N-(2,2-dimethoxyethyl)cyclohexanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-(3-(1,5-dimethyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 37 Step ii)] (0.3 g) and DIPEA (0.545 mL) in DMF (4 mL) was added HATU (0.475 g) and the mixture was stirred at ambient temperature for 10 min. To this solution was added N-(2,2-dimethoxyethyl)cyclohexanamine (0.214 g) and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was poured onto water and extracted with ethyl acetate (2×100 mL). The organics were washed well with water, then brine and dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20-70% ethyl acetate in isohexane to afford the titled compound (0.185 g) as an oil. MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33-7.27 (m, 1H), 7.22-7.17 (m, 2H), 7.12 (d, 1H), 3.84 (s, 3H), 3.79 (dt, 2H), 3.70 (dt, 2H), 3.40 (s, 6H), 3.37 (d, 1H), 3.30 (d, 1H), 2.94-2.88 (m, 2H), 2.74-2.65 (m, 2H), 2.38 (s, 3H), 1.86-1.73 (m, 2H), 1.73-1.59 (m, 3H), 1.53-1.19 (m, 5H), 1.14-1.02 (m, 1H). the reaction mixture was stirred at ambient temperature for 2.5 h The reaction mixture was poured onto water extracted with ethyl acetate (2×100 mL) The organics were washed well with water brine and dried over anhydrous sodium sulfate filtered evaporated The crude product was purified by flash silica chromatography, elution gradient 20-70% ethyl acetate in isohexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The subtitled compound (267 mg) was prepared from 3-(3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 36 Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=456 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.81 and 7.80 (2×s, 1H), 7.40-7.37 (m, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.23 and 7.22 (2×t, J=7.7 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.30 (t, J=5.2 Hz, 2H), 4.04-3.95 and 3.69-3.60 (2×m, 1H), 3.77-3.63 (m, 6H), 3.34 (s, 3H), 3.32 (s, 3H), 3.31 (s, 3H), 3.34 and 3.25 (2×d, J=5.1 Hz, 2H), 2.87-2.81 (m, 2H), 2.67-2.60 (m, 2H), 1.93-0.99 (m, 10H); a ˜1:1 mixture of rotamers is observed. a ˜1:1 mixture of rotamers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The subtitled compound (3.3 g) was prepared from 3-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 17, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.81 and 7.80 (2×s, 1H), 7.19 (m, 1H), 7.09 (dt, J=10.0, 1.9 Hz, 1H), 6.80 (m, 1H), 4.52 and 4.36 (2×t, J=5.0 Hz, 1H), 4.00 and 3.64 (2×tt, J=3.6 and 11.7 Hz, 1H), 3.902 and 3.898 (2×s, 3H), 3.76-3.64 (m, 4H), 3.34 (s, 3H), 3.33 and 3.25 (2×d, J=5.1 Hz, 2H), 3.32 (s, 3H), 2.85 and 2.84 (2×t, J=6.2 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.69 (m, 2H), 1.68-1.49 (m, 3H), 1.49-1.19 (m, 4H), 1.16-1.01 (m, 1H); a ˜1:1 mixture of rotamers is observed. a ˜1:1 mixture of rotamers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The subtitled compound (1.6 g) was prepared form 3-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 16, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.46 (td, J=2.0 and 7.6 Hz, 1H), 7.15-7.02 (m, 2H), 4.53 and 4.37 (2×t, J=5.4 Hz, 1H), 4.04-3.94 and 3.70-3.60 (2×m, 1H), 3.92 (s, 3H), 3.76-3.64 (m, 4H), 3.35 and 3.33 (2×s, 6H), 3.36-3.26 (m, 2H), 2.95-2.88 (m, 2H), 2.65 and 2.63 (2×t, J=6.3 Hz, 2H), 1.81-1.00 (m, 10H); a ˜1:1 mixture of rotamers is observed. a ˜1:1 mixture of rotamers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The subtitled compound (1.6 g) was prepared form 3-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 16, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.46 (td, J=2.0 and 7.6 Hz, 1H), 7.15-7.02 (m, 2H), 4.53 and 4.37 (2×t, J=5.4 Hz, 1H), 4.04-3.94 and 3.70-3.60 (2×m, 1H), 3.92 (s, 3H), 3.76-3.64 (m, 4H), 3.35 and 3.33 (2×s, 6H), 3.36-3.26 (m, 2H), 2.95-2.88 (m, 2H), 2.65 and 2.63 (2×t, J=6.3 Hz, 2H), 1.81-1.00 (m, 10H); a ˜1:1 mixture of rotamers is observed. a ˜1:1 mixture of rotamers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The subtitled compound (450 mg) was prepared from 3-(3-(2-allyl-2H-tetrazol-5-yl)phenethoxy)propanoic acid [Example 7, Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 14, Step iii). 1H NMR (300 MHz, CD3OD) δ 8.04-7.92 (m, 2H), 7.49-7.36 (m, 2H), 6.29-6.11 (m, 1H), 5.47-5.30 (m, 4H), 4.56 and 4.39 (2×t, J=5.3 Hz, 1H), 4.09-3.94 (m, 1H), 3.81-3.67 (m, 4H), 3.372 and 3.368 (2×s, 6H), 3.34 and 3.29 (d, J=5.3 Hz, 2H), 3.00-2.91 (m, 2H), 2.72-2.64 (m, 2H), 1.84-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed. a ˜1:1 mixture of rotamers