) 7.85 (s, 1H) 7.65-7.72 (m, 2H) 7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H) 4.41-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.07 (m, 4H) 2.67 (q, J=7.58 Hz, 2H) 1.16 (t, J=7.58 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-bromosuccinimide (213 mg, 1.2 mmol) in Tetrahydrofuran (5.99 ml) was stirred in a sealed tube for 1 h at 70° C. Aqueous sodium hydroxide (4.0 ml, 23.97 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (378 mg, 1.2 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 314, 316 (M, M+2) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (181 mg, 0.57 mmol) [Prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.87 mmol) in Dichloromethane (4.23 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (295 mg, 0.632 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (240 mg, 0.37 mmol, 64.8% yield) as a white foam: LCMS (ES) m/e 645, 647 (M, M+2) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (240 mg, 0.37 mmol) in tetrahydrofuran (1.31 ml) and methanol (1.31 ml) at 25° C. was added hydrazine (0.12 ml, 3.72 mmol) dropwise. After 12 h, the solution was concentrated, purified via column chromatography (silica, 5% MeOH in DCM (1% NH 4 OH)) and converted to the HCl salt by adding excess 4M HCl in dioxane (2 ml) to the residue in MeOH (5 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide (167 mg, 0.28 mmol, 76% yield) as a white solid: LCMS (ES) m/z=515, 517 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (dd, J=15.66, 9.09 Hz, 1H) 8.02 (br. s., 3H) 7.80 (s, 1H) 7.66-7.72 (m, 2H) 7.54-7.61 (m, 2H) 7.41-7.48 (m, 1H) 4.42-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.06 (m, 4H) 2.66 (dd, J=7.45, 3.16 Hz, 2H) 1.15 (t, J=7.45 Hz, 3H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.75 g, 11.64 mmol) [Prepared in Example 99] and N-chlorosuccinimide (1.55 g, 11.64 mmol) in tetrahydrofuran (58 ml) was stirred in a sealed tube for 1 h at 70° C. Sodium hydroxide (9.70 ml, 58 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated then purified via column chromatography (silica, 20% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (2.3 g, 8.96 mmol, 77% yield) as a yellow oil: LCMS (ES) m/e 257, 259 (M, M+2) + .

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (159 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 525, 527 (M, M+2) + .

c) N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml) at 25° C. was added hydrazine (0.14 ml, 4.40 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.51 (br. s., 1H) 7.97 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H) 2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61-1.64 (m, 4H) 1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 1.06 mmol) [Prepared in Example 99] in 6N sodium hydroxide (1.76 ml, 10.6 mmol) and tetrahydrofuran (5.290 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (151 mg, 0.68 mmol, 64% yield) as a white solid; LCMS (ES) m/z=223 (M+H) + .

b) N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.62 mmol), N,N-diisopropylethylamine (0.541 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol)[Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (285 mg, 0.581 mmol, 94% yield) as a white foam: LCMS (ES) m/e 491, 493 (M, M+2) + .

c) N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (285 mg, 0.581 mmol) in tetrahydrofuran (2.905 ml) and methanol (2.91 ml) at 25° C. was added hydrazine (0.18 ml, 5.81 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was then transferred to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (173 mg, 0.40 mmol, 69% yield) as a yellow solid: LCMS (ES) m/z=360 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.55 (d, J=8.59 Hz, 1H) 8.01 (br. s., 3) 7.94 (s, 1H) 7.52 (d, J=2.02 Hz, 1H) 6.35 (d, J=1.77 Hz, 1H) 4.24-4.27 (m, 1H) 3.77 (s, 3H) 2.91-2.94 (m, 2H) 2.39 (s, 3H) 1.72-1.77 (m, 1H) 1.60-1.64 (m, 4H) 1.49-1.52 (m, 1H) 1.21-1.29 (m, 2H) 1.15-1.25 (m, 2H) 0.89-0.94 (m, 2H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513 (M, M+2) + .

b) N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol) in tetrahydrofuran (1.644 ml) and methanol (1.644 ml) at 25° C. was added hydrazine (0.10 ml, 3.29 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (silica, 5% MeOH in DCM (1% NH 4 OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 mL) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (79 mg, 0.17 mmol, 53% yield) as a yellow solid: LCMS (ES) m/z=380, 382 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 8.82 (d, J=8.59 Hz, 1H) 8.10 (s, 1H) 7.99 (br. s., 3H) 7.55 (d, J=1.77 Hz, 1H) 6.48 (d, J=2.02 Hz, 1H) 4.22-4.28 (m, 1H) 3.81 (s, 3H) 2.90-2.95 (m, 2H) 1.74-1.78 (m, 1H) 1.62-1.65 (m, 4H) 1.48-1.51 (m, 1H) 1.37-1.39 (m, 2H) 1.09-1.13 (m, 2H) 0.92-0.96 (m, 2H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 1.058 mmol) [prepared in Example 99] and N-bromosuccinimide (188 mg, 1.06 mmol) in tetrahydrofuran (5.29 ml) was stirred in a sealed tube for 1 h at 70° C. Sodium hydroxide (3.53 ml, 21.16 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (289 mg, 0.96 mmol, 91% yield) as a yellow oil: LCMS (ES) m/e 301, 303 (M, M+2) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol)) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (226 mg, 0.40 mmol, 64% yield) as a white foam: LCMS (ES) m/e 569, 571 (M, M+2) + .

c) N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (226 mg, 0.40 mmol) in tetrahydrofuran (1.98 ml) and methanol (1.98 ml) at 25° C. was added hydrazine (0.13 ml, 3.97 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography. The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (153 mg, 0.30 mmol, 75% yield) as a yellow solid: LCMS (ES) m/z=439, 441 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.51 (br. s., 1H) 7.96 (br. s., 3H) 7.83 (br. s., 1H) 7.70 (s, 1H) 4.21-4.25 (m, 1H) 3.94 (s, 3H) 2.89-2.92 (m, 2H) 2.35 (s, 3H) 1.76-1.79 (m, 1H) 1.60-1.64 (m, 4H) 1.48-1.54 (m, 1H) 1.26-1.32 (m, 2H) 1.09-1.16 (m, 2H) 0.92-0.95 (m, 1H) 0.82-0.86 (m, 1H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (216 mg, 0.78 mmol) [prepared according to Example 96], N,N-diisopropylethylamine (0.68 ml, 3.90 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (252 mg, 0.78 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (401 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 545, 547 (M, M+2) + .

b) N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol) in tetrahydrofuran (2.78 ml) and methanol (2.78 ml) at 25° C. was added hydrazine (0.17 ml, 5.55 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (190 mg, 0.389 mmol, 70.0% yield) as a yellow solid: LCMS (ES) m/z=415, 417 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.84 (br. s., 1H) 8.06 (s, 4H) 7.74 (s, 1H) 4.25 (dd, J=8.84, 4.29 Hz, 1H) 3.77 (s, 3H) 2.87-2.93 (m, 2H) 1.71-1.79 (m, 1H) 1.64 (d, J=9.85 Hz, 3H) 1.54 (br. s., 1H) 1.48 (br. s., 1H) 1.37 (dd, J=13.26, 4.93 Hz, 1H) 1.14 (br. s., 1H) 1.17 (d, J=7.33 Hz, 2H) 0.93 (d, J=10.86 Hz, 1H) 0.82-0.89 (m, 1H).

Preparation of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-Pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid

A solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (50 mg, 0.21 mmol) [prepared in Example 95] and NBS (36.7 mg, 0.21 mmol) in tetrahydrofuran (2.06 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (82 mg, 0.16 mmol, 79% yield) as a yellow oil: LCMS (ES) m/e 257, 259 (M, M+2) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (81 mg, 0.252 mmol), n,n-diisopropylethylamine (0.22 ml, 1.26 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (81 mg, 0.25 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (141 mg, 0.302 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (47 mg, 0.080 mmol, 31.6% yield) as a clear oil: LCMS (ES) m/e 589, 591 (M, M+2) + .

c) N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (48 mg, 0.08 mmol) in tetrahydrofuran (0.41 ml) and methanol (0.41 ml) at 25° C. was added hydrazine (0.03 ml, 0.81 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide (11 mg, 0.02 mmol, 24% yield) as a yellow solid: LCMS (ES) m/z=459, 461 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.73 (br. s., 1H) 7.96 (br. s., 4H) 7.74 (s, 1H) 4.21-4.26 (m, 1H) 3.77 (s, 3H) 2.92-2.99 (m, 2H) 1.73-1.79 (m, 1H) 1.62-1.67 (m, 4H) 1.49-1.51 (m, 1H) 1.25 (br. s., 2H) 1.06-1.13 (m, 2H) 0.95 (d, J=6.82 Hz, 1H) 0.82-0.89 (m, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4,5-dibromo-2-furancarboxylate

To a solution of 4,5-dibromo-2-furancarboxylic acid (5.7 g, 21.1 mmol) in methanol (106 ml) was added sulfuric acid (11.3 ml, 211 mmol). The resulting solution stirred at 50° C. over 4 days. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (5.5 g, 19.4 mmol, 92% yield): LCMS (ES) m/e 283 (M+H) + .

b) methyl 4-bromo-2-furancarboxylate

To a solution of methyl 4,5-dibromo-2-furancarboxylate (1 g, 3.52 mmol) in tetrahydrofuran (14.1 ml) at −40° C. was added isopropylmagnesium chloride (1.85 ml, 3.70 mmol). After 2 h, H 2 O (3.52 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (470 mg, 2.04 mmol, 58% yield) as a white solid: LCMS (ES) m/e 204, 206 (M, M+2) + .

c) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1.58 g, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (525 mg, 2.52 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (58.6 mg, 0.115 mmol) in 1,4-Dioxane (9.5 ml) and water (1.9 ml) was stirred at 80° C. in a sealed tube for 1 h. The solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (30% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (124 mg, 0.60 mmol, 26% yield) as a white powder: LCMS (ES) m/e 206 (M+H) + .

d) 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (124 mg, 0.60 mmol) in 6N sodium hydroxide (2.0 ml, 12.0 mmol) and tetrahydrofuran (3.0 ml) was stirred at 70° C. in a sealed tube for 2 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol, 47% yield) as a white solid: LCMS (ES) m/e 192 (M+H) + .

e) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (108 mg, 0.28 mmol) [prepared in Preparation 6] and N,N-diisopropylethylamine (0.24 ml, 1.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (158 mg, 0.34 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (100 mg, 0.14 mmol, 50% yield) as a white solid: LCMS (ES) m/e 523 (M+H) + .

f) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (100 mg, 0.19 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) at 25° C. was added hydrazine (0.06 ml, 1.91 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (56 mg, 0.12 mmol, 62% yield) as a yellow solid: LCMS (ES) m/z=393 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.70 (d, J=9.09 Hz, 1H) 8.28 (s, 1H) 8.07 (br. s., 3H) 7.69 (d, J=8.08 Hz, 1H) 7.56 (d, J=8.08 Hz, 2H) 7.50 (s, 1H) 7.45 (d, J=1.77 Hz, 2H) 6.51 (d, J=1.77 Hz, 1H) 4.50-4.57 (m, 1H) 3.93 (s, 3H) 3.02-3.16 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (200 mg, 0.64 mmol) [prepared in Example 99], potassium carbonate (438 mg, 3.17 mmol), bis(tri-t-butylphosphine)palladium(0) (324 mg, 0.64 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (77 mg, 0.32 mmol) in 1,4-dioxane (5.3 ml) and H 2 O (1 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (135 mg, 0.515 mmol, 81% yield) as a yellow oil: LCMS (ES) m/z=250 (M+H) + .

b) methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

To a solution of methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (135 mg, 0.52 mmol) in methanol (2.6 ml) was added Pd—C (21.9 mg, 0.21 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (145 mg, 0.51 mmol, 99% yield) as a yellow oil which was used without further purification: LCMS (ES) m/e 265 (M+H) + .

c) 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

A solution of methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (145 mg, 0.55 mmol) in 6N sodium hydroxide (1.8 ml, 10.97 mmol) and tetrahydrofuran (4.8 ml) was stirred at 60° C. in a sealed tube for 12 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 250 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (211 mg, 0.55 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.48 ml, 2.74 mmol) in Dichloromethane (5.47 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (281 mg, 0.60 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 40-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (262 mg, 0.45 mmol, 82% yield) as a clear oil: LCMS (ES) m/e 581 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (262 mg, 0.45 mmol) in tetrahydrofuran (2.256 ml) and methanol (2.256 ml) at 25° C. was added hydrazine (0.14 ml, 4.51 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (170 mg, 0.32 mmol, 72° A yield) as a yellow solid: LCMS (ES) m/z=451 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.72 (br. s., 1H) 8.05 (br. s., 2H) 7.76 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.49-7.52 (m, 2H) 7.40-7.45 (m, 2H) 4.42-4.47 (m, 1H) 3.61 (br. s., 3H) 3.01-3.07 (m, 4H) 2.52-2.59 (m, 2H) 2.26 (s, 3H) 1.02-1.09 (m, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (980 mg, 3.92 mmol) [prepared in Example 98] and N-bromosuccinimide (697 mg, 3.92 mmol) in tetrahydrofuran (19.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated then purified via column chromatography (silica, 10-40% EtOAC in hexanes) yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.1 g, 3.34 mmol, 85% yield) as a yellow oil: LCMS (ES) m/e 329, 331 (M, M+2) + .

b) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300 mg, 0.911 mmol), potassium carbonate (630 mg, 4.56 mmol), PdCl 2 (dppf) (66.7 mg, 0.091 mmol) and trimethylboroxin (0.25 ml, 1.82 mmol) in N,N-dimethylformamide (9.1 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (143 mg, 0.51 mmol, 56° A yield) as a yellow oil: LCMS (ES) m/z=265 (M+H) + .

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid

A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (143 mg, 0.54 mmol) in 6N sodium hydroxide (0.90 ml, 5.41 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (136 mg, 0.54 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 251 (M+H) + .

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.48 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.15 ml, 4.79 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (3-15% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 2M HCl in Et 2 O (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide (196 mg, 0.36 mmol, 76% yield) as a yellow solid: LCMS (ES) m/z=451 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.86-8.93 (m, 1H) 8.15 (br. s., 3H) 7.83 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.55 (br. s., 1H) 7.52 (t, J=7.45 Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 7.38 (s, 1H) 4.22-4.27 (m, 1H) 3.62 (s, 3H) 2.97-3.09 (m, 4H) 2.60 (q, J=7.49 Hz, 2H) 1.88 (s, 3H) 1.13 (t, J=7.58 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

a) methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (300 mg, 0.95 mmol), potassium carbonate (658 mg, 4.76 mmol), bis(tri-t-butylphosphine)palladium(0) (24.32 mg, 0.05 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.18 ml, 0.95 mmol) in 1,4-dioxane (5.3 ml) and H 2 O (1.0 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (171 mg, 0.58 mmol, 61% yield) as a yellow oil: LCMS (ES) m/z=276 (M+H) + .

b) methyl 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate

To a solution of methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (171 mg, 0.62 mmol) in methanol (3 ml) was added PdOH 2 (34.8 mg, 0.25 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (173 mg, 0.62 mmol, 100% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H) + .

c) 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid

A solution of methyl 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (173 mg, 0.62 mmol) in 6N sodium hydroxide (1 ml, 6.21 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (148 mg, 0.49 mmol, 79% yield) as a white foam: LCMS (ES) m/e 265 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

To a solution of 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (137 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared in Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.572 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (211 mg, 0.334 mmol, 64.2% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (211 mg, 0.36 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.11 ml, 3.55 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (108 mg, 0.20 mmol, 57% yield) as a yellow solid: LCMS (ES) m/z=465 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.71 (d, J=8.59 Hz, 1H) 8.07 (br. s., 3H) 7.74 (s, 1H) 7.65-7.68 (m, 1H) 7.55-7.60 (m, 1H) 7.46-7.49 (m, 1H) 7.39-7.46 (m, 2H) 4.47 (br. s., 1H) 3.57 (s, 3H) 2.99-3.05 (m, 4H) 2.49-2.52 (m, 1H) 2.25 (s, 3H) 1.07-1.14 (m, 6H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

a) methyl 4-bromo-5-propyl-2-thiophenecarboxylate

To a solution of 4-bromo-5-propyl-2-thiophenecarboxylic acid (5.0 g, 20.07 mmol) in methanol (100 ml) was added sulfuric acid (5.35 ml, 100 mmol). The resulting solution stirred at 50° C. for 36 h. H 2 O (50 mL) was added the aqueous phase was washed several times with DCM. The combined organic fractions were washed with saturated NaHCO 3 , dried over Na 2 SO 4 , concentrated and used directly without further purification providing methyl 4-bromo-5-propyl-2-thiophenecarboxylate (5.1 g, 18.61 mmol, 93° A yield) as a yellow oil: LCMS (ES) m/e 262, 264 (M, M+2) + .

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate

A solution of methyl 4-bromo-5-propyl-2-thiophenecarboxylate (1.0 g, 3.80 mmol), potassium carbonate (2.63 g, 19.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.949 g, 4.56 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.097 g, 0.19 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated and purified by column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (1.07 g, 3.76 mmol, 99% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H) + .

c) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (356 mg, 1.35 mmol) and N-chlorosuccinimide (180 mg, 1.35 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (2.2 ml, 13.47 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (357 mg, 1.25 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2) + .

d) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (148 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.39 mmol, 75% yield) as a yellow oil: LCMS (ES) m/e 615, 617 (M, M+2) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.40 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.12 ml, 3.98 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide (178 mg, 0.32 mmol, 80% yield) as a yellow solid: LCMS (ES) m/z=485, 487 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.96 (br. s., 1H) 8.13 (br. s., 3H) 7.93 (s, 1H) 7.66-7.73 (m, 2H) 7.62 (br. s., 1H) 7.55 (t, J=7.45 Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s, 3H) 2.99-3.08 (m, 4H) 2.63 (t, J=7.20 Hz, 2H) 1.53-1.57 (m, 2H) 0.83 (t, J=7.33 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol) [prepared in Example 112] and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (2.251 ml, 13.51 mmol). The reaction mixture stirred at 70° C. in a sealed tube for 12 h and was partitioned between H 2 O-DCM. The pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (445 mg, 1.35 mmol, 50% yield): LCMS (ES) m/e 329, 331 (M, M+2) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (171 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661 (M, M+2) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.38 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.12 ml, 3.81 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide (178 mg, 0.30 mmol, 78% yield) as a yellow solid: LCMS (ES) m/z=529, 531 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.94 (d, J=8.84 Hz, 1H) 8.10 (br. s., 3H) 7.87 (d, J=1.77 Hz, 1H) 7.65-7.72 (m, 2H) 7.58 (dd, J=14.78, 7.71 Hz, 2H) 7.43 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s, 3H) 2.99-3.08 (m, 4H) 2.58-2.66 (m, 2H) 1.53 (ddd, J=13.89, 6.82, 6.57 Hz, 2H) 0.83 (dd, J=7.33, 2.02 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol) and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half was partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (464 mg, 1.35 mmol, 50% yield) as an orange oil: LCMS (ES) m/e 343, 345 (M, M+2) + .

b) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (242 mg, 0.71 mmol). PdCl 2 (dppf) (52 mg, 0.07 mmol), potassium carbonate (487 mg, 3.53 mmol) and trimethylboroxine (0.20 ml, 1.41 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (184 mg, 0.60 mmol, 84° A yield) as a yellow oil: LCMS (ES) m/z=279 (M+H) + .

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxylic acid

A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (0.184 g, 0.66 mmol) in 6N sodium hydroxide (2.2 ml, 13.22 mmol) and tetrahydrofuran (6.6 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.66 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H) + .

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[2-(trifluoromethyl)benzyl]ethyl}-5-propylthiophene-2-carboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (262 mg, 0.68 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.59 ml, 3.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75 mmol) in one portion. The solution stirred at 25° C. for 2 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H) + .

e) N-{(1S)-2-amino-1-[2-(trifluoromethyl)benzyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propylthiophene-2-carboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) at 25° C. was added hydrazine (0.13 ml, 4.09 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide (172 mg, 0.30 mmol, 74% yield) as a yellow solid: LCMS (ES) m/z=465 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.80 (br. s., 1H) 8.08 (br. s., 3H) 7.78 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.50-7.55 (m, 2H) 7.43 (t, J=7.71 Hz, 1H) 7.37 (s, 1H) 4.49 (d, J=10.36 Hz, 1H) 3.61 (s, 3H) 2.99-3.06 (m, 4H) 2.54-2.59 (m, 2H) 1.87 (s, 3H) 1.48-1.55 (m, 2H) 0.81 (t, J=7.33 Hz, 3H).

Preparation of N-{(1S)-2-amino-1-[2-(trifluoromethyl)benzyl]ethyl}-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)thiophene-2-carboxamide

a) methyl 5-methyl-4-{1-methyl-4-[(1E)-prop-1-en-1-yl]-1H-pyrazol-5-yl}thiophene-2-carboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (320 mg, 1.015 mmol) [prepared in Example 99], potassium carbonate (702 mg, 5.08 mmol), bis(tri-t-butylphosphine)palladium(0) (25.9 mg, 0.05 mmol) and (1Z)-1-propen-1-ylboronic acid (87 mg, 1.01 mmol) in 1,4-dioxane (5.3 ml) and water (1.3 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol, 87% yield) as a yellow oil: LCMS (ES) m/z=277 (M+H) + .

b) methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol) in methanol (6.8 ml) was added Pd(OH) 2 (49 mg, 0.35 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.69 mmol, 78% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H) + .

c) 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.78 mmol) in 6N sodium hydroxide (2.60 ml, 15.59 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (242 mg, 0.78 mmol, 100° A yield) as a white foam: LCMS (ES) m/e 265 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.78 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (300 mg, 0.78 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.48 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.15 ml, 4.76 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (186 mg, 0.35 mmol, 73% yield) as a yellow solid: LCMS (ES) m/z=465 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.81 (br. s., 1H) 8.13 (br. s., 3H) 7.79 (s, 1H) 7.68 (d, J=7.58 Hz, 1H) 7.59 (d, J=7.07 Hz, 1H) 7.42-7.51 (m, 1H) 7.38-7.45 (m, 2H) 4.47 (br. s., 1H) 3.61 (d, J=2.78 Hz, 3H) 2.99-3.08 (m, 4H) 2.25 (s, 3H) 2.11-2.21 (m, 2H) 1.41-1.48 (m, 2H) 0.83 (br. s., 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4-bromo-5-methyl-2-furancarboxylate

To a solution of methyl 5-methyl-2-furancarboxylate (1.5 g, 10.70 mmol) and aluminum trichloride (2.14 g, 16.06 mmol) in chloroform (21 ml) at 0° C. was added bromine (0.77 ml, 14.99 mmol). The resulting solution stirred at 0° C. and warmed to RT over 12 h. This reaction was run in batches (1.5 g and 1 g) and the batches were combined, added to ice and partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (0.5-10% EtOAc in hexanes) affording the title compound (2.1 g, 54%) as a white solid; LCMS (ES) m/z=219, 221 (M, M+2) + .

b) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H) + .

c) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (200 mg, 0.91 mmol) in 6N sodium hydroxide (2.3 ml, 13.62 mmol) and tetrahydrofuran (4.5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (130 mg, 0.57 mmol, 63% yield) as a yellow oil: LCMS (ES) m/e 207 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (130 mg, 0.63 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (243 mg, 0.63 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.55 ml, 3.15 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (324 mg, 0.69 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (190 mg, 0.23 mmol, 37% yield) as a clear oil: LCMS (ES) m/e 537 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (190 mg, 0.35 mmol) in tetrahydrofuran (1.5 ml) and methanol (1.5 ml) at 25° C. was added hydrazine (0.11 ml, 3.54 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (71 mg, 0.15 mmol, 42% yield) as a yellow solid: LCMS (ES) m/z 407 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.60 (d, J=9.60 Hz, 1H) 8.04 (br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.53-7.59 (m, 2H) 7.49 (d, J=1.77 Hz, 1H) 7.38-7.45 (m, 2H) 6.33 (br. s., 1H) 4.52 (br. s., 1H) 3.80 (s, 3H) 2.98-3.09 (m, 4H) 2.38 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and n-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (4.54 ml, 27.2 mmol) which stirred at 70° C. in a sealed tube for 4 h. The solution was partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (369 mg, 1.29 mmol, 48% yield) as an orange oil: LCMS (ES) m/e 285, 287 (M, M+2) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (270 mg, 0.70 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.61 ml, 3.51 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.77 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (232 mg, 0.32 mmol, 46% yield) as a clear oil: LCMS (ES) m/e 615, 617 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (232 mg, 0.38 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) at 25° C. was added hydrazine (0.12 ml, 3.77 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide (106 mg, 0.19 mmol, 50% yield) as a yellow solid: LCMS (ES) m/z=485, 487 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.60 (d, J=9.60 Hz, 1H) 7.99 (br. s., 3H) 7.68 (s, 2H) 7.71 (d, J=8.08 Hz, 1H) 7.59 (d, J=7.33 Hz, 1H) 7.44-7.56 (m, 1H) 7.25-7.33 (m, 1H) 4.50-4.57 (m, 1H) 3.74 (s, 3H) 2.99-3.07 (m, 4H) 2.32 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.36 mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (3.4 ml, 20.4 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (275 mg, 1.14 mmol, 84% yield) as a orange oil: LCMS (ES) m/e 241, 243 (M, M+2) + .

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.83 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (320 mg, 0.83 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.72 ml, 4.16 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (427 mg, 0.91 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.40 mmol, 49% yield) as a clear oil: LCMS (ES) m/e 571, 573 (M, M+2) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.43 mmol) in tetrahydrofuran (2.1 ml) and methanol (2.1 ml) at 25° C. was added hydrazine (135 μl, 4.31 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide (125 mg, 0.24 mmol, 56% yield) as a yellow solid: LCMS (ES) m/z=441, 443 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.63 (d, J=9.09 Hz, 1H) 8.04 (br. s., 3H) 7.65-7.72 (m, 2H) 7.59 (d, J=7.33 Hz, 1H) 7.57 (br. s., 1H) 7.39-7.47 (m, 1H) 7.29-7.37 (m, 1H) 4.54 (br. s., 1H) 3.73 (s, 3H) 2.98-3.09 (m, 4H) 2.33 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol) [prepared in Example 116] and N-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (5-15% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.41 mmol, 15% yield) as an orange oil: LCMS (ES) m/e 299, 301 (M, M+2) + .

b) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.43 mmol) potassium carbonate (300 mg, 2.17 mmol), PdCl 2 (dppf) (15.9 mg, 0.02 mmol) and trimethylboroxine (0.12 ml, 0.87 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol, 59° A yield) as a yellow oil: LCMS (ES) m/z=235 (M+H) + .

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid

A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol) in 6N sodium hydroxide (0.8 ml, 5.1 mmol) and tetrahydrofuran (2.5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol, 94% yield) as a white foam: LCMS (ES) m/e 221(M+H) + .

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (93 mg, 0.24 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.21 ml, 1.20 mmol) in dichloromethane (2.4 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (124 mg, 0.26 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (113 mg, 0.21 mmol, 85% yield) as a white foam: LCMS (ES) m/e 551 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide

To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (113 mg, 0.21 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) at 25° C. was added hydrazine (64 μl, 2.05 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide (32 mg, 0.06 mmol, 32% yield) as a yellow solid: LCMS (ES) m/z=421 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.60 (d, J=9.09 Hz, 1H) 8.05 (br. s., 3H) 7.70 (d, J=7.58 Hz, 1H) 7.54-7.61 (m, 2H) 7.40-7.47 (m, 1H) 7.35 (s, 1H) 7.27 (s, 1H) 4.54 (br. s., 1H) 3.65 (s, 3H) 2.98-3.07 (m, 4H) 2.26 (s, 3H) 1.90 (s, 3H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 100, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (155 mg, 0.46 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=421, 423 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.76 (br. s., 1H) 8.06 (br. s., 3H) 7.85 (s, 1H) 7.69 (s, 1H) 7.28-7.36 (m, 1H) 7.12 (d, J=7.07 Hz, 2H) 7.03 (dd, J=17.05, 2.15 Hz, 1H) 4.36 (br. s., 1H) 3.69 (s, 3H) 2.93-3.02 (m, 4H) 2.67 (q, J=7.33 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).

N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 110, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (241 mg, 0.72 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=401 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.76 (br. S., 1H) 8.11 (br. S., 3H) 7.79 (s, 1H) 7.37 (s, 1H) 7.28-7.36 (m, 1H) 7.12 (d, J=6.82 Hz, 2H) 7.03 (td, J=8.65, 1.64 Hz, 1H) 4.41-4.43 (m, 1H, obscured) 3.60 (br. S., 3H) 2.99-3.02 (m, 4H) 2.60 (q, J=7.33 Hz, 2H) 1.86 (s, 3H) 1.13 (t, J=7.45 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 110, except substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (277 mg, 0.72 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=451 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.70 (br. s., 1H) 8.06 (br. s., 3H) 7.68-7.75 (m, 1H) 7.52 (s, 1H) 7.50-7.56 (m, 3H) 7.37 (s, 1H) 4.36 (d, J=8.84 Hz, 1H) 3.58 (br. s., 3H) 2.98-3.02 (m, 4H) 2.55-2.61 (m, 2H) 1.86 (s, 3H) 1.12 (t, J=7.58 Hz, 3H).

Preparation of N-((1S)-2-amino-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1 g, 3.99 mmol) [prepared in Example 98] and N-bromosuccinimide (0.711 g, 3.99 mmol) in tetrahydrofuran (8 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (10-50% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.2 g, 3.54 mmol, 89% yield) as an orange oil: LCMS (ES) m/e 329, 331 (M, M+2) + .

b) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300 mg, 0.911 mmol), potassium carbonate (630 mg, 4.56 mmol), bis(tri-t-butylphosphine)palladium(0) (23.29 mg, 0.05 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (110 mg, 0.45 mmol) in 1,4-dioxane (5 ml) and Water (1 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (187 mg, 0.66 mmol, 73% yield) as a clear oil: LCMS (ES) m/z=277 (M+H) + .

c) methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (187 mg, 0.68 mmol) in methanol (2.5 ml) was added Pd—C (7.20 mg, 0.07 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (187 mg, 0.64 mmol, 95% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H) + .

d) 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (181 mg, 0.65 mmol) in 6N sodium hydroxide (2.16 ml, 13.0 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (175 mg, 0.65 mmol, 100% yield) as a white foam: LCMS (ES) m/e 265 (M+H) + .

e) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (175 mg, 0.66 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (255 mg, 0.66 mmol) [prepared according to Procedure 6] and N,N-diisopropylethylamine (0.58 ml, 3.31 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (340 mg, 0.73 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (232 mg, 0.38 mmol, 57% yield) as a clear oil: LCMS (ES) m/e 595 (M+H) + .

f) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (232 mg, 0.39 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) at 25° C. was added hydrazine (122 μl, 3.90 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (176 mg, 0.38 mmol, 97% yield) as a yellow solid: LCMS (ES) m/z=529, 531 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.64 (br. s., 1H) 7.97 (br. s., 3H) 7.65-7.73 (m, 3H) 7.57 (d, J=5.05 Hz, 2H) 7.59 (br. s., 1H) 7.44 (br. s., 1H) 4.48 (br. s., 1H) 3.69 (s, 3H) 2.98-3.12 (m, 4H) 1.24 (dd, J=6.82, 2.27 Hz, 3H) 1.16 (dd, J=6.82, 2.53 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 123, except substituting (1Z)-1-propen-1-ylboronic acid (78 mg, 0.91 mmol) for 2,4,6-trivinylcycloboroxane-pyridine complex: LCMS (ES) m/z=479 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.63 (s, 1H) 8.01 (br. s., 3H) 7.67 (s, 2H) 7.56 (d, J=5.05 Hz, 2H) 7.38-7.46 (m, 2H) 4.42-4.47 (m, 1H) 3.59 (s, 3H) 2.98-3.02 (m, 4H) 2.66-2.71 (m, 2H) 1.40-1.47 (m, 2H) 1.13 (t, J=7.52 Hz, 3H) 0.83 (t, J=7.26 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-bromo-2-thiophenecarboxylate

To a solution of 4-bromo-2-thiophenecarboxylic acid (25 g, 121 mmol) in methanol (241 ml) was added sulfuric acid (32 ml, 604 mmol). The resulting solution stirred at 50° C. over 4d. The solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification providing methyl 4-bromo-2-thiophenecarboxylate (26 g, 118 mmol, 97% yield), LCMS (ES) m/e 222 (M+H) + .

b) methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol), potassium carbonate (7.81 g, 56.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) in 1,4-dioxane (47 ml) and water (9 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) were added and the reaction stirred an additional 1 h. The mixture was partitioned between H 2 O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol, 99% yield) as a yellow solid: LCMS (ES) m/e 223 (M+H) + .

c) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol) and n-bromosuccinimide (2.002 g, 11.25 mmol) in tetrahydrofuran (56.2 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (10-50% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.7 g, 8.97 mmol, 80% yield) as a yellow solid: LCMS (ES) m/e 301, 303 (M, M+2) + .

d) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (300 mg, 0.91 mmol), potassium carbonate (630 mg, 4.56 mmol), bis(tri-t-butylphosphine)palladium(0) (23 mg, 0.05 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (110 mg, 0.46 mmol) in 1,4-dioxane (5 ml) and water (1 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (187 mg, 0.66 mmol, 73% yield) as a clear oil: LCMS (ES) m/z=277 (M+H) + .

e) methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a solution of methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (187 mg, 0.68 mmol) in methanol (2.5 ml) was added Pd—C (7.20 mg, 0.07 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (187 mg, 0.64 mmol, 95% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H) + .

f) methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

A solution of methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (202 mg, 0.81 mmol) and NCS (108 mg, 0.81 mmol) in N,N-dimethylformamide (4 ml) was stirred in a sealed tube for 1 h at 100° C. Additional NCS (108 mg, 0.81 mmol) was added and the solution stirred 1 h. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (2-30% EtOAc in hexanes) affording methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.45 mmol, 56% yield) as a yellow oil: LCMS (ES) m/e 285 (M+H) + .

g) 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

A solution of methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.47 mmol) in 6N sodium hydroxide (1.6 ml, 9.48 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 12 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.41 mmol, 87% yield) as a white foam: LCMS (ES) m/e 270, 272 (M, M+2) + .

h) 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol) [prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.30 mmol, 68° A yield) as a white solid: LCMS (ES) m/e 601, 603 (M, M+2) + .

i) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.32 mmol) in tetrahydrofuran (1.58 ml) and methanol (1.58 ml) at 25° C. was added hydrazine (0.08 ml, 2.53 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (145 mg, 0.26 mmol, 83% yield) as a yellow solid: LCMS (ES) m/z=471, 473 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.80 (br. s., 1H) 7.87-7.99 (m, 6H) 7.69 (d, J=7.71 Hz, 1H)) 7.57 (d, J=7.83 Hz, 1H) 7.40-7.44 (m, 1H) 4.43-4.48 (m, 1H) 3.74 (s, 3H) 2.99-3.06 (m, 4H) 2.40 (d, J=7.58 Hz, 2H) 1.04 (t, J=7.58 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

The title compound was prepared as a yellow solid according to Example 125, except substituting (1Z)-1-propen-1-ylboronic acid (125 mg, 1.46 mmol) for 2,4,6-trivinylcycloboroxane-pyridine complex: LCMS (ES) m/z=485, 487 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.94 (d, J=9.09 Hz, 1H) 8.05 (s, 4H) 7.98 (s, 1H) 7.69 (d, J=7.58 Hz, 1H) 7.55-7.63 (m, 1H) 7.52 (t, J=7.58 Hz, 1H) 7.42 (t, J=7.33 Hz, 1H) 4.49 (d, J=4.29 Hz, 1H) 3.74 (s, 3H) 2.98-3.09 (m, 4H) 2.37 (q, J=7.07 Hz, 2H) 1.37-1.45 (m, 2H) 0.80 (t, J=7.33 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) methyl 4,5-dibromo-2-furancarboxylate

To a solution of 4,5-dibromo-2-furancarboxylic acid (25 g, 93 mmol) in methanol (185 ml) was added sulfuric acid (24.7 ml, 463 mmol). The resulting solution stirred at 50° C. over 12 h. The solution was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (23.67 g, 83 mmol, 90% yield), LCMS (ES) m/e 283, 285, 287 (M, M+2, M+4) + .

b) methyl 4-bromo-2-furancarboxylate

To a solution of methyl 4,5-dibromo-2-furancarboxylate (3.3 g, 11.62 mmol) in tetrahydrofuran (46 ml) at −40° C. was added isopropylmagnesium chloride (6.97 ml, 13.95 mmol). After 1 h, Water (11 ml) was added and the solution warmed to 25° C. The reaction mixture was then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified by column chromatography (3% EtOAc in hexanes) affording methyl 4-bromo-2-furancarboxylate (1.4 g, 6.49 mmol, 56% yield) as a yellow solid: LCMS (ES) m/e 205, 207 (M, M+2) + .

c) methyl 4-bromo-5-chloro-2-furancarboxylate

A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) and NCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirred in a sealed tube for 1 h at 100° C. After 1 h, the solution was partitioned between DCM-H 2 O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (2-10% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2-furancarboxylate (1.348 g, 5.12 mmol, 75% yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M, M+2, M+4) + .

d) methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.05 g, 5.05 mmol) [prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53 mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2) + .

e) 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.25 mmol) in 6N sodium hydroxide (4.16 ml, 24.93 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H 2 O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 and concentrated affording 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (267 mg, 0.59 mmol, 47% yield) as a white foam: LCMS (ES) m/e 265 (M+H) + .

f) 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (134 mg, 0.59 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (228 mg, 0.59 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.52 ml, 2.96 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (304 mg, 0.65 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.33 mmol, 55.8% yield) as a yellow oil: LCMS (ES) m/e 557, 559 (M, M+2) + .

g) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.36 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.08 ml, 2.54 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in diethyl ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (120 mg, 0.24 mmol, 66% yield) as a yellow solid: LCMS (ES) m/z=427, 429 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.87 (d, J=9.09 Hz, 1H) 8.11 (br. s., 3H) 7.66-7.73 (m, 2H) 7.57 (t, J=7.45 Hz, 2H) 7.53 (d, J=1.52 Hz, 1H) 7.44 (d, J=6.82 Hz, 1H) 6.50 (d, J=1.52 Hz, 1H) 4.43-4.51 (m, 1H) 3.86 (s, 3H) 2.99-3.17 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid

A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.25 mmol) [prepared according to Example 127] and n-chlorosuccinimide (166 mg, 1.25 mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (4.1 ml, 24.94 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (232 mg, 0.44 mmol, 36% yield) as a yellow oil: LCMS (ES) m/e 261, 263 (M, M+2) + .

b) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (116 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol) [prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.19 mmol, 42% yield) as a yellow oil: LCMS (ES) m/e 591, 593 (M, M+2) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.20 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) at 25° C. was added hydrazine (0.04 ml, 1.37 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (68 mg, 0.13 mmol, 65% yield) as a yellow solid: LCMS (ES) m/z=461, 463 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.80 (d, J=9.09 Hz, 1H) 8.03 (br. s., 3H) 7.66-7.73 (m, 2H) 7.58-7.61 (m, 1H) 7.52-7.59 (m, 2H) 7.40-7.48 (m, 1H) 4.5-4.57 (m, 1H) 3.77 (s, 3H) 2.98-3.09 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example 125, except substituting methyl 4-bromo-2-furancarboxylate (5 g, 24.39 mmol) for methyl 4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z=455, 457 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.75 (d, J=9.09 Hz, 1H) 8.23 (s, 1H) 8.05 (br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.53-7.60 (m, 2H) 7.42=0-7.43 (m, 2H) 4.50-4.55 (m, 1H) 3.74 (s, 3H) 2.99-3.08 (m, 4H) 2.39 (q, J=7.33 Hz, 2H) 1.03 (t, J=7.45 Hz, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example 125, except substituting trimethylboroxine (0.78 ml, 5.61 mmol) for 2,4,6-trivinylcycloboroxane-pyridine complex and methyl 4-bromo-2-furancarboxylate (5 g, 24.39 mmol) for methyl 4-bromo-2-thiophenecarboxylate: LCMS (ES) m/z=441, 443 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.71 (d, J=9.35 Hz, 1H) 8.27 (s, 1H) 8.01 (br. s., 3H) 7.70 (d, J=7.58 Hz, 1H) 7.55 (t, J=6.06 Hz, 2H) 7.40-7.47 (m, 2H) 4.50-4.57 (m, 1H) 3.78 (s, 3H) 2.99-3.08 (m, 4H) 1.98 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

a) methyl 5-ethenyl-2-furancarboxylate

A solution of methyl 5-bromo-2-furancarboxylate (2.5 g, 12.19 mmol), potassium carbonate (8.43 g, 61.0 mmol), bis(tri-t-butylphosphine)palladium(0) (0.312 g, 0.61 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (1.47 g, 6.10 mmol) in 1,4-dioxane (50 ml) and water (10 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction contents were partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethenyl-2-furancarboxylate (1.3 g, 7.09 mmol, 58% yield) as a yellow oil: LCMS (ES) m/z=153 (M+H) + .

b) methyl 5-ethyl-2-furancarboxylate

To a solution of methyl 5-ethenyl-2-furancarboxylate (1.3 g, 8.54 mmol) in methanol (15 ml) was added PdOH 2 (0.240 g, 1.71 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N 2 , filtered through Celite and concentrated affording methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.16 mmol, 84% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 155 (M+H) + .

c) methyl 4-bromo-5-ethyl-2-furancarboxylate

To a solution of methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.78 mmol) and aluminum trichloride (1.56 g, 11.68 mmol) in chloroform (15 ml) at 25° C. was added bromine (0.56 ml, 10.90 mmol). The resulting solution stirred at 70° C. in a sealed tube for 2 h and the solution was cooled, concentrated and purified via column chromatography (silica, 5% EtOAc in hexanes) affording methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 3.26 mmol, 41.8% yield) as a white solid; LCMS (ES) m/z=233, 235 (M, M+2) + .

d) methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate

A solution of methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 4.72 mmol), potassium carbonate (3.26 g, 23.60 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. LCMS showed 4:1 pdt/sm. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were added and the solution stirred an additional 2 h where crude LCMS showed nearly complete conversion to product. The reaction contents were then partitioned between H 2 O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 3.37 mmol, 71.3% yield) as a yellow oil: LCMS (ES) m/e 235 (M+H) + .

e) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid

A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 4.06 mmol) and N-chlorosuccinimide (542 mg, 4.06 mmol) in tetrahydrofuran (20 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (13.5 ml, 81 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H 2 O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na 2 SO 4 , concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (683 mg, 2.55 mmol, 62.8% yield) as a yellow oil: LCMS (ES) m/e 254, 256 (M, M+2) + .

f) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (145 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (219 mg, 0.57 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.85 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (292 mg, 0.63 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.41 mmol, 71% yield) as a white solid: LCMS (ES) m/e 585, 587 (M, M+2) + .

g) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.43 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.13 ml, 4.27 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH 4 OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide (166 mg, 0.30 mmol, 70% yield) as a yellow solid: LCMS (ES) m/z=455, 457 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.59 (br. s., 1H) 8.06 (br. s., 3H) 7.67 (s, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.59 (d, J=4.29 Hz, 2H) 7.44 (d, J=4.04 Hz, 1H) 7.31 (d, J=5.81 Hz, 1H) 4.50-4.57 (m, 1H) 3.72 (s, 3H) 2.99-3.12 (m, 4H) 2.63 (q, J=7.33 Hz, 2H) 1.21 (t, J=7.45 Hz, 3H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-Pyrazol-5-yl)-5-ethyl-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example 131, except substituting 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (170 mg, 0.57 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=405, 407(M, M+2) + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (d, J=8.59 Hz, 1H) 8.09 (br. s., 3H) 7.67 (s, 1H) 7.33 (s, 1H) 7.31 (dd, J=8.34, 5.81 Hz, 2H) 7.12 (t, J=8.72 Hz, 2H) 4.36-4.39 (m, 1H) 3.71 (s, 3H) 2.91-3.03 (m, 4H) 2.62 (q, J=7.58 Hz, 2H) 1.20 (t, J=7.45 Hz, 3H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide

The title compound was prepared as a yellow solid according to Example 131, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (170 mg, 0.57 mmol) [prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=405, 407 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.62 (d, J=8.59 Hz, 1H) 8.13 (br. s., 3H) 7.67 (s, 1H) 7.30-7.37 (m, 2H) 7.12 (d, J=6.32 Hz, 2H) 7.04 (t, J=8.59 Hz, 1H) 4.40-4.47 (m, 1H) 3.71 (s, 3H) 2.95-3.09 (m, 4H) 2.62 (q, J=7.07 Hz, 2H) 1.20 (t, J=7.33 Hz, 3H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 127, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (295 mg, 0.88 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=377, 379 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.87 (d, J=8.84 Hz, 1H) 8.16 (br. s., 3H) 7.70-7.77 (m, 1H) 7.53 (d, J=1.77 Hz, 1H) 7.32 (t, J=7.20 Hz, 1H) 7.09-7.14 (m, 1H) 7.11 (d, J=6.57 Hz, 2H) 7.04 (t, J=8.59 Hz, 1H) 6.49 (d, J=1.77 Hz, 1H) 4.41-4.44 (m, 1H) 3.86 (s, 3H) 2.95-3.00 (m, 4H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 127, except substituting 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (295 mg, 0.88 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=377, 379 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.80 (d, J=8.84 Hz, 1H) 8.11 (br. s., 3H) 7.71 (s, 1H) 7.53 (d, J=1.77 Hz, 1H) 7.29 (dd, J=8.59, 5.56 Hz, 2H) 7.12 (t, J=8.84 Hz, 2H) 6.49 (d, J=1.77 Hz, 1H) 4.32-4.38 (m, 1H) 3.86 (s, 3H) 2.99-3.01 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 127, except substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (340 mg, 0.88 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=427, 429 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.83 (d, J=8.84 Hz, 1H) 8.11 (br. s., 3H) 7.62-7.69 (m, 2H) 7.51-7.59 (m, 4H) 6.48 (d, J=1.77 Hz, 1H) 4.39-4.44 (m, 1H) 3.85 (s, 3H) 2.97-3.05 (m, 4H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 128, except substituting 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (321 mg, 0.96 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=411, 413 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.77 (d, J=8.84 Hz, 1H) 8.04 (br. s., 3H) 7.72 (s, 1H) 7.59 (s, 1H) 7.30-7.38 (m, 1H) 7.11 (d, J=7.58 Hz, 2H) 7.05 (t, J=8.59 Hz, 1H) 4.39-4.43 (m, 1H) 3.77 (s, 3H) 2.97-3.03 (m, 4H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 128, except substituting 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (221 mg, 0.58 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=461, 463 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.83 (d, J=8.84 Hz, 1H) 8.10 (br. s., 3H) 7.72 (s, 1H) 7.64 (s, 1H) 7.52-7.60 (m, 4H) 4.39-4.41 (m, 1H) 3.76 (s, 3H) 2.98-3.05 (m, 4H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white foam according to the procedure of Example 128, except substituting 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (256 mg, 0.77 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=411, 413 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.78 (d, J=8.59 Hz, 1H) 8.06 (br. s., 3H) 7.72 (s, 1H) 7.60 (s, 1H) 7.30 (dd, J=8.59, 5.56 Hz, 2H) 7.13 (t, J=8.84 Hz, 2H) 4.35-4.42 (m, 1H) 3.77 (s, 3H) 2.99 (br. s., 2H) 2.86-2.93 (m, 2H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a white solid according to the procedure of Example 127, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.02 g, 4.59 mmol) [prepared according to Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (132 mg, 0.39 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=391, 393 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.75 (d, J=8.84 Hz, 1H) 8.04 (br. s., 3H) 7.55 (s, 1H) 7.37 (s, 1H) 7.30-7.36 (m, 1H) 7.11-7.15 (m, 2H) 7.05-7.10 (m, 1H) 4.42 (br. s., 1H) 3.70 (s, 3H) 2.97 (br. s., 2H) 2.92-2.96 (m, 2H) 1.94 (s, 3H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 127, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.06 g, 13.78 mmol) [prepared according to Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (174 mg, 0.52 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=391, 393 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.81 (d, J=8.59 Hz, 1H) 8.14 (br. s., 3H) 7.59 (s, 1H) 7.37 (s, 1H) 7.30 (dd, J=8.59, 5.56 Hz, 2H) 7.12 (t, J=8.84 Hz, 2H) 4.32-4.38 (m, 1H) 3.70 (s, 3H) 2.98 (d, J=5.81 Hz, 2H) 2.91 (d, J=6.32 Hz, 2H) 1.94 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 127, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.06 g, 13.78 mmol) [prepared according to Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=441, 443 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.83 (br. s., 1H) 8.15 (br. s., 2H) 7.63 (br. s., 1H) 7.52-7.58 (m, 4H) 7.37 (s, 1H) 4.38-4.42 (m, 1H) 3.68 (s, 3H) 2.97-3.08 (m, 4H) 1.93 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-furancarboxamide

The title compound was prepared as a yellow solid according to the procedure of Example 127, except substituting 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.06 g, 13.78 mmol) [prepared according to Preparation 17] for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione: LCMS (ES) m/z=441, 443 (M, M+2) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.87 (d, J=9.35 Hz, 1H) 8.11 (br. s., 3H) 7.70 (d, J=7.83 Hz, 1H) 7.52-7.57 (m, 3H) 7.41-7.47 (m, 1H) 7.38 (s, 1H) 4.39-4.43 (m, 1H) 3.71 (s, 3H) 2.98-3.09 (m, 4H) 1.95 (s, 3H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (3.30 g, 11.54 mmol) in dioxane/H 2 O (4:1, 100 mL) was added K 2 CO 3 (5.5 g, 40.0 mmol), tetrakistriphenylphosphine Pd(0) (671 mg, 0.58 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (2.66 g, 13.71 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 hours. The reaction mixture was partitioned between H 2 O and CHCl 3 . The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl 3 . The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (3.3 g, quant.): LC-MS (ES) m/z=289 (M+H) + .

b) 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

N-chlorosuccinimide (NCS) (299 mg, 2.194 mmol) was added in portions to a 30 mL sealed tube reactor containing 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (503 mg, 1.23 mmol) in tetrahydrofuran (THF) (6 mL) at room temperature. The mixture was heated to 70° C. for 2 hours. Upon completion, the reaction mixture was partitioned between CHCl 3 and H 2 O, the organic layer dried with Na 2 SO 4 , solvents removed by vacuum distillation affording the title compound (0.54 mg, quant.) which was used without further purification. LC-MS (ES) m/z=321 (M+H) +

c) 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (224 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (295 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.63 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (hexanes/EtOAc) affording the title compound (153 mg, 43%): LC-MS (ES) m/z=651 (M+H) + .

d) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-bromo-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (153 mg, 0.223 mmol) in tetrahydrofuran (THF) (2.5 mL) and Methanol (0.5 mL). Hydrazine (50 μL, 1.59 mmol) was added and the mixture stirred overnight at room temperature. Upon completion, the mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (68 mg, 0.11 mmol, 48.7% yield): LC-MS (ES) m/z=523 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.02-3.14 (m, 4H) 3.73 (s, 3H) 4.50 (s, 1H) 7.40-7.48 (m, 1H) 7.56-7.64 (m, 2H) 7.71 (d, J=7.83 Hz, 1H) 7.77 (s, 1H) 8.14 (s, 3H) 8.21 (s, 1H) 9.24 (d, J=9.09 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

The title compound was prepared according to the procedure of Example 144 except substituting N-bromosuccinimide (NBS) (287 mg, 1.596 mmol) for NCS: LC-MS (ES) m/z=364 (M+H) + .

b) 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (238 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (293 mg, 0.63 mmol) in chloroform (4 mL). DIEA (0.46 mL, 2.62 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (silica) (3:1 hex/EtOAc) affording the title compound (229 mg, 60%): LC-MS (ES) m/z=695 (M+H) + .

c) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-bromo-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (229 mg, 0.312 mmol) in Tetrahydrofuran (THF) (2.5 mL) and methanol (0.5 mL). Hydrazine (60 μL, 1.91 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica gel and purified by column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH; 12 g column).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O (500 mL) and concentrated affording the HCl salt of the title compound (104 mg, 0.15 mmol, 49% yield): LC-MS (ES) m/z=567 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.10 (s, 4H) 3.74 (s, 3H) 4.50 (s, 1H) 7.45 (ddd, J=7.96, 4.17, 4.04 Hz, 1H) 7.60 (d, J=4.04 Hz, 2H) 7.71 (d, J=7.58 Hz, 1H) 7.76 (s, 1H) 8.11 (s, 3H) 8.19 (s, 1H) 9.19 (d, J=8.84 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a solution of 4-bromo-2-thiophenecarboxylic acid (3.91 g, 18.9 mmol) in dioxane/H 2 O (4:1, 100 mL) was added Cs 2 CO 3 (21.7 g, 66.6 mmol), tetrakistriphenylphosphine Pd(0) (1.1 g, 0.95 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.94 g, 18.94 mmol) [prepared according to the procedure of Preparation 7]. The reaction mixture was heated to 85° C. in a sealed tube for 12 hours and partitioned between H 2 O and CHCl 3 . The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl 3 . The combined organic fractions were dried (Na 2 SO 4 ), concentrated under vacuum and used directly without further purification (2.84 g, 13.64 mmol, 72%): LC-MS (ES) m/z=209 (M+H) + .

b) N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (183 mg, 0.88 mmol), 2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.3 g, 0.85 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3,4-difluoro-L-phenylalanine (2.03 g, 6.74 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (528 mg, 1.13 mmol) in chloroform (5 mL). DIEA (0.77 mL, 4.41 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 30%): LC-MS (ES) m/z=507 (M+H) +

c) N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (149 mg, 0.265 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (60 μL, 1.91 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (71 mg, 0.15 mmol, 57% yield): LC-MS (ES) m/z=377 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.96 (d, J=6.06 Hz, 2H) 3.00-3.06 (m, 2H) 3.97 (s, 3H) 4.33-4.42 (m, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.14 (s, 1H) 7.30-7.42 (m, 2H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.22 (s, 3H) 8.35 (d, J=1.26 Hz, 1H) 9.09 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(3,4-dichlorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.26 g, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting 3,4-dichloro-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (2.03 g, 6.07 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (376 mg, 0.80 mmol) in chloroform (4 mL). DIEA (0.55 mL, 3.15 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 30%): LC-MS (ES) m/z=539 (M+H) +

b) N-{(1S)-2-amino-1-[(3,4-dichlorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(3,4-dichlorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (211 mg, 0.34 mmol) in Tetrahydrofuran (THF) (4.5 mL) and Methanol (0.45 mL). Hydrazine (75 μL, 2.390 mmol) was added and the mixture stirred overnight at room temperature. Upon completion the mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (83 mg, 0.16 mmol, 48% yield): LC-MS (ES) m/z=411 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.95-3.07 (m, 4H) 3.97 (s, 3H) 4.32-4.43 (m, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.29 (dd, J=8.21, 1.89 Hz, 1H) 7.47 (d, J=2.02 Hz, 1H) 7.54 (d, J=8.08 Hz, 1H) 7.60 (d, J=1.77 Hz, 1H) 8.00 (d, J=1.26 Hz, 1H) 8.22 (s, 3H) 8.35 (d, J=1.01 Hz, 1H) 9.11 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(2,6-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (231 mg, 0.69 mmol) [prepared according to the procedure of Preparation 18] and PyBrop (353 mg, 0.75 mmol) in chloroform (8 mL). DIEA (0.64 mL, 3.66 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 0.21 mmol, 30%): LC-MS (ES) m/z=507 (M+H) +

b) N-{(1S)-2-amino-1-[(2,6-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(2,6-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.32 mmol) in Tetrahydrofuran (THF) (3.6 mL) and Methanol (0.4 mL). Hydrazine (70 μL, 2.23 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (101 mg, 0.214 mmol, 68%): LC-MS (ES) m/z=377 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.92-3.03 (m, 3H) 3.17 (m, 1H) 3.97 (s, 3H) 4.46 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.05 (t, J=7.83 Hz, 2H) 7.27-7.38 (m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.23 (d, J=1.26 Hz, 4H) 8.92 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (257 mg, 0.93 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (476 mg, 0.81 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (15 mL). DIEA (0.808 mL, 4.63 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (225 mg, 34%): LC-MS (ES) m/z=507 (M+H) +

b) N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (225 mg, 0.31 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (0.8 mL). Hydrazine (60 μL, 1.91 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH). The compound was further purified on reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 95-5%) affording the TFA salt which was neutralized on silica (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (90.5 mg, 0.19 mmol, 63%): LC-MS (ES) m/z=377 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.95-3.01 (m, 2H) 3.03-3.10 (m, 2H) 3.92-3.98 (m, 3H) 4.41-4.51 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.05-7.13 (m, 1H) 7.20 (td, J=9.09, 4.55 Hz, 1H) 7.27 (ddd, J=9.09, 5.81, 3.28 Hz, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.52 Hz, 1H) 8.18 (s, 3H) 8.29 (d, J=1.26 Hz, 1H) 9.03 (d, J=8.84 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(2,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(2,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 0.80 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (331 mg, 0.78 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (1.0 g, 4.97 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (448 mg, 0.96 mmol) in chloroform (10 mL). DIEA (700 μL, 4.01 mmol) was added and the reaction stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (249 mg, 0.36 mmol, 46%): LC-MS (ES) m/z=507 (M+H) + .

b) N-{(1S)-2-amino-1-[(2,4-difluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(2,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (249 mg, 0.36 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (1 mL). Hydrazine (80 μL, 2.55 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH). The compound was further purified on reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 95-5%) affording the TFA salt which was neutralized on silica (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (81 mg, 0.18 mmol, 50%): LC-MS (ES) m/z=377 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.88-2.98 (m, 2H) 2.98-3.09 (m, 2H) 3.93-3.98 (m, 3H) 4.38-4.47 (m, 1H) 6.47 (d, J=1.77 Hz, 1H) 7.00 (td, J=8.46, 2.27 Hz, 1H) 7.19 (td, J=9.85, 2.53 Hz, 1H) 7.38-7.45 (m, 1H) 7.47 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.26 Hz, 1H) 8.18 (br. s, 3H) 8.27 (d, J=1.26 Hz, 1H) 8.99 (d, J=8.59 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 125 mL sealed flask was added methyl 4-bromo-5-methyl-2-thiophenecarboxylate (1.56 g, 6.64 mmol) [Prepared according to the procedure of Preparation 10], 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.67 g, 8.03 mmol) [prepared according to the procedure of Preparation 7], K 2 CO 3 (2.76 g, 19.97 mmol) and Pd(PtBu 3 ) 2 (170 mg, 0.33 mmol) in 1,4-Dioxane (27 ml) and water (7 ml). The reaction mixture was heated to 85° C. in a sealed tube for 3 hours, cooled to room temperature and partitioned between H 2 O and CHCl 3 . The organic fraction was dried (Na 2 SO 4 ), adsorbed onto silica and purified via column chromatography (0-15% EtOAc/Hexane). (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=237 (M+H) + .

b) 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a 100 mL round-bottomed flask was added methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.34 g, 5.67 mmol) in Tetrahydrofuran (THF) (31 ml). 6N NaOH (31 ml, 186 mmol) was added and the reaction mixture stirred at 70° C. overnight. The reaction mixture was neutralized by slow addition of 6N HCl and partitioned between CHCl 3 and H 2 O. The layers were separated, the organic layer dried with Na 2 SO 4 and solvent removed. The resulting solid was used without further purification (0.71 g, 2.81 mmol, 96%): LC-MS (ES) m/z=223 (M+H) + .

c) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 14.95 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=553 (M+H) + .

d) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (374 mg, 0.64 mmol) in Tetrahydrofuran (THF) (6 mL) and Methanol (600 μL). Hydrazine (125 μL, 3.98 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified by column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (135 mg, 0.27 mmol, 42% yield): LC-MS (ES) m/z=423 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.37 (s, 3H) 2.95-3.11 (m, 4H) 3.78 (s, 3H) 4.32-4.42 (m, 1H) 6.34 (d, J=1.77 Hz, 1H) 7.48-7.56 (m, 3H) 7.58-7.61 (m, 1H) 7.67 (s, 1H) 8.04 (s, 1H) 8.21 (s, 3H) 8.98 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol) [prepared according to the procedure of Example 95], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (186 mg, 32%): LC-MS (ES) m/z=553 (M+H) + .

b) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (185 mg, 0.34 mmol) in Tetrahydrofuran (THF) (10 mL) and Methanol (1 mL). Hydrazine (63 μL, 2.0 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (101 mg, 0.24 mmol, 72%): LC-MS (ES) m/z=393 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.90-3.1 (m, 4H) 3.85 (s, 3H) 4.33 (s, 1H) 6.48 (d, J=1.77 Hz, 1H) 7.10 (t, J=8.84 Hz, 2H) 7.32 (dd, J=8.46, 5.68 Hz, 2H) 7.55 (d, J=2.02 Hz, 1H) 8.19 (s, 3H) 8.23-8.28 (m, 1H) 9.25 (d, J=8.59 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (226 mg, 0.93 mmol) [prepared according to the procedure of Example 95], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (519 mg, 1.349 mmol) [prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (515 mg, 1.1 mmol) in chloroform (10 mL). DIEA (820 μL, 4.70 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (379 mg, 69%): LC-MS (ES) m/z=573 (M+H) + .

b) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (378 mg, 0.64 mmol) in Tetrahydrofuran (THF) (10 mL) and Methanol (1 mL). Hydrazine (122 μL, 3.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified by column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (222 mg, 0.41 mmol, 64%): LC-MS (ES) m/z=443 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.05 (d, J=6.82 Hz, 4H) 3.84 (s, 3H) 4.37 (d, J=5.05 Hz, 1H) 6.46 (d, J=1.77 Hz, 1H) 7.49-7.57 (m, 3H) 7.58-7.61 (m, 1H) 7.67 (s, 1H) 8.20 (s, 3H) 8.24 (s, 1H) 9.31 (d, J=8.84 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (288 mg, 0.86 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (162 mg, 32%): LC-MS (ES) m/z=503 (M+H) + .

b) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (162 mg, 0.29 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (300 μL). Hydrazine (58 μL, 1.85 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH). The compound was further purified on reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 95-5%) affording the TFA salt which was neutralized on silica (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (222 mg, 0.41 mmol, 64%): LC-MS (ES) m/z=373 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.38 (s, 3H) 2.89-3.02 (m, 4H) 3.79 (s, 3H) 4.26-4.48 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 7.10 (t, J=8.72 Hz, 2H) 7.26-7.35 (m, 2H) 7.52 (d, J=1.77 Hz, 1H) 8.02 (s, 1H) 8.17 (s, 3H) 8.88 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (291 mg, 0.87 mmol) [Prepared according to the procedure of preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (250 mg, 50%): LC-MS (ES) m/z=503 (M+H) + .

b) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (250 mg, 0.45 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (400 μL). Hydrazine (66 μL, 2.10 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH). The compound was further purified on reverse-phase HPLC (C18 column: H 2 O/CH 3 CN, 95-5%) affording the TFA salt which was neutralized on silica (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (142 mg, 0.31 mmol, 70%): LC-MS (ES) m/z=373 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.38 (s, 3H) 2.92-3.04 (m, 4H) 3.79 (s, 3H) 4.30-4.43 (m, 1H) 6.36 (d, J=1.77 Hz, 1H) 7.02 (td, J=8.53, 2.15 Hz, 1H) 7.13 (t, J=7.83 Hz, 2H) 7.26-7.35 (m, 1H) 7.52 (d, J=2.02 Hz, 1H) 8.04 (s, 1H) 8.19 (s, 3H) 8.93 (d, J=8.34 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

NBS (747 mg, 4.20 mmol) was added in portions to a 50 mL sealed tube reactor containing methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (860 mg, 3.48 mmol) [prepared according to the procedure of Example 37] in Tetrahydrofuran (THF) (17 mL) at room temperature. The mixture was heated to 70° C. for 1.5 hours, cooled to room temperature and partitioned between CHCl 3 and H 2 O. The organic layer was dried with Na 2 SO 4 , adsorbed onto silica and purified via column chromatography (20-40% EtOAc/hexanes) affording the title compound (867 mg, 83%): LC-MS (ES) m/z=303 (M+H) + .

b) methyl 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 20 mL sealed tube reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (505 mg, 1.68 mmol), cyclopropylboronic acid (447 mg, 5.20 mmol), Cesium Carbonate (1.90 g, 5.84 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 Adduct (43.6 mg, 0.05 mmol) in Tetrahydrofuran (THF) (8.5 mL). The reaction was heated to 70° C. for 1.5 hours, cooled and partitioned between CHCl 3 and H 2 O. The organic layer was dried with Na 2 SO 4 , adsorbed onto silica and purified via column chromatography (20-40% EtOAc/Hexane) affording the title compound (0.42 g, 1.60 mmol, 95%): LC-MS (ES) m/z=251 (M+H) + .

c) 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a 100 mL round-bottomed flask was added methyl 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.42 g, 1.60 mmol) in Tetrahydrofuran (THF) (8 ml). 6N NaOH (8 ml, 48.0 mmol) was added slowly and the reaction stirred at 70° C. overnight. The reaction was cooled and partitioned between CHCl 3 and H 2 O. The pH of the aqueous layer was adjusted to ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na 2 SO 4 and solvent removed affording the title compound (0.42 g, 1.60 mmol, 95%) which was used without further purification: LC-MS (ES) m/z=249 (M+H) + .

d) 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (105 mg, 0.42 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (152 mg, 0.39 mmol) [prepared according to Preparation 6] and PyBrop (246 mg, 0.52 mmol) in Chloroform (6 mL). DIEA (370 μL, 2.19 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 66%): LC-MS (ES) m/z=579 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (102 mg, 0.18 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (2 mL). Hydrazine (40 μL, 1.27 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (65 mg, 0.12 mmol, 66% yield): LC-MS (ES) m/z=449 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 0.45-0.54 (m, 2H) 0.76-0.83 (m, 2H) 1.62-1.71 (m, 1H) 3.03-3.21 (m, 4H) 3.82 (s, 3H) 4.46-4.56 (m, 1H) 7.21 (s, 1H) 7.42 (t, J=7.45 Hz, 1H) 7.53 (t, J=7.45 Hz, 1H) 7.66 (dd, J=19.96, 7.58 Hz, 2H) 7.95 (d, J=1.26 Hz, 1H) 8.18 (s, 3H) 8.24 (d, J=1.26 Hz, 1H) 9.11 (d, J=9.09 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 5 mL sealed tube reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (473 mg, 1.57 mmol) [prepared according to the procedure of Example 156], pyridine-triethenylboroxine (1:1) (666 mg, 2.77 mmol), Pd(PtBu 3 ) 2 (16.8 mg, 0.03 mmol) and Cs 2 CO 3 (1.72 g, 5.28 mmol) in 1,4-Dioxane (6.3 mL) and water (1.6 mL). The reaction was heated at 70° C. for 2 hours and partitioned between CHCl 3 (75 mL)/H 2 O (75 mL). The organic layer was dried with Na 2 SO 4 , adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hexane) affording the desired product: LC-MS (ES) m/z=249 (M+H) + .

b) methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate

To a 100 mL round-bottomed flask was added methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate and 10% Pd/C in ethyl acetate (15 mL). The mixture was evacuated slightly, refilled with H 2 from a balloon and stirred vigorously under an atmosphere of H 2 for 1 hour. The reaction was filtered through a 0.2 μm PTFE membrane filter and used without further purification (153 mg, 0.60 mmol, 87%): LC-MS (ES) m/z=251 (M+H) + .

c) 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid

To a 100 mL round-bottomed flask was added methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (192 mg, 0.77 mmol) in Tetrahydrofuran (THF) (4 mL). 6N NaOH (4 mL, 24.0 mmol) was added slowly, the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl 3 and H 2 O and the pH of the aqueous layer adjusted to pH ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried with Na 2 SO 4 and solvent removed affording the title compound (181 mg, quant.) used without further purification: LC-MS (ES) m/z=237 (M+H) + .

d) N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (106 mg, 0.45 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (164 mg, 0.43 mmol) [prepared according to Preparation 6] and PyBrop (254 mg, 0.54 mmol) in Chloroform (6 mL). DIEA (400 μL, 2.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (182 mg, 0.32 mmol, 71%): LC-MS (ES) m/z=567 (M+H) + .

e) N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (101 mg, 0.18 mmol) in Tetrahydrofuran (THF) (5 mL) and Methanol (2 mL). Hydrazine (40 μL, 1.27 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (65 mg, 0.12 mmol, 68%): LC-MS (ES) m/z=437 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.10 (t, J=7.45 Hz, 3H) 2.44 (q, J=7.41 Hz, 2H) 2.94-3.17 (m, 4H) 3.80 (s, 3H) 4.41-4.57 (m, 1H) 7.37-7.45 (m, 2H) 7.53 (t, J=7.45 Hz, 1H) 7.66 (dd, J=19.96, 7.58 Hz, 2H) 7.88 (d, J=1.01 Hz, 1H) 8.16 (s, 4H) 9.10 (d, J=8.84 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

NCS (1.355 g, 10.15 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.0 g, 8.46 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 2 h. 6N NaOH (28 ml, 168 mmol) was added and the mixture stirred at 70° C. for an additional 2 h. The mixture was cooled to room temperature and partitioned between CHCl 3 and H 2 O. The pH of the aqueous layer was adjusted to ˜3 by the addition of 6N HCl. The aqueous phase was washed several times with DCM and the combined organic fractions were dried with Na 2 SO 4 and concentrated affording the title compound (2.36 g, 9.19 mmol, quant.): LC-MS (ES) m/z=257 (M+H) + .

b) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (181 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (250 mg, 0.65 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (399 mg, 0.85 mmol) in chloroform (8 mL). DIEA (620 μL, 3.55 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=587 (M+H) + .

c) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide (319 mg, 0.50 mmol) in Tetrahydrofuran (THF) (4.9 mL) and Methanol (0.5 mL). Hydrazine (119 μL, 3.79 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified by column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (204 mg, 0.39 mmol, 79%): LC-MS (ES) m/z=457 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.33 (s, 3H) 2.95-3.10 (m, 4H) 3.71 (s, 3H) 4.31-4.41 (m, 1H) 7.49-7.61 (m, 3H) 7.66 (s, 1H) 7.69 (s, 1H) 7.94 (s, 1H) 8.16 (s, 3H) 8.90 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

NBS (1.84 g, 10.33 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2 g, 8.46 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (28 ml, 168 mmol) was then added and the mixture stirred at 70° C. for 2 h. The mixture was partitioned between CHCl 3 and H 2 O and the aqueous layer was made acidic with 6N HCl. The aqueous phase was washed several times with CHCl 3 and the organic fractions were combined, dried over Na 2 SO 4 and concentrated affording the title compound (2.68 g, 8.9 mmol, quant.): LC-MS (ES) m/z=302 (M+H) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (256 mg, 0.85 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1272 mg, 3.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (485 mg, 1.03 mmol) in Chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=583 (M+H) + .

c) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (133 mg, 0.21 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL). Hydrazine (50 μL, 1.59 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (90 mg, 0.17 mmole, 83%): LC-MS (ES) m/z=453 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.33 (s, 3H) 2.82-3.08 (m, 4H) 3.72 (s, 3H) 4.24-4.39 (m, 1H) 7.11 (t, J=8.84 Hz, 2H) 7.26-7.35 (m, 2H) 7.69 (s, 1H) 7.89 (s, 1H) 8.03-8.25 (m, 3H) 8.73-8.90 (m, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (276 mg, 1.08 mmol) [Prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (317 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (612 mg, 1.31 mmol) in Chloroform (14 mL). DIEA (940 μL, 5.38 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=537 (M+H) + .

c) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (145 mg, 0.25 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (60 μL, 1.91 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified by column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (88 mg, 0.19 mmol, 77%): LC-MS (ES) m/z=407 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.34 (s, 3H) 2.81-3.10 (m, 4H) 3.72 (s, 3H) 4.25-4.40 (m, 1H) 7.10 (t, J=8.84 Hz, 2H) 7.31 (dd, J=8.21, 5.68 Hz, 2H) 7.69 (s, 1H) 7.94 (s, 1H) 8.15 (s, 3H) 8.85 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.73 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (233 mg, 0.70 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (412 mg, 0.88 mmol) in Chloroform (9 mL). DIEA (640 μL, 3.66 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (180 mg, 0.30 mmol, 42%): LC-MS (ES) m/z=537 (M+H) + .

b) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (186 mg, 0.31 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (76 μL, 2.42 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (108 mg, 0.231, 74%): LC-MS (ES) m/z=407 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.34 (s, 3H) 2.91-3.03 (m, 4H) 3.71 (s, 3H) 4.31-4.41 (m, 1H) 7.02 (td, J=8.59, 2.02 Hz, 1H) 7.13 (t, J=7.07 Hz, 2H) 7.26-7.36 (m, 1H) 7.69 (s, 1H) 7.95 (s, 1H) 8.15 (s, 3H) 8.88 (d, J=6.32 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (191 mg, 0.63 mmol) [prepared according to the procedure of Example 159], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (209 mg, 0.62 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (359 mg, 0.77 mmol) in chloroform (7 mL). DIEA (560 μL, 3.21 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 0.29 mmol, 46%): LC-MS (ES) m/z=583 (M+H) + .

b) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (171 mg, 0.29 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL). Hydrazine (66 μL, 2.10 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified by column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (123 mg, 0.26 mmol, 88%): LC-MS (ES) m/z=453 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.33 (s, 3H) 2.91-3.03 (m, 4H) 3.72 (s, 3H) 4.31-4.41 (m, 1H) 7.02 (td, J=8.46, 2.02 Hz, 1H) 7.12 (d, J=7.33 Hz, 2H) 7.27-7.35 (m, 1H) 7.64-7.71 (m, 1H) 7.92 (s, 1H) 8.14 (s, 3H) 8.79-8.93 (m, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (180 mg, 0.60 mmol) [prepared according to the procedure of Example 159], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (203 mg, 0.58 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (340 mg, 0.72 mmol) in Chloroform (6 mL). DIEA (530 μL, 3.03 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (259 mg, 0.41 mmol, 69%): LC-MS (ES) m/z=633 (M+H) + .

b) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide (259 mg, 0.41 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1 mL). Hydrazine (90 μL, 2.87 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (172 mg, 0.33 mmol, 80%): LC-MS (ES) m/z=503 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.32 (s, 3H) 3.03 (d, J=6.06 Hz, 4H) 3.71 (d, J=5.81 Hz, 3H) 4.31-4.41 (m, 1H) 7.49-7.56 (m, 2H) 7.60 (d, J=6.82 Hz, 1H) 7.64-7.71 (m, 2H) 7.93 (d, J=12.88 Hz, 1H) 8.18 (s, 3H) 8.88-8.99 (m, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

NBS (2.03 g, 11.41 mmol) was added in portions to a 75 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.1 g, 8.89 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran

(THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 hour. The reaction mixture was partitioned between CHCl 3 and H 2 O, the organic layer dried with Na 2 SO 4 , the reaction mixture adsorbed onto silica and purified via column chromatography (15-40% EtOAc/Hex) affording the title compound (2.57 g, 8.15 mmol, 92%): LC-MS (ES) m/z=316 (M+H) + .

b) methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate

To a 350 mL sealed flask reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (2.57 g, 8.15 mmol), trimethylboroxine (2.27 ml, 16.31 mmol), K 2 CO 3 (3.47 g, 25.1 mmol) and Pd(dppf)Cl 2 (426 mg, 0.83 mmol) in N,N-Dimethylformamide (DMF) (41 ml). The reaction was heated at 110° C. for 1 hour. The mixture was partitioned between CHCl 3 /H 2 O, organic layer separated and dried with Na 2 SO 4 . The resulting material was adsorbed onto silica and purified via column chromatography (0-15% EtOAc/Hexane) affording the title compound (1.3 g, 4.76 mmol, 58%): LC-MS (ES) m/z=251 (M+H) + .

c) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid

To a 100 mL round-bottomed flask was added methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (1.31 g, 5.23 mmol) in Tetrahydrofuran (THF) (25 mL). 6N NaOH (30 mL, 180 mmol) was added slowly and the reaction stirred at 70° C. overnight. The reaction was cooled to room temperature, partitioned between CHCl 3 and H 2 O and the pH of the aqueous layer adjusted to pH 3 by the addition of 6N HCl. The layers were separated, the organic layer was dried with Na 2 SO 4 and the solvent was removed affording the title compound (1.3 g, 5.5 mmol, quant.) which was used without further purification: LC-MS (ES) m/z=237 (M+H) + .

d) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (170 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (256 mg, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (387 mg, 0.83 mmol) in chloroform (7 mL). DIEA (600 μL, 3.44 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (311 mg, 0.55 mmol, 80%): LC-MS (ES) m/z=567 (M+H) + .

e) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-thiophenecarboxamide (311 mg, 0.55 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.4 mL). Hydrazine (122 μL, 3.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (234 mg, 0.44 mmol, 79%): LC-MS (ES) m/z=437 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.87 (s, 3H) 2.26 (s, 3H) 3.03 (d, J=6.82 Hz, 4H) 3.62 (s, 3H) 4.31-4.41 (m, 1H) 7.38 (s, 1H) 7.49-7.56 (m, 2H) 7.58-7.61 (m, 1H) 7.65 (s, 1H) 7.87 (s, 1H) 8.20 (s, 3H) 8.89 (d, J=8.59 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (207 mg, 0.83 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (279 mg, 0.83 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (469 mg, 1.00 mmol) in chloroform (8 mL). DIEA (730 μL, 4.18 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (209 mg, 0.36 mmol, 43%): LC-MS (ES) m/z=517 (M+H) + .

b) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (201 mg, 0.39 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (86 μL, 2.74 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (163 mg, 0.34 mmol, 87%): LC-MS (ES) m/z=387 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.88 (s, 3H) 2.27 (s, 3H) 2.87-3.09 (m, 4H) 3.17-3.63 (s, 3H) 4.28-4.45 (m, 1H) 6.97-7.06 (m, 1H) 7.13 (t, J=7.20 Hz, 2H) 7.27-7.35 (m, 1H) 7.38 (s, 1H) 7.89 (s, 1H) 8.20 (s, 3H) 8.88 (d, J=7.58 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (253 mg, 1.02 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (335 mg, 1.00 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (574 mg, 1.23 mmol) in chloroform (10 mL). DIEA (930 μL, 5.32 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (132 mg, 0.25 mmol, 24%): LC-MS (ES) m/z=517 (M+H) + .

b) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (132 mg, 0.26 mmol) in Tetrahydrofuran (THF) (2 mL) and Methanol (1 mL). Hydrazine (57 μL, 1.82 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (95:5:0.5 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (104 mg, 0.22 mmol, 84%): LC-MS (ES) m/z=387 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.88 (s, 3H) 2.27 (s, 3H) 2.84-3.11 (m, 4H) 3.63 (s, 3H) 4.24-4.39 (m, 1H) 7.10 (t, J=8.72 Hz, 2H) 7.31 (dd, J=8.21, 5.68 Hz, 2H) 7.38 (s, 1H) 7.87 (s, 1H) 8.18 (s, 3H) 8.83 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid

NBS (1.243 g, 6.98 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.47 g, 5.73 mmol) [Prepared according to the procedure of Example 151] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (20 ml, 120 mmol) was then added and the mixture stirred at 70° C. for an additional 2 h. The mixture was partitioned between CHCl 3 and H 2 O, the organic layer dried with Na 2 SO 4 and concentrated affording the title compound which was used without further purification (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=302 (M+H) + .

b) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (204 mg, 0.60 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (215 mg, 0.64 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.7 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (380 mg, 0.81 mmol) in chloroform (6 mL). DIEA (570 μL, 3.26 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=603 (M+H) + .

c) N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (133 mg, 0.22 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1.2 mL). Hydrazine (50 μL, 1.59 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (145 mg, 0.30 mmol, 66% yield): LC-MS (ES) m/z=473 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.91-3.03 (m, 4H) 3.77 (s, 3H) 4.30-4.41 (m, 1H) 7.04 (td, J=8.53, 2.15 Hz, 1H) 7.12 (d, J=7.07 Hz, 2H) 7.28-7.36 (m, 1H) 7.74 (s, 1H) 8.02-8.14 (m, 4H) 9.06 (s, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (264 mg, 0.95 mmol) [prepared according to the procedure of Example 96], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (306 mg, 0.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (450 mg, 0.96 mmol) in chloroform (7 mL). DIEA (660 μl, 3.78 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.44 mmol, 56%): LC-MS (ES) m/z=607 (M+H) + .

b) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (303 mg, 0.50 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.5 mL). Hydrazine (120 μL, 3.82 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (177 mg, 0.31 mmol, 61% yield): LC-MS (ES) m/z=479 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.97-3.08 (m, 4H) 3.76 (s, 3H) 4.28-4.44 (m, 1H) 7.50-7.61 (m, 3H) 7.66 (s, 1H) 7.71-7.75 (m, 1H) 8.10 (s, 4H) 9.16 (d, J=8.59 Hz, 1H).

Preparation of N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (183 mg, 0.54 mmol) [prepared according to the procedure of Example 167], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (298 mg, 0.64 mmol) in chloroform (5 mL). DIEA (470 μL, 2.69 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.36 mmol, 69%): LC-MS (ES) m/z=653 (M+H) + .

d) N-((1S)-2-amino-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[3-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (246 mg, 0.38 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (0.083 mL, 2.64 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (134 mg, 0.22 mmol, 57% yield): LC-MS (ES) m/z=523 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.04 (d, J=4.55 Hz, 4H) 3.76 (s, 3H) 4.29-443 (m, 1H) 7.50-7.61 (m, 3H) 7.66 (s, 1H) 7.70-7.75 (m, 1H) 8.06-8.18 (m, 4H) 9.17 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

a) 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (340 mg, 1.00 mmol) [prepared according to the procedure of Example 167], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (374 mg, 1.12 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (626 mg, 1.34 mmol) in chloroform (10 mL). DIEA (980 μL, 5.61 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (229 mg, 0.35 mmol, 31%): LC-MS (ES) m/z=603 (M+H) + .

b) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (229 mg, 0.38 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1.2 mL). Hydrazine (90 μL, 2.87 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (99 mg, 0.17 mmol, 45% yield): LC-MS (ES) m/z=473 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.90 (d, J=6.82 Hz, 2H) 2.95-3.06 (m, 2H) 3.77 (s, 3H) 4.27-4.39 (m, 1H) 7.11 (t, J=8.72 Hz, 2H) 7.26-7.35 (m, 2H) 7.74 (s, 1H) 8.01-8.21 (m, 4H) 9.06 (s, 1H).

Preparation of N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

a) 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (320 mg, 1.16 mmol) [prepared according to the procedure of Example 168], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (318 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (9.5 mL). DIEA (840 μl, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (106 mg, 0.16 mmol, 17%): LC-MS (ES) m/z=557 (M+H) + .

b) N-{(1S)-2-amino-1-[(4-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(4-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (106 mg, 0.19 mmol) in Tetrahydrofuran (THF) (3 mL) and Methanol (1.5 mL). Hydrazine (45 μL, 1.43 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (65 mg, 0.12 mmol, 65% yield): LC-MS (ES) m/z=429 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.82-3.10 (m, 4H) 3.77 (s, 3H) 4.27-4.38 (m, 1H) 7.11 (t, J=8.72 Hz, 2H) 7.26-7.35 (m, 2H) 7.68-7.76 (m, 1H) 8.10 (s, 4H) 9.11 (d, J=7.33 Hz, 1H).

Preparation of N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

a) 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (219 mg, 0.85 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (290 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (481 mg, 1.03 mmol) in chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=555 (M+H) + .

b) N-{(1S)-2-amino-1-[(2,5-difluorophenyl)methyl]ethyl}-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide

To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(2,5-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (246 mg, 0.44 mmol) in Tetrahydrofuran (THF) (4 mL) and Methanol (1 mL). Hydrazine (100 μL, 3.19 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica gel and purified via column chromatography (90:10:1 CHCl 3 /MeOH/NH 4 OH).

The neutral compound was dissolved in MeOH (2 mL), treated with excess 2M HCl in Et 2 O and concentrated affording the HCl salt of the title compound (147 mg, 0.28 mmol, 64% yield): LC-MS (ES) m/z=425 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.34 (s, 3H) 2.93-3.07 (m, 4H) 3.71 (s, 3H) 4.34-4.50 (m, 1H) 7.04-7.14 (m, 1H) 7.19 (td, J=9.03, 4.67 Hz, 2H) 7.69 (s, 1H) 7.9