Journal of Medicinal Chemistry
ARTICLE
the method of compound 5, using 2-chloro-4-fluoro-benzonitrile (Aldrich,
344265) in step 1. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 1H), 6.94
(s, 1H), 6.79 (d,1H,), 5.47 (bd, 1H), 3.97 (d, 2H), 2.04 (s, 3H), 1.19 (s, 6H),
was prepared by the method of compound 30, using 2-chloro-4-fluoro-
benzonitrile in step 1 and 1-(tetrahydro-pyran-2-yl)-1H-pyrazole-4-
carboxylic acid (Anichem, K11582) in step 2. After silica gel chromatog-
raphy, the THP group was then removed by treatment with excess 4.0 M
HCl/dioxane solution at room temperature for 18 h. The resulting
monhydrochloride salt was collected by suction filtration. 1H NMR
(400MHz, DMSO-d6): δ 1.10 (s, 6 H), 1.21 (s, 6 H), 4.05 (d, J = 9.35 Hz,
1 H), 4.30 (s, 1 H), 7.00 (dd, J = 8.72, 2.40 Hz, 1 H), 7.21 (d, J = 2.53 Hz,
1 H), 7.34 (d, J = 9.35 Hz, 1 H), 7.90 (d, J = 8.84 Hz, 1 H), 8.14 (s, 2 H).
HRMS: [M + H]+ calcd, 373.14258; found, 373.14173; error, ꢀ2.28
ppm. Anal. calcd for C19H21ClN4O2 1.75H2O 1.0HCl: C, 51.77; H,
1.16 (s, 6H). MS (APCI): 321 (M + H)+. Anal. calcd for C17H21ClN2O2
3
0.1H2O: C, 63.29; H, 6.62; N, 8.68. Found: C, 63.10; H, 6.42; N, 8.45.
Preparation of 12: N-[trans-3-(4-Cyano-3-methylphenoxy)-2,2,4,
4-tetramethylcyclobutyl]acetamide. Compound 12 was prepared by
the method of compound 5, using 4-fluoro-2-methylbenzonitrile
(Aldrich, 594660) in step 1. 1H NMR (400 MHz, CDCl3): δ 0.97ꢀ1.38
(m, 12 H), 2.02ꢀ2.10 (m, 3 H), 2.51 (s, 3 H), 3.78ꢀ4.12 (m, 2 H), 5.51
(s, 1 H), 6.58ꢀ6.82 (m, 2 H), 7.50 (d, J = 8.59 Hz, 1 H). MS (APCI):
3
3
301.2 (M + H)+. Anal. calcd for C18H24N2O2 1.0H2O: C, 67.90; H,
5.83; N, 12.71. Found: C, 51.68; H, 6.03; N, 12.42.
3
8.23; N, 8.80. Found: C, 67.72; H, 8.04; N, 8.67.
Preparation of 19: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-1-methyl-1H-pyrazole-4-carboxamide.
Compound 19 was prepared by the method of compound 30, using
2-chloro-4-fluoro-benzonitrile in step 1 and 1-methyl-1H-pyrazole-4-
Preparation of 13: N-{trans-3-[4-Cyano-3-(trifluoromethyl)phenoxy]-
2,2,4,4-tetramethylcyclobutyl}acetamide. Compound 13 was prepared by
the method of compound 5, using 4-fluoro-2-trifluoromethylbenzonitrile
(Alfa Aesar, B20617) in step 1. 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J =
8.34 Hz, 1 H), 7.29 (d, J = 2.53 Hz, 1 H), 7.10 (dd, J = 8.59, 2.53 Hz, 1 H),
4.92 (s, 1 H), 3.84 (s, 1 H), 1.57 (s, 4 H), 1.32 (s, 6 H), 1.25 (s, 6 H). MS
(APCI): 355.2 (M + H)+. HRMS: [M + H]+ calcd, 354.155510; found,
1
carboxylic acid (Anichem, K11201) in step 2. H NMR (400 MHz,
DMSO-d6):δ1.10 (s, 6 H), 1.20 (s, 6 H), 3.86 (s, 3 H), 4.04 (d, J=9.35Hz,
1 H), 4.29 (s, 1 H), 7.00 (dd, J = 8.84, 2.53 Hz, 1 H), 7.21 (d, J = 2.27 Hz,
1 H), 7.31 (d, J = 9.35 Hz, 1 H), 7.90 (t, J = 4.29 Hz, 2 H), 8.25 (s, 1 H).
HRMS: [M + H]+ calcd, 387.15823; found, 387.157169; error, ꢀ2.74 ppm.
Anal. calcd for C20H23ClN4O2 0.75H2O 0.25AcOH: C, 59.27; H, 6.19; N,
354.152381. Anal. calcd for C18H21F3N2O2 0.25H2O: C, 60.24; H, 6.04;
3
N, 7.81. Found: C, 60.15; H, 5.89; N, 7.75.
3
3
Preparation of 14: N-[trans-3-(2-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]acetamide. Compound 14 was prepared by
the method of compound 5, using 3-chloro-4-fluorobenzonitrile (Aldrich,
376582) in step 1. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 2.02 Hz,
1 H), 7.49 (dd, J = 8.59, 2.02 Hz, 1 H), 6.73 (d, J = 8.59 Hz, 1 H), 5.50
(d, J = 6.57 Hz, 1 H), 3.99ꢀ4.08 (m, 2 H), 2.06 (s, 3 H), 1.21 (s, 6 H),
13.49. Found: C, 59.31; H, 6.26; N, 13.65.
Preparation of 20: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide.
Compound 20 was prepared by the method of compound 30, using
2-chloro-4-fluoro-benzonitrile (Aldrich, 344265) in step 1 and 1,5-
dimethyl-1H-pyrazole-3-carboxylic acid (Aldrich, 722359) in step 2.
1H NMR (400 MHz, CDCl3): δ 1.21 (s, 6 H), 1.28 (s, 6 H), 2.30 (s, 3 H),
3.81 (s, 3 H), 4.06 (s, 1 H), 4.12 (d, J = 8.59 Hz, 1 H), 6.55 (s, 1 H), 6.81 (d,
J = 7.33 Hz, 1 H), 6.97 (s, 1 H), 7.04 (d, J = 8.34 Hz, 1 H), 7.57 (d, J = 8.84
1.21 (s, 6 H). MS (APCI): 321 (M + H)+. Anal. calcd for C17H21ClN2O2
3
1.0H2O 0.3AcOH: C, 59.24; H, 6.84; N, 7.85. Found: C, 59.01; H, 6.59;
3
N, 8.05.
Hz, 1 H). MS (APCI): 401 (M + H)+. Anal. calcd for C21H25ClN4O2
Preparation of 15: N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-
2,2,4,4-tetramethylcyclobutyl}acetamide. Compound 15 was prepared
by the method of compound 5, using 6-fluoro-2-methylnicotinonitrile
(Ryan Scientific, PC5881) in step 1. 1H NMR (400 MHz, DMSO-d6): δ
7.97 (d, J = 8.59 Hz, 1 H), 7.49 (d, J = 9.09 Hz, 1 H), 6.76 (d, J = 8.59 Hz,
1 H), 4.51 (s, 1 H), 3.73 (d, J = 9.35 Hz, 1 H), 2.47 (s, 3 H), 1.82 (s, 3 H),
1.04 (s, 6 H), 0.94 (s, 6 H). MS (APCI): 302 (M + H)+. HRMS: [M + H]+
calcd, 302.186303; found, 302.186859. Anal. calcd For C17H23N3O2: C,
67.75; H, 7.69; N, 13.94. Found: C, 67.68; H, 7.57; N, 13.93.
Preparation of 16: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]pyrazine-2-carboxamide. Compound 16 was
prepared by the method of compound 30, using 2-chloro-4-fluoro-
benzonitrile in step 1 and pyrazine-2-carboxylic acid (Fluka, 82611) in
step 2. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (s, 6 H), 1.23 (s, 6 H),
4.02 (d, J = 9.09 Hz, 1 H), 4.45 (s, 1 H), 7.03 (dd, J = 8.84, 2.27 Hz, 1 H),
7.24 (d, J = 2.27 Hz, 1 H), 7.90 (d, J = 8.59 Hz, 1 H), 8.26 (d, J = 9.09 Hz,
1 H), 8.79 (s, 1 H), 8.92 (d, J = 2.53 Hz, 1 H), 9.21 (s, 1 H). HRMS: [M +
H]+ calcd, 385.14258; found, 385.1429; error, 0.83 ppm. Anal. calcd for
3
0.5H2O: C, 61.53; H, 6.39; N, 13.67. Found: C, 61.31; H, 6.38; N, 13.59.
Preparation of 21: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide.
Compound 21 was prepared by the method of compound 30, using
2-chloro-4-fluoro-benzonitrile (Aldrich, 344265) in step 1 and 5-methyl-
1
[1,3,4]oxadiazole-2-carboxylic acid (Oakwood 047529) in step 2. H
NMR (400 MHz, CDCl3): δ 1.22 (s, 6 H), 1.30 (s, 6 H), 2.66 (s, 3 H),
4.08 (s, 1 H), 4.13 (d, J = 8.84 Hz, 1 H), 6.81 (dd, J = 8.72, 2.40 Hz,
1 H), 6.97 (d, J = 2.27 Hz, 1 H), 7.18 (d, J = 8.34 Hz, 1 H), 7.58 (d, J =
8.84 Hz, 1 H). MS (APCI): 389 (M + H)+. Anal. calcd for C19H21-
ClN4O3 1.0H2O: C, 56.09; H, 5.70; N, 13.77. Found: C, 56.46; H,
3
5.73; N, 13.41.
Preparation of 22: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]imidazo[1,2-a]pyrimidine-3-carboxamide.
Compound 22 was prepared by the method of compound 30, using
2-chloro-4-fluoro-benzonitrile (Aldrich, 344265) in step 1. 1H NMR
(400 MHz, CDCl3): δ 1.25 (s, 6 H), 1.32 (s, 6 H), 4.10 (s, 1 H), 4.18
(d, J = 8.34 Hz, 1 H), 6.09 (d, J = 8.08 Hz, 1 H), 6.83 (dd, J = 8.59,
2.53 Hz, 1 H), 6.99 (d, J = 2.53 Hz, 1 H), 7.09 (dd, J = 6.95, 4.17 Hz,
1 H), 7.59 (d, J = 8.59 Hz, 1 H), 8.22 (s, 1 H), 8.73 (dd, J = 4.29, 2.02 Hz,
1 H), 9.76 (d, J = 5.05 Hz, 1 H). MS (APCI): 424 (M + H)+. Anal. calcd
C20H21ClN4O2 0.25H2O: C, 61.69, H, 5.57; N, 14.39. Found: C, 61.75;
3
H, 5.45; N, 14.33.
Preparation of 17: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-1H-pyrazole-3-carboxamide. Compound 17
was prepared by the method of compound 30, using 2-chloro-4-fluoro-
benzonitrile (Aldrich, 344265) in step 1 and 1H-pyrazole-3-carboxylic
acid (Aldrich, 707384) in step 2. 1H NMR (400 MHz, CDCl3): δ 1.22 (s,
6 H), 1.29 (s, 6 H), 4.07 (s, 1 H), 4.16 (d, J = 8.59 Hz, 1 H), 6.82 (dd, J =
8.72, 2.40 Hz, 1 H), 6.89 (d, J = 2.53 Hz, 1 H), 6.98 (d, J = 2.53 Hz, 1 H),
7.10 (br. s., 1 H), 7.57 (d, J = 8.59 Hz, 1 H), 7.63 (d, J = 2.27 Hz, 1 H),
10.29 (br. s., 1 H). MS (APCI): 373.2 (M + H)+. Anal. calcd for
C19H21ClN4O2: C, 61.21; H, 5.68; N, 15.03. Found: C, 61.09; H, 5.72;
N, 14.90.
for C22H22ClN5O2 1.15H2O: C, 59.43; H, 5.51; N, 15.75. Found: C,
3
59.19; H, 5.18; N, 15.60.
Preparation of 23: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-2-methylimidazo[1,2-a]pyrimidine-3-carbo-
xamide. Compound 23 was prepared by the method of compound 30,
using 2-chloro-4-fluoro-benzonitrile (Aldrich, 344265) in step 1 and
2-methyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (Ryan Scientific,
CA10041) in step 2. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (s, 6 H),
1.27 (s, 6 H), 2.67 (s, 3 H), 3.97 (d, J = 8.08 Hz, 1 H), 4.34 (s, 1 H), 7.03
(dd, J = 8.72, 2.40 Hz, 1 H), 7.18 (dd, J = 6.95, 4.17 Hz, 1 H), 7.24 (d, J =
2.27 Hz, 1 H), 7.54 (d, J = 8.08 Hz, 1 H), 7.91 (d, J = 8.59 Hz, 1 H), 8.63
Preparation of 18: N-[trans-3-(3-Chloro-4-cyanophenoxy)-2,2,4,
4-tetramethylcyclobutyl]-1H-pyrazole-4-carboxamide. Compound 18
7701
dx.doi.org/10.1021/jm201059s |J. Med. Chem. 2011, 54, 7693–7704