US2003186970A1PendingUtilityA1
Androgen receptor modulator compounds and methods
Priority: Aug 27, 1999Filed: Sep 9, 2002Published: Oct 2, 2003
Est. expiryAug 27, 2019(expired)· nominal 20-yr term from priority
Inventors:Robert I. HiguchiKristen L. ArientiMani NeelakandhaBarbara PioLin ZhiPenghui ChenThomas Raymond Caferro
A61P 5/28A61P 7/00A61P 7/06A61P 5/24A61P 5/00A61P 5/26A61P 35/00A61P 17/14A61P 13/08A61P 15/16A61P 15/10A61P 15/08A61P 17/10A61P 19/10C07D 513/04C07D 498/04C07D 498/14C07D 471/04
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Claims
Abstract
Compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. In particular, preparation and methods of use of non-steroidal compounds and compositions that are agonists, partial agonists, and antagonists for the androgen receptor (AR) are described. Further, described are the methods of making and use of critical intermediates including a stereoselective synthetic route to intermediates for the AR modulators.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
wherein:
R 1 is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 , S(O) m R 9 , C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 aryl, C 1 -C 8 arylalkyl, C 1 -C 8 heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 2 is selected from the group of hydrogen, F, Cl, Br, I, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) m R 9 , NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 3 is selected from the group of hydrogen, F, Cl, Br, I, OR 9 , S(O) m R 9 , NR 10 R 11 , or C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 1 -C 6 haloalkyl and wherein the alkyl, heteroalkyl and haloalkyl groups are optionally substituted;
R 4 and R 5 are each independently selected from the group of hydrogen, OR 9 , S(O) m R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted, or
R 4 and R 5 taken together form a saturated or unsaturated three- to seven-membered ring that is optionally substituted;
R 6 and R 7 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted, or
R 6 and R 7 taken together form a saturated or unsaturated three- to seven-membered ring that is optionally substituted, or
R 6 and R 5 taken together form a saturated or unsaturated three- to seven-membered ring that is optionally substituted;
R 8 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 and S(O) m R 9 and wherein the alkyl, heteroalkyl and haloalkyl groups are optionally substituted;
R 9 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, arylalkyl, C 2 -C 4 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 10 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C(Y)R 12 , C(Y)OR 12 , aryl, heteroaryl, C 2 -C 4 alkynyl, C 2 -C 8 alkenyl, arylalkyl, SO 2 R 12 and S(O)R 12 and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 11 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, arylalkyl, C 2 -C 4 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 12 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, arylalkyl, C 2 -C 4 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted,
R 13 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C 2 -C 4 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkynyl, and alkenyl groups are optionally substituted; or
R 13 and R 4 taken together form a saturated or unsaturated three- to seven-membered ring that is optionally substituted; or
any two of R 4 through R 7 , and R 13 taken together form a saturated or unsaturated three- to seven-membered ring that is optionally substituted;
R 14 and R 15 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, arylalkyl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl and alkenyl are optionally substituted;
R A is selected from the group of hydrogen, F, Br, Cl, I, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, OR 16 , NR 16 R 17 , SR 16 , CH 2 R 16 , COR 17 , CO 2 R 17 , CONR 17 R 17 , SOR 17 and SO 2 R 17 and wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;
R 16 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, COR 17 , CO 2 R 17 , CONR 17 R 17 , C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, aryl, and heteroaryl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 17 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl and wherein the alkyl, haloalkyl, and heteroalkyl groups are optionally substituted;
m is 0, 1 or 2;
n is 1 or 2;
V is selected from the group of O, S and CR 14 R 15 ;
W is selected from the group of 0, S, NH, NR 13 , NC(Y)R 11 and NSO 2 R 11 ;
X and Z each independently is selected from the group of O, S(O) m , NH, NR 11 , NC(Y)R 11 , NSO 2 R 12 and NS(O)R 12 ; and
Y is O or S;
and pharmaceutically acceptable salts thereof.
2 . A compound according to claim 1 , wherein Z is NR 11 .
3 . A compound according to claim 2 , wherein R 11 is hydrogen.
4 . A compound according to claim 2 , wherein R 2 is CF 3 .
5 . A compound according to claim 1 , wherein W is NR 13 .
6 . A compound according to claim 5 , wherein R 13 and one of R 4 and R 5 together form a five or six-membered ring.
7 . A compound according to claim 5 , wherein R 13 is alkyl.
8 . A compound according to claim 7 , wherein R 13 is selected from the group of methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, and t-butyl.
9 . A compound according to claim 5 , wherein R 13 is haloalkyl.
10 . A compound according to claim 9 , wherein R 13 is trifluoroethyl.
11 . A compound according to claim 1 , wherein each of R 4 , R 5 , R 6 and R 7 are independently hydrogen or optionally substituted C 1 -C 6 alkyl.
12 . A compound according to claim 11 , wherein one of R 4 , R 5 , R 6 and R 7 is optionally substituted C 1 -C 6 alkyl.
13 . A compound according to claim 11 , wherein one of R 4 and R 5 is optionally substituted C 1 -C 6 alkyl.
14 . A compound according to claim 13 , wherein one of R 4 and R 5 is OR 9 .
15 . A compound according to any one of claims 11 or 13, wherein one of R 6 and R 7 is optionally substituted C 1 -C 6 alkyl.
16 . A compound according to claim, 15 , wherein one of R 6 and R 7 is OR 9 .
17 . A compound according to claim 1 , wherein R 3 and R 8 are each hydrogen; X and Y are each independently O or S; W is NR 13 ; and Z is NR 11 .
18 . A compound according to claim 17 , wherein X and Y are each O.
19 . A compound according to claim 18 , wherein R 2 is selected from the group of hydrogen, halogen, CF 3 , C 1 -C 8 alkyl and C 1 -C 8 haloalkyl.
20 . A compound according to claim 19 , wherein R 2 is CF 3
21 . A compound according to claim 20 , wherein R 13 is selected from the group of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, and C 1 -C 8 haloalkyl.
22 . A compound according to claim 21 , wherein R 13 is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.
23 . A compound according to claim 21 , wherein R 11 is selected from the group of hydrogen, optionally substituted C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl.
24 . A compound according to claim 23 , wherein R 11 is hydrogen or optionally substituted C 1 -C 6 alkyl.
25 . A compound according to claim 24 , wherein R 11 is hydrogen.
26 . A compound according to claim 23 , wherein R 6 and R 7 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, and C 1 -C 8 haloalkyl.
27 . A compound according to claim 26 , wherein R 6 and R 7 are each independently hydrogen or C 1 -C 8 alkyl.
28 . A compound according to claim 27 , wherein R 6 and R 7 are each hydrogen.
29 . A compound according to claim 26 , wherein R 4 and R 5 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, and OR 9 .
30 . A compound according to claim 29 , wherein R 4 and R 5 are each independently hydrogen or C 1 -C 8 alkyl.
31 . A compound according to claim 30 , wherein R 4 and R 5 are each hydrogen.
32 . A compound according to claim 1 , wherein:
R 1 is selected from the group of hydrogen, F, Cl, Br, I, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; R 2 is selected from the group of hydrogen, halogen, CF 3 , C 1 -C 8 alkyl, and C 1 -C 8 haloalkyl; R 3 is selected from the group of hydrogen, C 1 -C 8 alkyl, and C 1 -C 8 haloalkyl; R 4 and R 5 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl and OR 9 ; R 6 and R 7 are each independently hydrogen or C 1 -C 8 alkyl; R 8 is selected from the group of hydrogen, F, Cl, Br, I, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl; R A is selected from the group of hydrogen, F, Cl, Br, I, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; m is 1 or 2; W is selected from the group of O, NH, NR 13 , NC(Y)R 11 , and NSO 2 R 11 ; X and Z are each independently selected from the group of O, S and NR 11 ; and Y is O.
33 . A compound according to claim 32 , wherein:
R 1 , R 3 and R 8 are each hydrogen; R 2 is CF 3 or haloalkyl; R 5 , R 6 , and R 7 each are independently hydrogen or C 1 -C 8 alkyl; m is 1; W is NH or NR 13 ; X and Z are each independently O or NR 11 ; and Y is O.
34 . A compound according to claim 33 , wherein:
R 2 is CF 3 ; R 4 is selected from the group of hydrogen, C 1 -C 4 alkyl, and C 1 -C 2 haloalkyl; R 5 , R 6 , and R 7 are each independently hydrogen; W is NR 13 ; X is O; and Z is NR 11 .
35 . A method for the preparation of compounds of the formula:
wherein:
R 3 is selected from the group of hydrogen, F, Cl, Br, I, OR 9 , S(O) m R 9 , NR 10 R 11 , or C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 1 -C 6 haloalkyl and wherein the alkyl, heteroalkyl and haloalkyl groups are optionally substituted;
R 4 and R 5 are each independently selected from the group of hydrogen, OR 9 , S(O) m R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted, or
R 4 and R 5 taken together can form a three- to seven-membered ring that is optionally substituted;
R 6 and R 7 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted, or
R 6 and R 7 taken together can form a three- to seven-membered ring that is optionally substituted; or
R 6 and R 5 taken together form a three- to seven-membered ring that optionally substituted; or
any two of R 4 through R 7 taken together form a three- to seven-membered ring that is optionally substituted;
R 8 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 and S(O) m R 9 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 9 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionally substituted;
R 10 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl, arylalkyl, SO 2 R 12 and S(O)R 12 and wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionally substituted;
R 11 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionally substituted;
R 12 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl or arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionally substituted;
R 13 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, C 3 -C 8 alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups are optionally substituted;
m is 0, 1, or 2;
that comprises the steps of:
(a) treating either a single enantiomer, diastereomers, or the racemate of a β-aminoalcohol of the formula:
with a 3,4-dihalonitrobenzene of the formula:
where X is fluorine or chlorine, to afford arylamino alcohol 36
(b) treating arylamino alcohol 36 with aldehyde R x (CO)H or the corresponding hydrate or hemiacetal R x HC(OH)(OR), where R is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 1 -C 10 haloalkyl, and R x CH 2 is equivalent to R 13 , to form oxazolidine 37
(c) reducing oxazolidine 37 to form amino alcohol 38
(d) treating amino alcohol 38 with a base to form the 3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39
as either a single enantiomer, diastereomers or the racemate.
36 . A method according to claim 35 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 13 each independently are selected from the group of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
37 . A method according to claim 36 , wherein R 3 , R 6 , R 7 , and R 8 each are hydrogen.
38 . A method according to claim 37 , wherein one of R 4 and R 5 is hydrogen and the other one of R 4 and R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
39 . A method according to claim 38 , wherein R 13 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
40 . A method for the preparation of compounds of the formula:
wherein:
R 3 is selected from the group of hydrogen, F, Cl, Br, I, OR 9 , S(O) m R 9 , NR 10 R 11 , or C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 1 -C 6 haloalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 4 and R 5 are each independently selected from the group of hydrogen, OR 9 , S(O) m R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted, or
R 4 and R 5 taken together can form a three- to seven-membered ring that is optionally substituted;
R 6 and R 7 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted, or
R 6 and R 7 taken together form a three- to seven-membered ring that is optionally substituted; or
any two of R 4 through R 7 taken together can form a three- to seven-membered ring that is optionally substituted; or
R 6 and R 5 taken together form a three- to seven-membered ring that is optionally substituted;
R 8 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 and S(O) m R 9 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 9 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 10 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl, arylalkyl, SO 2 R 12 and S(O)R 12 and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 11 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 12 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 allyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 13 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, C 3 -C 8 alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
m is 0, 1, or 2;
that comprises the steps of:
(a) treating either a single enantiomer, diastereomers, or the racemate of a β-aminoalcohol of the formula:
with a 3,4-dihalonitrobenzene of the formula:
where X is fluorine or chlorine, to afford arylamino alcohol 36
(b) treating arylamino alcohol 36 with aldehyde R x (CO)H or the corresponding hydrate or hemiacetal R x HC(OH)(OR), where R is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 1 -C 10 haloalkyl, and R x CH 2 is equivalent to R 13 , to form oxazolidine 37
(c) reducing oxazolidine 37 to form amino alcohol 38
(d) treating amino alcohol 38 with a base to form the 3,4-dihydro-7-nitro-2H-1,4-benzoxazine compound 39
(e) treating nitro benzoxazine compound 39 with a reducing agent to form amino benzoxazine compound 40:
41 . A method according to claim 40 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 13 are each independently selected from the group of hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
42 . A method according to claim 41 , wherein R 3 , R 6 , R 7 , and R 8 each are hydrogen.
43 . A method according to claim 42 , wherein one of R 4 and R 5 is hydrogen and the other one of R 4 and R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
44 . A method according to claim 43 , wherein R 13 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
45 . A compound according to claim 1 , wherein said compound is selected from the group of:
1,2,3,6-Tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-1,6-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1-Ethyl-1,2,3,6-tetrahydro-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 8-Fluoro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 8-Chloro-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 9-(Difluoromethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-6-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 7-Chloro-2,3-dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, 1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-thione, 1,2,3,6-Tetrahydro-1-propyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-1-isobutyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-1-isobutyl-6-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (−)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-1,3-dimethyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-3-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-3-Ethyl-1,2,3,6-tetrahydro-1-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1-Cyclopropylmethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-1-(pyridylmethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-trans-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-cis-1,2,3,6-Tetrahydro-2,3-dimethyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-trans-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-cis-3-Ethyl-1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-(acetoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (+)-1,2,3,6-Tetrahydro-2-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-2-(Ethoxymethyl)-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-(propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2-Dihydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]quinolin-2,7-dione, (±)-1,2,3,6-Tetrahydro-2-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2-Dihydro-3-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-3H-[1,4]oxazino[3,2-g]-quinolin-2,7-dione 1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-2-thioxo-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1-Cyclopropylmethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-2-Ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1-Cyclopropylmethyl-2-ethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, 1,2,3,6-Tetrahydro-1-isopropyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2-Diethyl-1,2,3,6-tetrahydro-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (+)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (−)-1,2,3,6-Tetrahydro-1-(2,2,2-trifluoroethyl)-2,9-bis(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1-Ethyl-1,2,3,6-tetrahydro-2-methyl-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (2R)-(−)-1,2,3,6-Tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (2R)-2-Ethyl-1,2,3,6-tetrahydro-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (2R)-1,2,3,6-Tetrahydro-2-isopropyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, (±)-1,2,3,4,4a,5-Hexahydro-11-(trifluoromethyl)-pyrido[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-7-one, (R)-2,3,3a,4-Tetrahydro-10-(trifluoromethyl)-pyrrolo[1′,2′:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one, 1,3,4,6-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)-pyrazino[3,2-g]quinolin-2,7-dione, 1,2,3,4-Tetrahydro-1,3,3-trimethyl-9-(trifluoromethyl)-pyrazino[3,2-g]quinolin-7(6H)one, 9-(Trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one, 1-Methyl-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one, 1-(2,2,2-Trifluoroethyl)-9-(trifluoromethyl)-1,2,3,6-tetrahydro-7H-[1,4]thiazino[3,2-g]quinolin-7-one.
46 . A pharmaceutical composition comprising in a pharmaceutically acceptable vehicle suitable for enteral, parenteral, or topical administration, one or more compounds according to any one of claims 1 , 20 , 23 , 26 and 29 .
47 . A compound according to any one of claims 1 , 20 , 23 , 26 and 29 for administration to a mammalian subject to modulate a process mediated by one or more steroid receptors from the group consisting of progesterone receptors, androgen receptors, estrogen receptors, glucorticoid receptors, and mineralocorticoid receptors.
48 . A compound according to any one of claims 1 , 20 , 23 , 26 and 29 for use in modulation of male and female hormone responsive diseases.
49 . A method for the preparation of compounds of the formula:
wherein:
R 1 is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 , S(O) m R 9 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 2 is selected from the group of hydrogen, F, Cl, Br, I, CF 3 , CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) m R 9 , NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 3 is selected from the group of hydrogen, F, Cl, Br, I, OR 9 , S(O) m R 9 , NR 10 R 11 , or C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 1 -C 6 haloalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 4 and R 5 are each independently is selected from the group of hydrogen, OR 9 , S(O) m R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted, or R 4 and R 5 taken together a three- to seven-membered ring that is optionally substituted;
R 6 and R 7 are each independently is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted; or
R 6 and R 7 taken together form a three- to seven-membered ring that is optionally substituted; or
any two of R 4 through R 7 taken together can form a three- to seven-membered ring that is optionally substituted; or
R 6 and R 5 taken together form a three- to seven-membered ring that is optionally substituted;
R 8 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 and S(O) m R 9 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 9 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 10 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl, arylalkyl, SO 2 R 12 and S(O)R 12 and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 11 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 12 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 13 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, C 3 -C 8 alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R A is hydrogen, F, Br, Cl, I, CN, a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, OR 16 , NR 16 R 17 , SR 16 , CH 2 R 16 , COR 17 , CO 2 R 17 , CONR 17 R 17 , SOR 17 or SO 2 R 17 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 16 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl., C 1 -C 8 heteroalkyl, COR 17 , CO 2 R 17 and CONR 17 R 17 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 17 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
m is 0, 1, or 2;
Y is O or S;
Z is selected from the group of O, S(O) m , NH, NR 11 , NC(Y)R 11 , NSO 2 R 12 and NS(O)R 12 ;
that comprises the steps of:
(a) treating either a single enantiomer, diastereomers, or the racemate of a β-aminoalcohol of the formula:
with a 3,4-dihalonitrobenzene of the formula
where X is fluorine or chlorine, to afford arylamino alcohol 36
(b) treating arylamino alcohol 36 with aldehyde R x (CO)H or the corresponding hydrate or hemiacetal R x HC(OH)(OR), where R is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 1 -C 10 haloalkyl, and R x CH 2 is equivalent to R 13 , to form oxazolidine 37
(c) reducing oxazolidine 37 to form amino alcohol 38
and
(d) treating amino alcohol 38 with a base to form the 3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39
(e) treating nitro benzoxazine compound 39 with a reducing agent to form amino benzoxazine compound 40
as either a single enantiomer, diastereomers, or the racemate; and
(f) treating amino benzoxazine compound 40 with a β-ketoester or its corresponding hydrate at elevated temperature to form acetanilide compound; and
(g) treating said acetanilide compound with an acid to yield quinoline compound 41:
50 . A method according to claim 49 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 13 are each independently selected from the group of hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
51 . A method according to claim 49 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each hydrogen.
52 . A method for the preparation of N-(2-haloethyl) arylamino alcohols comprising:
(a) treating either a single enantiomer, diastereomers, or the racemate of an arylamino alcohol of the formula with aldehyde CH n X 3-n COH or the hydrate or hemiacetal CH n X 3-n CH(OH)OR, where X is a halogen, n is 0, 1 or 2, and R is selected from the group of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 1 -C 10 haloalkyl, in the presence of an acid catalyst to form an oxazolidine of the formula: and (b) treating said oxazolidine with a reducing agent, preferably triethylsilane or sodium cyanoborohydride, in the presence of a Lewis acid or a Bronsted acid as a catalyst to form a product of the formula: wherein
R 4-7 are each independently selected from the group of hydrogen C 1 -C 8 alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl, and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted; and
Ar is aryl or heteroaryl, optionally substituted at one or more positions; as either a single enantiomer, diastereomers, or the racemate.
53 . A method for the preparation of compounds of the formula
wherein:
R 1 is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 , S(O) m R 9 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally;
R 2 is selected from the group of hydrogen, F, Cl, Br, I, CF 3 , CF 2 H, CFH 2 , CF 2 OR 9 , CH 2 OR 9 , OR 9 , S(O) m R 9 , NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups are optionally substituted;
R 3 is selected from the group of hydrogen, F, Cl, Br, I, OR 9 , S(O) m R 9 , NR 10 R 11 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 1 -C 6 haloalkyl;
R 4 and R 5 are each independently selected from the group of hydrogen, OR 9 , S(O) m R 9 , NR 10 R 11 , C(Y)OR 11 , C(Y)NR 10 R 11 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted, or
R 4 and R 5 taken together form a three- to seven-membered ring that is optionally substituted;
R 6 and R 7 are each independently selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8 alkynyl, and C 2 -C 8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted; or
R 6 and R 7 taken together form a three- to seven-membered ring that is optionally substituted; or
any two of R 4 through R 7 taken together can form a three- to seven-membered ring that is optionally substituted;
R 6 and R 5 taken together form a three- to seven-membered ring that is optionally substituted;
R 8 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, F, Cl, Br, I, NO 2 , OR 9 , NR 10 R 11 and S(O) m R 9 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 9 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 10 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl, arylalkyl, SO 2 R 12 and S(O)R 12 and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 11 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 12 is selected from the group of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 6 alkenyl and arylalkyl and wherein the alkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and alkenyl groups are optionally substituted;
R 13 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 haloalkyl, aryl, heteroaryl, C 3 -C 8 alkenyl, arylalkyl and heteroarylalkyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, arylalkyl and alkenyl groups are optionally substituted;
R A is selected from the group of hydrogen, F, Br, Cl, I, CN, a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, OR 16 , NR 16 R 17 , SR 16 , CH 2 R 16 , COR 17 , CO 2 R 17 , CONR 17 R 17 , SOR 17 and SO 2 R 17 and wherein the alkyl, haloalkyl and heteroalkyl are optionally substituted;
R 16 is selected from the group of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, COR 17 , CO 2 R 17 and CONR 17 R 17 and wherein the alkyl, heteroalkyl, and haloalkyl groups are optionally substituted;
R 17 is selected from the group of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 heteroalkyl and wherein the alkyl, haloalkyl and heteroalkyl groups are optionally substituted;
m is 0, 1, or 2;
Y is O or S;
Z is selected from the group of O, S(O) m , NH, NR 11 , NC(Y)R 11 , NSO 2 R 12 or NS(O)R 12 ;
that comprises the steps of:
(a) treating either a single enantiomer, diastereomers, or the racemate of a secondary aminoalcohol of the formula
with a 3,4-dihalonitrobenzene of the formula
where X is fluorine or chlorine, to afford tertiary aminoalcohol 42
(b) treating tertiary aminoalcohol 42 with a base to form the 3,4-dihydro-7-nitro-2H-1,4-benzoxazine intermediate 39
as either a single enantiomer, diastereomers, or the racemate.Join the waitlist — get patent alerts
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