Dihydroisoxazoles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7499
1
three steps) was prepared by the method used to prepare compound
22. H NMR (200 MHz, CDCl3): δ 2.8-3.4 (m, 4H), 3.680 (s,
25a. H NMR (500 MHz, DMSO-d6): δ 2.87-3.1 (m, 3H),
1
3.186-3.325 (ddd, 1H, J ) 5.0, 5.0, 14.5), 3.257-3.313 (dd, 1H,
J ) 10.5, 17.5), 3.98-3.54 (m, 1H), 4.247-4.293 (m, 1H), 4.644-
4.700 (m, 1H), 5.111-5.226 (dd, 2H, J ) 8.0, 44.5), 6.833-6.925
(ddd, 1H, J ) 3.0, 9.5, 9.5), 7.261-7.265 (d, 1H, J ) 2.0), 7.311-
7.338 (dd, 1H, J ) 4.5, 4.5), 7.473-7.498 (dd, 1H, J ) 2.5, 10.0),
7.604-7.636 (dd, 1H, J ) 8.0, 8.0), 7.633-7.652 (dd, 1H, J )
1.5, 7.0), 7.757-7.790 (ddd, 1H, J ) 1.5, 7.0, 8.0), 7.927-7.945
(dd, 1H, J ) 1.0, 8.0), 8.023-8.040 (d, 1H, J ) 8.5), 8.236-
8.239 (d, 1H, J ) 1.5), 8.441-8.464 (dd, 1H, J ) 6.0, 6.0), 8.856-
8.860 (d, 1H, J ) 2.0), 10.944-10.948 (d, 1H, J ) 2.0). 13C NMR
(125 MHz, DMSO-d6): δ 173.4, 158.3, 156.5, 151.3, 147.8, 138.8,
135.2, 133.4, 130.7, 130.3, 129.5, 128.7, 128.1, 127.9, 127.7, 127.0,
112.9, 111.1, 109.8, 109.6, 104.2, 80.8, 64.9, 56.2, 44.1, 42.0, 28.7.
[R]22D +18.7 (c 0.5, DMSO-d6). HRMS (TOF MS ES+) m/z calcd
for C26H23N5O4FBr, 568.0996, found, 568.0094 (M + H)+.
25b. 1H NMR (500 MHz, DMSO-d6): δ 2.867-2.916 (dd, 1H,
J ) 10.0, 14.5), 2.995-3.052 (m, 1H), 3.257-3.337 (m, 1H),
4.236-4.287 (m, 1H), 4.664-4.721 (m,1H), 5.112-5.232 (dd, 2H,
J ) 13.0, 47.0), 6.880-6.921 (ddd, 1H, J ) 2.0, 8.0, 8.0), 7.274
(s, 1H), 7.308-7.335 (dd, 1H, J ) 5.0, 9.0), 7.471-7.496 (dd,
1H, J ) 2.0, 20.0), 7.578-7.594 (d, 1H, J ) 8.0), 7.621-7.651
(dd, 1H, J ) 7.0,7.0), 7.757-7.790 (ddd, 1H, J ) 1.0, 8.0, 8.0),
7.929-7.945 (d, 1H, J ) 8.0), 8.023-8.040 (d, 1H, J ) 8.5),
8.427-8.451 (dd, 1H, J ) 6.0, 6.0), 8.858-8.861 (d, 1H, J ) 1.5),
10.947 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ 173.2, 158.3,
156.5, 151.3, 147.8, 139.0, 135.2, 133.4, 130.8, 130.3, 129.5, 128.7,
128.0, 127.7, 127.0, 112.9, 111.1, 109.7, 109.5, 104.0, 80.8, 69.7,
3H), 4.1-4.3 (m, 1H), 4.5-4.7 (m, 1H), 5.087-5.121 (d, 2H, J )
6.8), 6.604-6.659 (dd, 1H, J ) 2.3, 8.7), 7.116-7.159 (d, 1H, J
) 8.6), 7.462-7.588 (m, 2H), 7.661-7.729 (dd, 1H, J ) 1, 6.8),
7.838-7.970 (dd, 2H, J ) 8.4, 17.8), 8.167 (s, 1H), 8.22-8.38
(m, 1H), 8.781-8.791 (d, 1H, J ) 2.0), 10.590 (s, 1H).
Quinolin-3-ylmethyl 1-((3-Bromo-4,5-dihydroisoxazol-5-yl)-
methylamino)-3-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-ylcar-
bamate (21). Compound 21 (4.7 mg, 0.0083 mmol, 2.4% for three
steps) was prepared by the method used to prepare compound 22.
1H NMR (200 MHz, DMSO-d6): δ 2.9-3.55 (m, 4H), 4.387-
4.497 (dd, 1H, J ) 7.6, 14.8), 4.6-4.76 (m, 1H), 5.199 (s, 2H),
6.541-6.575 (d, 1H, J ) 6.8), 6.770-6.873 (ddd, 1H, J ) 2.2,
9.0), 7.24-7.38 (m, 4H), 7.515-7.590 (m, 2H), 7.658-7.742 (ddd,
1H, J ) 1.6, 7.0), 7.849-7.888 (d, 1H, J ) 8.0), 7.973-8.015 (d,
1H, J ) 8.4) 8.8 (s, 1H), 10.18 (bs, 1H).
(S)-Quinolin-3-ylmethyl 2-(((3-Bromo-4,5-dihydroisoxazol-5-
yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (23). Compound
23 (5.2 mg, 0.0113 mmol, 5.1% for three steps) was prepared by
1
the method used to prepare compound 22. H NMR (200 MHz,
CDCl3): δ 1.6-1.8 (m, 4H), 2.8-3.4 (m,6H), 4.05-4.25 (m, 1H),
4.45-4.7 (m, 1H), 5.1-5.25 (m, 2H), 7.522-7.738 (m, 2H),
7.866-7.977 (m, 2H), 8.15-8.3 (m, 2H), 8.765-8.859 (d, 1H, J
) 18.4).
Quinolin-3-ylmethyl (S)-1-(((S)-3-Bromo-4,5-dihydroisoxazol-
5-yl)methylamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-ylcar-
bamate (24a) and Quinolin-3-ylmethyl (S)-1-(((R)-3-Bromo-4,5-
dihydroisoxazol-5-yl)methylamino)-3-(4-hydroxyphenyl)-1-oxo-
propan-2-ylcarbamate (24b). Compounds 24a and 24b (24a, 40.6
mg, 0.077 mmol, 77% in the coupling reaction; 24b, 26.0 mg, 0.049
mmol, 58%) were prepared by the method used to prepare
compound 22, with the exception that the enantiomerically enriched
dihydroisoxazoles, 32 and 32b, were used.
56.1, 44.0, 41.7, 28.5). [R]22 -30.8 (c 0.5, DMSO-d6). HRMS
D
(TOF MS ES+) m/z calcd for C26H23N5O4FBr, 568.0996, found,
568.0980 (M + H)+.
(S)-Quinolin-3-ylmethyl 2-((((S)-3-Bromo-4,5-dihydroisoxazol-
5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (26a) and (S)-
Quinolin-3-ylmethyl 2-((((R)-3-Bromo-4,5-dihydroisoxazol-5-
yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (26b). Compounds
26a and 26b (26a, 22.2 mg, 0.048 mmol, 48.2% in the coupling
reaction; 26b, 26.0 mg, 0.056 mmol, 66%) were prepared by the
method used to prepare compound 22, with the exception that the
enantiomerically enriched dihydroisoxazoles, 32 and 32b, were
used.
24a. 1H NMR (500 MHz, DMSO-d6): δ 2.799-2.836 (dd, 1H,
J ) 4.5, 13.5), 2.935-2.985 (dd, 1H, J ) 7.5, 17.5), 3.179-3.228
(ddd, 1H, J ) 5.0, 5.0, 14.0), 3.293-3.350 (dd, 1H, J ) 11.0, 18.0),
3.378-3.430 (m, 1H), 4.146-4.193 (m, 1H), 4.653-4.709 (m, 1H),
5.144-5.229 (dd, 2H, J ) 13.0, 29.5), 6.644-6.661 (d, 2H, J )
8.5), 7.062-7.079 (d, 2H, J ) 8.5), 7.952-7.609 (d, 1H, J ) 8.5),
7.625-7.655 (ddd, 1.0, 7.0, 7.0), 7.761-7.794 (ddd, 1H, J ) 1.0,
8.5, 8.5), 7.952-7.968 (d, 1H, J ) 8.0), 8.029-8.046 (d, 1H, J )
8.5), 8.245-8.247 (d, 1H, J ) 1.0), 8.331-8.355 (dd, 1H, J )
6.0, 6.0), 8.865-8.869 (d, 1H, J ) 1.5), 9.213 (s, 1H); 13C NMR
(125 MHz, DMSO-d6) δ 173.2, 156.5, 156.4, 151.3, 147.8, 138.9,
135.2, 130.8, 130.3, 129.5, 128.7, 127.9, 127.7, 115.6, 80.8, 64.0,
1
26a. H NMR (500 MHz, CD3CN): δ 1.867-1.972 (bm, 3H),
2.909-3.059 (ddd, 1H, J ) 7.5, 17.5, 50.0), 3.153-3.209 (dd, 1H,
J ) 10.0, 17.5), 3.273-3.396 (m, 2H), 3.462-3.538 (m, 2H),
3.573-3.616 (m, 1H), 4.205-4.279 (ddd, 1H, J ) 3.0, 8.5, 25.0),
4.587-4.644 (m, 1H), 4.755-4.811 (m, 1H), 5.233-5.371 (dd, 1H,
J ) 13.0, 57.0), 5.358 (s, 1H), 6.904-6.971 (bd, 1H, J ) 33.5),
7.637-7.664 (dd, 1H, J ) 7.0, 7.0), 7.781-7.810 (dd, 1H, J )
8.5, 8.5), 7.946-7.991 (dd, 1H, J ) 8.0, 14.5), 8.231-8307 (d,
1H, J ) 38.0), 8.892-8.969 (d, 1H, J ) 38.5). 13C NMR (125
MHz, CD3CN): δ 173.5, 173.1, 155.2, 154.6, 151.0, 148.0, 137.9,
135.0, 134.8, 130.4, 129.8, 129.3, 128.3, 127.9, 127.2,80.8, 80.6,
64.7, 61.3, 60.7, 47.5, 47.1, 43.9, 43.7, 41.6, 41.2, 31.6, 300.2, 24.4,
57.4, 44.2, 41.9, 37.6, 28.58, 23.4. [R]22 +40.0 (c 0.5, DMSO-
D
d6). HRMS (TOF MS ES+) m/z calcd for C24H23N4O5Br, 527.0930,
found, 527.0915 (M + H)+.
24b. 1H NMR (500 MHz, CD3OD): δ 2.790-2.835 (dd, 1H, J
) 8.5, 13.5), 2.965-3.012 (m, 2H), 3.187-3.243 (dd, 1H, J )
10.5, 17.5), 3.328-3.454 (ddd, 2H, J ) 10.2, 14.0, 44.0), 4.279-
4.308 (dd, 1H, J ) 6.5, 8.0), 4.652-4.709 (m, 1H), 5.294 (s, 2H),
6.688-6.705 (dd, 2H, J ) 2.0, 6.5), 7.048-7.066 (d, 2H, 9.0),
7.641-7.671 (dd, 1H, J ) 7.0, 7.0), 7.953-7.97 (d, 1H, J ) 8.5),
8.041-8.058 (d, 1H, 8.5), 8.304 (s, 1H), 8.859-8.862 (d, 1H, J )
1.5). 13C NMR (125 MHz, CD3OD): δ 173.7, 156.7, 156.2, 150.2,
147.0, 138.0, 136.0, 130.5, 130.2, 128.2, 128.1, 127.8, 127.3, 115.1,
80.5, 57.2, 43.7, 41.5, 37.1. [R]22D -38.8 (c 0.5, CD3OD). HRMS
(TOF MS ES+) m/z calcd for C24H23N4O5Br, 527.0930, found,
527.0942 (M + H)+.
23.6. [R]22 +17.2 (c 0.5, CD3CN). HRMS (TOF MS ES+) m/z
D
calcd for C20H21N4O4Br, 461.0824, found, 461.086 (M + H)+.
1
26b. H NMR (500 MHz, CD3OD): δ 1.900-2.035 (m, 3H),
2.201-2.370 (m, 1H), 2.892-2.943 (dd, 1H, J ) 8.0, 17.5), 3.266-
3.324 (m, 1H), 3.358-3.434 (dd, 1H, J ) 4.5, 33.5), 3.387-3.406
(dd, 1H, J ) 4.5, 4.5), 3.522-3.649 (m, 2H), 4.272-4.341 (ddd,
1H, J ) 3.5, 8.5, 22.0), 4.618-4.815 (m, 1H), 5.292-5.442 (dd,
1H, J ) 13.0, 62.5), 5.388 (s, 1H), 7.651-7.683 (ddd, 1H, J )
1.0, 8.0, 8.0), 7.800-7.833 (ddd, 1H, J ) 1.0, 8.0, 8.0), 7.982-
8.011 (dd, 1H, J ) 7.0, 7.0), 8.052-8.069 (d, 1H, J ) 9.0), 8.356-
8.416 (d, 1H, J ) 30.0), 8.862-8.936 (d, 1H, J ) 42.0). 13C NMR
(125 MHz, CD3OD): δ 174.8, 150.4, 150.3, 147.1, 137.6, 136.4,
136.2, 130.2, 128.2, 127.8, 127.4, 80.7, 80.3, 60.9, 43.7, 41.8, 41.3,
31.6, 30.3, 24.3, 23.4. [R]22D -68.0 (c 0.54, CD3OD). HRMS (TOF
MS ES+) m/z calcd for C20H21N4O4BrNa, 483.0664, found,
483.0646 (M + H)+.
Quinolin-3-ylmethyl (S)-1-(((S)-3-Bromo-4,5-dihydroisoxazol-
5-yl)methylamino)-3-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-yl-
carbamate (25a) and Quinolin-3-ylmethyl (S)-1-(((R)-3-Bromo-
4,5-dihydroisoxazol-5-yl)methylamino)-3-(5-fluoro-1H-indol-3-
yl)-1-oxopropan-2-ylcarbamate (25b). Compounds 25a and 25b
(25a, 12.2 mg, 0.0214 mmol, 67% in the coupling reaction; 25b,
14.6 mg, 0.026 mmol, 81%) were prepared by the method used to
prepare compound 22, with the exception that the enantiomerically
enriched dihydroisoxazoles, 32 and 32b, were used.
Benzyl (S)-1-(((S)-3-Bromo-4,5-dihydroisoxazol-5-yl)methy-
lamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-ylcarbamate (27a)
and Benzyl (S)-1-(((R)-3-Bromo-4,5-dihydroisoxazol-5-yl)methy-