U.S. patent application number 13/046529 was filed with the patent office on 2011-07-07 for fused ring azadecalin glucocorticoid receptor modulators.
This patent application is currently assigned to Corcept Therapeutics, Inc.. Invention is credited to Paul M. Blaney, Robin D. Clark, Christopher A. Hurley, Nicholas C. Ray, Karen Williams.
Application Number | 20110166110 13/046529 |
Document ID | / |
Family ID | 34961932 |
Filed Date | 2011-07-07 |
United States Patent
Application |
20110166110 |
Kind Code |
A1 |
Clark; Robin D. ; et
al. |
July 7, 2011 |
Fused Ring Azadecalin Glucocorticoid Receptor Modulators
Abstract
The present invention provides a novel class of fused ring
azadecalin compounds and methods of using the compounds as
glucocorticoid receptor modulators.
Inventors: |
Clark; Robin D.; (Lawai,
HI) ; Ray; Nicholas C.; (Harlow, GB) ; Blaney;
Paul M.; (Harlow, GB) ; Hurley; Christopher A.;
(Harlow, GB) ; Williams; Karen; (Harlow,
GB) |
Assignee: |
Corcept Therapeutics, Inc.
Menlo Park
CA
|
Family ID: |
34961932 |
Appl. No.: |
13/046529 |
Filed: |
March 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10591884 |
May 7, 2007 |
7928237 |
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PCT/US05/08049 |
Mar 9, 2005 |
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13046529 |
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60551836 |
Mar 9, 2004 |
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Current U.S.
Class: |
514/158 ;
514/210.21; 514/230.5; 514/232.8; 514/253.03; 514/267; 514/293 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
9/04 20180101; A61P 37/08 20180101; A61P 9/06 20180101; A61P 25/36
20180101; A61P 5/42 20180101; A61P 19/00 20180101; A61P 25/00
20180101; A61P 25/16 20180101; A61P 25/22 20180101; A61P 25/24
20180101; A61P 9/12 20180101; A61P 43/00 20180101; A61P 3/12
20180101; A61P 17/02 20180101; A61P 27/16 20180101; A61P 31/00
20180101; A61P 5/46 20180101; A61P 9/00 20180101; C07D 471/04
20130101; A61P 29/00 20180101; A61P 37/00 20180101; A61P 3/10
20180101; A61P 13/12 20180101; A61P 25/06 20180101; A61P 25/28
20180101; A61P 19/02 20180101; A61P 27/06 20180101; A61P 31/12
20180101 |
Class at
Publication: |
514/158 ;
514/293; 514/232.8; 514/230.5; 514/210.21; 514/253.03; 514/267 |
International
Class: |
A61K 31/655 20060101
A61K031/655; A61K 31/437 20060101 A61K031/437; A61K 31/5377
20060101 A61K031/5377; A61K 31/538 20060101 A61K031/538; A61K
31/397 20060101 A61K031/397; A61K 31/496 20060101 A61K031/496; A61K
31/519 20060101 A61K031/519; A61P 25/00 20060101 A61P025/00; A61P
31/00 20060101 A61P031/00; A61P 27/06 20060101 A61P027/06; A61P
29/00 20060101 A61P029/00; A61P 19/00 20060101 A61P019/00; A61P
37/08 20060101 A61P037/08 |
Claims
1. A compound having the formula: ##STR00386## wherein, L.sup.1 and
L.sup.2 are members independently selected from a bond, --O--,
--S--, S(O)--, --S(O.sub.2)--, --C(O)--, --C(O)O--, --C(O)NH--,
substituted or unsubstituted alkylene, and substituted or
unsubstituted heteroalkylene; the dashed line b is optionally a
bond; the ring A is a member selected from substituted or
unsubstituted 5 to 6 membered heterocycloalkyl, and substituted or
unsubstituted heteroaryl; R.sup.1 is a member selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.1A, --NR.sup.1CR.sup.1D, --C(O)NR.sup.1CR.sup.1D,
--C(O)OR.sup.1A, wherein R.sup.1A is a member selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R.sup.1C and R.sup.1D are members independently selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl, wherein R.sup.1C
and R.sup.1D are optionally joined to form a substituted or
unsubstituted ring with the nitrogen to which they are attached,
wherein said ring optionally comprises an additional ring nitrogen,
and R.sup.2 is a member selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --S(O.sub.2)R.sup.2A,
--S(O.sub.2)NR.sup.2BR.sup.2C, and .dbd.NOR.sup.2D, wherein
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are members
independently selected from substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
2. The compound of claim 1, wherein A is a member selected from:
unsubstituted 5 to 6 membered heterocycloalkyl comprising at least
one heteroatom selected from N, O and S; substituted 5 to 6
membered heterocycloalkyl comprising 1 to 3 substituents and at
least one ring heteroatom selected from N, O and S; unsubstituted
aryl comprising at least one heteroatom selected from N, O and S;
and substituted aryl comprising 1 to 3 substituents and at least
one ring heteroatom selected from N, O and S.
3. The compound of claim 1, wherein A is a member selected from
substituted or unsubstituted pyrrolidinyl, substituted or
unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl,
substituted or unsubstituted imidazolyl, substituted or
unsubstituted furanyl, substituted or unsubstituted oxazolyl,
substituted or unsubstituted isoxazolyl, substituted or
unsubstituted thienyl, substituted or unsubstituted thiazolyl,
substituted or unsubstituted isothiazolyl, substituted or
unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl,
and substituted or unsubstituted pyrazinyl.
4. The compound of claim 1, wherein A is a substituted or
unsubstituted pyrazolyl.
5. The compound of claim 1, wherein A is substituted with a member
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aryl, --NR.sup.3AR.sup.3B, and --OR.sup.3C, wherein
R.sup.3A and R.sup.3B are members independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted
heterocycloalkyl, and substituted or unsubstituted heteroaryl,
wherein R.sup.3A and R.sup.3B are optionally joined to form a
substituted or unsubstituted ring with the nitrogen to which they
are attached, wherein said ring optionally comprises an additional
ring heteroatom, and R.sup.3C is a member selected from substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
6. The compound of claim 5, wherein A is substituted with a member
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
7. The compound of claim 1 having the formula ##STR00387## wherein,
the dashed ring represents unsaturated, partially saturated, or
fully saturated bonds within ring E; Z.sup.1 is a member selected
from --NR.sup.5--, .dbd.N--, --O--, and --S--, wherein R.sup.5 is a
member selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted heteroaryl, and
substituted or unsubstituted aryl; Z.sup.2 is a member selected
from --CR.sup.6AR.sup.6B--, .dbd.CR.sup.6A--, --C(O)--,
--NR.sup.6C--, .dbd.N--, --O--, --CR.sup.6AR.sup.6B--NR.sup.6C--,
.dbd.CR.sup.6A--NR.sup.6C--, --CR.sup.6AR.sup.6B--N.dbd., and
.dbd.CR.sup.6A--N.dbd., wherein R.sup.6C is a member selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl,
R.sup.6A and R.sup.6B are members independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryl,
--NR.sup.6A1R.sup.6A2, and --OR.sup.6A3, wherein R.sup.6A1 and
R.sup.6A2 are members independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl, wherein
R.sup.6A1 and R.sup.6A2 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached,
wherein said ring optionally comprises an additional ring
heteroatom, and R.sup.6A3 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl, wherein R.sup.6A and
R.sup.6C are optionally joined together to form a substituted or
unsubstituted ring, wherein said ring optionally comprises an
additional ring heteroatom; Z.sup.3 is a member selected from
--CR.sup.7AR.sup.7B--, .dbd.CR.sup.7A--, --C(O)--, --NR.sup.7C--,
.dbd.N--, --O--, and --S--, wherein R.sup.7C is a member selected
from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroaryl, and substituted or unsubstituted aryl,
R.sup.7A and R.sup.7B are independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aryl,
--NR.sup.7A1R.sup.7A2, and --OR.sup.7A3, wherein R.sup.7A1 and
R.sup.7A2 are members independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl, wherein
R.sup.7A1 and R.sup.7A2 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached,
wherein said ring optionally comprises an additional ring
heteroatom, and R.sup.7A3 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl; wherein R.sup.5 is
optionally joined with R.sup.6A or R.sup.6C to form a substituted
or unsubstituted ring, wherein said ring optionally comprises an
additional ring heteroatom; wherein R.sup.7A is optionally joined
with R.sup.6A or R.sup.6C to form a substituted or unsubstituted
ring, wherein said ring optionally comprises an additional ring
heteroatom; and wherein R.sup.7C is optionally joined with R.sup.6A
or R.sup.6C to form a substituted or unsubstituted ring, wherein
said ring optionally comprises an additional ring heteroatom.
8. The compound of claim 7, wherein Z.sup.1 is --NR.sup.5--;
Z.sup.2 is .dbd.N--; and Z.sup.3 is .dbd.CR.sup.7A--.
9. The compound of claim 8, wherein R.sup.7A is hydrogen; and
R.sup.5 is a member selected from hydrogensubstituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl and substituted or
unsubstituted heteroarylalkyl.
10. The compound of claim 7, wherein R.sup.5 has the formula:
##STR00388## wherein, R.sup.5A is a member selected from hydrogen,
halogen, --OR.sup.5A1, --NR.sup.5A2R.sup.5A3,
--S(O.sub.2)NR.sup.5A2R.sup.5A3, --CN, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl, wherein R.sup.5A1 is a
member selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl, and R.sup.5A2 and
R.sup.5A3 are members independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl; m is an integer
from 0 to 10; and n is an integer from 1 to 5.
11. The compound of claim 10, wherein n is 1; m is 0 or 1; and
R.sup.5A1, R.sup.5A2 and R.sup.5A3 are hydrogen.
12. The compound of claim 7, wherein Z.sup.1 is --NR.sup.5--;
Z.sup.2 is .dbd.CR.sup.6A--; and Z.sup.3 is .dbd.N--.
13. The compound of claim 12, wherein R.sup.5 is a member selected
from hydrogen and substituted or unsubstituted aryl.
14. The compound of claim 8, wherein R.sup.5 and R.sup.7A are
hydrogen and b is a bond.
15. The compound of claim 1, wherein R.sup.1 is a member selected
from substituted or unsubstituted (C.sub.1-C.sub.10) alkyl,
substituted or unsubstituted 2-10 membered heteroalkyl, substituted
or unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
16. The compound of claim 1, wherein R.sup.1 has the formula:
##STR00389## wherein, q is an integer selected from 1 to 5;
R.sup.1B is a member selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --NR.sup.1B1R.sup.1B2,
--OR.sup.1B3, and --C(O)NR.sup.1B4R.sup.1B5 wherein R.sup.1B1 and
R.sup.1B2 are members independently selected from hydrogen,
substituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted heterocycloalkyl, and substituted or
unsubstituted heteroaryl, wherein R.sup.1B1 and R.sup.1B2 are
optionally joined to form a substituted or unsubstituted ring with
the nitrogen to which they are attached, wherein said ring
optionally comprises an additional ring heteroatom, and R.sup.1B3
is a member selected from hydrogen, substituted or unsubstituted
heteroalkyl comprising a nitrogen, substituted or unsubstituted
heterocycloalkyl comprising a ring nitrogen, substituted or
unsubstituted heteroaryl comprising a ring nitrogen, and alkyl
substituted with a substituted or unsubstituted heteroalkyl
comprising a nitrogen, substituted or unsubstituted
heterocycloalkyl comprising a ring nitrogen, and substituted or
unsubstituted heteroaryl comprising a ring nitrogen; and R.sup.1B4
and R.sup.1B5 are members independently selected from hydrogen,
substituted or unsubstituted heteroalkyl comprising a nitrogen,
substituted or unsubstituted heterocycloalkyl comprising a ring
nitrogen, substituted or unsubstituted heteroaryl comprising a ring
nitrogen, and alkyl substituted with a substituted or unsubstituted
heteroalkyl comprising a nitrogen, substituted or unsubstituted
heterocycloalkyl comprising a ring nitrogen, and substituted or
unsubstituted heteroaryl comprising a ring nitrogen, wherein
R.sup.1B4 and R.sup.1B5 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached,
wherein said ring optionally comprises a heteroatom.
17. The compound of claim 16, wherein q is an integer selected from
1 to 3; R.sup.1B is a member selected from hydrogen, substituted
alkyl, substituted or unsubstituted heteroalkyl, substituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted aryl, and substituted or unsubstituted heteroaryl.
18. The compound of claim 16, wherein R.sup.1 has the formula:
##STR00390## wherein, R.sup.1B is a member selected from hydrogen,
--NR.sup.1B1R.sup.1B2, --OR.sup.1B3, substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7)cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
19. The compound of claim 16, wherein R.sup.1B is a member selected
from --C(O)NR.sup.1B4R.sup.1B5 and substituted or unsubstituted
heteroaryl comprising a ring nitrogen, wherein R.sup.1B4 and
R.sup.1B5 are members independently selected from hydrogen,
substituted or unsubstituted heteroalkyl comprising a nitrogen,
substituted or unsubstituted heterocycloalkyl comprising a ring
nitrogen, substituted or unsubstituted heteroaryl comprising a ring
nitrogen, and alkyl substituted with a substituted or unsubstituted
heteroalkyl comprising a nitrogen, substituted or unsubstituted
heterocycloalkyl comprising a ring nitrogen, and substituted or
unsubstituted heteroaryl comprising a ring nitrogen, wherein
R.sup.1B4 and R.sup.1B5 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached,
wherein said ring optionally comprises a heteroatom.
20. The compound of claim 19, wherein R.sup.1B1, R.sup.1B2,
R.sup.1B3, R.sup.1B4 and R.sup.1B5 are members independently
selected from hydrogen and a substituted or unsubstituted ring,
wherein said ring optionally comprises a nitrogen atom and at least
one additional ring heteroatom.
21. The compound of claim 1, wherein R.sup.2 is a member selected
from substituted or unsubstituted (C.sub.1-C.sub.10) alkyl,
substituted or unsubstituted 2-10 membered heteroalkyl, substituted
or unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
22. The compound of claim 1, R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are members independently selected from substituted or
unsubstituted (C.sub.1-C.sub.10) alkyl, substituted or
unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
23. The compound of claim 1, R.sup.2 has the formula: ##STR00391##
wherein, R.sup.2G is a member selected from hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl; J is a
substituted or unsubstituted ring selected from substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl; t
is an integer from 0 to 5; and X is a member selected from a bond,
--S(O.sub.2)--, and --S(O.sub.2)N.sup.2I--, wherein R.sup.2I is a
member selected from hydrogen, substituted or unsubstituted alkyl,
and substituted or unsubstituted heteroalkyl.
24. The compound of claim 23, wherein R.sup.2G is a member selected
from hydrogen, substituted or unsubstituted (C.sub.1-C.sub.10)
alkyl, substituted or unsubstituted 2-10 membered heteroalkyl,
substituted or unsubstituted (C.sub.3-C.sub.7)cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl; J is a substituted or unsubstituted ring selected from
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl; t is 1; and R.sup.2I is hydrogen.
25. The compound of claim 23, wherein R.sup.2G is a branched or
unbranched (C.sub.1-C.sub.10)alkyl.
26. The compound of claim 23, wherein X is --S(O.sub.2)--.
27. The compound of claim 1, wherein L.sup.1 and L.sup.2 are
members independently selected from a bond and unsubstituted
(C.sub.1-C.sub.6) alkylene.
28. The compound of claim 1, wherein the dashed line b is a bond;
R.sup.1 is substituted or unsubstituted benzyl; and R.sup.2 has the
formula: ##STR00392## wherein, R.sup.2G is a member selected from
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl, J is a substituted or unsubstituted ring selected from
substituted or unsubstituted (C.sub.3-C.sub.7) cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl, t is an integer fro 0 to 5, and X is --S(O.sub.2)--;
L.sup.1 is a bond; and L.sup.2 is a bond.
29. A method of treating a disorder or condition through modulating
a glucocorticoid receptor, the method comprising administering to a
subject in need of such treatment, an effective amount of the
compound of one of claims 1-28.
30. A method of treating a disorder or condition through
antagonizing a glucocorticoid receptor, the method comprising
administering to a subject in need of such treatment, an effective
amount of the compound of one of claims 1-28.
31. A method of modulating a glucocorticoid receptor including the
steps of contacting a glucocorticoid receptor with an effective
amount of the compound of one of claims 1-28 and detecting a change
in the activity of the glucocorticoid receptor.
32. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and the compound of one of claims 1-28.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/591,884, filed May 7, 2007, which is the U.S. National
Stage entry under .sctn.371 of PCT/US2005/008049, filed Mar. 9,
2005, which claims the benefit of U.S. Provisional Patent
Application No. 60/551,836, filed Mar. 9, 2004, the contents of
which are incorporated herein by reference in their entirety for
all purposes.
BACKGROUND OF THE INVENTION
[0002] In most species, including man, the physiological
glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are
secreted in response to ACTH (corticotropin), which shows both
circadian rhythm variation and elevations in response to stress and
food. Cortisol levels are responsive within minutes to many
physical and psychological stresses, including trauma, surgery,
exercise, anxiety and depression. Cortisol is a steroid and acts by
binding to an intracellular, glucocorticoid receptor (GR). In man,
glucocorticoid receptors are present in two forms: a ligand-binding
GR-alpha of 777 amino acids; and, a GR-beta isoform which differs
in only the last fifteen amino acids. The two types of GR have high
affinity for their specific ligands, and are considered to function
through the same transduction pathways.
[0003] The biologic effects of cortisol, including those caused by
hypercortisolemia, can be modulated at the GR level using receptor
modulators, such as agonists, partial agonists and antagonists.
Several different classes of agents are able to block the
physiologic effects of GR-agonist binding. These antagonists
include compositions which, by binding to GR, block the ability of
an agonist to effectively bind to and/or activate the GR. One such
known GR antagonist, mifepristone, has been found to be an
effective anti-glucocorticoid agent in humans (Bertagna (1984) J.
Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with
high affinity, with a dissociation constant (K.sub.d) of 10.sup.-9
M (Cadepond (1997) Annu. Rev. Med. 48:129).
[0004] Patients with some forms of psychiatric illnesses have been
found to have increased levels of cortisol (Krishnan (1992) Prog.
Neuro-Psychopharmacol. & Biol. Psychiat. 16:913-920). For
example, some depressed individuals can be responsive to treatments
which block the effect of cortisol, as by administering GR
antagonists (Van Look (1995) Human Reproduction Update 1:19-34). In
one study, a patient with depression secondary to Cushing's
Syndrome (hyperadrenocorticism) was responsive to a high dose, up
to 1400 mg per day, of GR antagonist mifepristone (Nieman (1985) J.
Clin Endocrinol. Metab. 61:536). Another study which used
mifepristone to treat Cushing's syndrome found that it improved the
patients' conditions, including their psychiatric status (Chrousos,
pp 273-284, In: Baulieu, ed. The Antiprogestin Steroid RU 486 and
Human Fertility Control. Plenum Press, New York (1989), Sartor
(1996) Clin. Obstetrics and Gynecol. 39:506-510).
[0005] Psychosis has also been associated with Cushing's syndrome
(Gerson (1985) Can. J. Psychiatry 30:223-224; Saad (1984) Am. J.
Med. 76:759-766). Mifepristone has been used to treat acute
psychiatric disturbances secondary to Cushing's syndrome. One study
showed that a relatively high dose of mifepristone (400 to 800 mg
per day) was useful in rapidly reversing acute psychosis in
patients with severe Cushing Syndrome due to adrenal cancers and
ectopic secretion of ACTH from lung cancer (Van der Lely (1991)
Ann. Intern. Med. 114:143; Van der Lely (1993) Pharmacy World &
Science 15:89-90; Sartor (1996) supra).
[0006] A treatment for psychosis or the psychotic component of
illnesses, such as psychotic major depression, has recently been
discovered (Schatzberg et al., U.S. Pat. No. 6,150,349). The
treatment includes administration of an amount of a glucocorticoid
receptor antagonist effective to ameliorate the psychosis. The
psychosis may also be associated with psychotic major depression,
Alzheimer's Disease and cocaine addiction.
[0007] Thus, there exists a great need for a more effective and
safer treatment for illnesses and conditions associated with the
glucocorticoid receptors, including psychotic major depression. The
present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
[0008] In a first aspect, the present invention provides a compound
having the formula:
##STR00001##
[0009] In Formula (I), L.sup.1 and L.sup.2 are independently
selected from a bond, --O--, --S--, S(O)--, --S(O.sub.2)--,
--C(O)--, --C(O)O--, --C(O)NH--, substituted or unsubstituted
alkylene, and substituted or unsubstituted heteroalkylene.
[0010] The dashed line b is optionally a bond.
[0011] The ring A is selected from substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl.
[0012] R.sup.1 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.1A,
C(O)NR.sup.1CR.sup.1D, C(O)OR.sup.1A. R.sup.1A is selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
R.sup.1C and R.sup.1D are selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. Alternatively R.sup.1C
and R.sup.1D may be joined together with the nitrogen atom to which
they are attached to form a substituted or unsubstituted ring
optionally containing a second heteroatom selected from O, N or
S.
[0013] R.sup.2 is selected from substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --S(O.sub.2)R.sup.2A,
--S(O.sub.2)NR.sup.2BR.sup.2C, .dbd.NOR.sup.2D. R.sup.2A, R.sup.2B,
R.sup.2C, and R.sup.2D are independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0014] In another aspect, the present invention provides methods of
treating a disorder or condition through modulating a
glucocorticoid receptor. The method includes administering to a
subject in need of such treatment, an effective amount of the
compound of the present invention.
[0015] In another aspect, the present invention provides methods of
treating a disorder or condition through antagonizing a
glucocorticoid receptor. The method includes administering to a
subject in need of such treatment, an effective amount of the
compound of the present invention.
[0016] In another aspect, the present invention provides methods of
modulating a glucocorticoid receptor including the steps of
contacting a glucocorticoid receptor with an effective amount of
the compound of the present invention and detecting a change in the
activity of the glucocorticoid receptor.
[0017] In another aspect, the present invention provides a
pharmaceutical composition including a pharmaceutically acceptable
excipient and the compound of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0018] The abbreviations used herein have their conventional
meaning within the chemical and biological arts.
[0019] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is equivalent to --OCH.sub.2--.
[0020] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight (i.e.
unbranched) or branched chain, or cyclic hydrocarbon radical, or
combination thereof, which may be fully saturated, mono- or
polyunsaturated and can include di- and multivalent radicals,
having the number of carbon atoms designated (i.e. C.sub.1-C.sub.10
means one to ten carbons). Examples of saturated hydrocarbon
radicals include, but are not limited to, groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,
cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and
isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and
the like. An unsaturated alkyl group is one having one or more
double bonds or triple bonds. Examples of unsaturated alkyl groups
include, but are not limited to, vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
higher homologs and isomers. Alkyl groups which are limited to
hydrocarbon groups are termed "homoalkyl".
[0021] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and further includes those
groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having five or fewer
carbon atoms.
[0022] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0023] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of the stated number of carbon atoms and at
least one heteroatom selected from the group consisting of O, N, P,
Si and S, and wherein the nitrogen and sulfur atoms may optionally
be oxidized and the nitrogen heteroatom may optionally be
quaternized. The heteroatom(s) O, N, P and S and Si may be placed
at any interior position of the heteroalkyl group or at the
position at which the alkyl group is attached to the remainder of
the molecule. Examples include, but are not limited to,
--CH.sub.2--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH--CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, O--CH.sub.3,
--O--CH.sub.2--CH.sub.3, and --CN. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3. Similarly, the term
"heteroalkylene" by itself or as part of another substituent means
a divalent radical derived from heteroalkyl, as exemplified, but
not limited by, --CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and
--R'C(O).sub.2--. As described above, heteroalkyl groups, as used
herein, include those groups that are attached to the remainder of
the molecule through a heteroatom, such as --C(O)R', --C(O)NR',
--NR'R'', --OR', --SR', and/or --S(O.sub.2)R'. Where "heteroalkyl"
is recited, followed by recitations of specific heteroalkyl groups,
such as --NR'R'' or the like, it will be understood that the terms
heteroalkyl and --NR'R'' are not redundant or mutually exclusive.
Rather, the specific heteroalkyl groups are recited to add clarity.
Thus, the term "heteroalkyl" should not be interpreted herein as
excluding specific heteroalkyl groups, such as --NR'R'' or the
like.
[0024] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-(1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0025] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0026] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon substituent which can be a
single ring or multiple rings (preferably from 1 to 3 rings) which
are fused together or linked covalently. The term "heteroaryl"
refers to aryl groups (or rings) that contain from one to four
heteroatoms selected from N, O, and S, wherein the nitrogen and
sulfur atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule through a carbon or heteroatom.
Non-limiting examples of aryl and heteroaryl groups include phenyl,
1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,
2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substituents
described below.
[0027] For brevity, the term "aryl" when used in combination with
other tell is (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl
group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like). Likewise, the term
"heteroarylalkyl" is meant to include those radicals in which a
heteroaryl group is attached to an alkyl group.
[0028] The term "oxo" as used herein means an oxygen that is double
bonded to a carbon atom.
[0029] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl" and "heteroaryl") are meant to include both substituted and
unsubstituted forms of the indicated radical. Examples of
substituents for each type of radical are provided below.
[0030] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one
or more of a variety of groups selected from, but not limited to:
--OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR(SO.sub.2)R, --CN and --NO.sub.2 in a
number ranging from zero to (2m'+1), where m' is the total number
of carbon atoms in such radical. R', R'', R''' and R'''' each
preferably independently refer to hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),
substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or
arylalkyl groups. When a compound of the invention includes more
than one R group, for example, each of the R groups is
independently selected as are each R', R'', R''' and R'''' groups
when more than one of these groups is present. When R' and R'' are
attached to the same nitrogen atom, they can be combined with the
nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For
example, --NR'R'' is meant to include, but not be limited to,
1-pyrrolidinyl and 4-morpholinyl. From the above discussion of
substituents, one of skill in the art will understand that the term
"alkyl" is meant to include groups including carbon atoms bound to
groups other than hydrogen groups, such as haloalkyl (e.g.,
--CF.sub.3 and --CH.sub.2CF.sub.3) and acyl (e.g., --C(O)CH.sub.3,
--C(O)CF.sub.3, --C(O)CH.sub.2OCH.sub.3, and the like).
[0031] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are varied and are
selected from, for example: halogen, --OR', --NR'R'', --SR',
-halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R',
--CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR(SO.sub.2)R', --CN and --NO.sub.2, --R',
--N.sub.3, --CH(Ph).sub.2, fluoro(C.sub.j--C.sub.4)alkoxy, and
fluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to the
total number of open valences on the aromatic ring system; and
where R', R'', R''' and R'''' are preferably independently selected
from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
When a compound of the invention includes more than one R group,
for example, each of the R groups is independently selected as are
each R', R'', R''' and R'''' groups when more than one of these
groups is present.
[0032] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally form a ring of the formula
-T-C(O)--(CRR').sub.q--U--, wherein T and U are independently
--NR--, --O--, --CRR'-- or a single bond, and q is an integer of
from 0 to 3. Alternatively, two of the substituents on adjacent
atoms of the aryl or heteroaryl ring may optionally be replaced
with a substituent of the formula -A-(CH.sub.2).sub.r--B--, wherein
A and B are independently --CRR'--, --O--, --NR--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r is an
integer of from 1 to 4. One of the single bonds of the new ring so
formed may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula --(CRR').sub.s--X'--(C''R''').sub.d--,
where s and d are independently integers of from 0 to 3, and X' is
--O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--, or
--S(O).sub.2NR'--. The substituents R, R', R'' and R''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0033] As used herein, the term "heteroatom" or "ring heteroatom"
is meant to include oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), and silicon (Si).
[0034] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds which are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds of the present invention contain
relatively basic functionalities, acid addition salts can be
obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired acid, either neat or in a suitable
inert solvent. Examples of pharmaceutically acceptable acid
addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0035] Where two substituents are "optionally joined together to
form a ring," the two substituents are covalently bonded together
with the atom or atoms to which the two substituents are joined to
form a substituted or unsubstituted aryl, a substituted or
unsubstituted heteroaryl, a substituted or unsubstituted
cycloalkyl, or a substituted or unsubstituted heterocycloalkyl
ring.
[0036] The term "cortisol" refers to a family of compositions also
referred to as hydrocortisone, and any synthetic or natural
analogues thereof.
[0037] The term "glucocorticoid receptor" ("GR") refers to a family
of intracellular receptors also referred to as the cortisol
receptor, which specifically bind to cortisol and/or cortisol
analogs (e.g. dexamethasone). The term includes isoforms of GR,
recombinant GR and mutated GR.
[0038] The term "glucocorticoid receptor antagonist" refers to any
composition or compound which partially or completely inhibits
(antagonizes) the binding of a glucocorticoid receptor (GR)
agonist, such as cortisol, or cortisol analogs, synthetic or
natural, to a GR. A "specific glucocorticoid receptor antagonist"
refers to any composition or compound which inhibits any biological
response associated with the binding of a GR to an agonist. By
"specific," we intend the drug to preferentially bind to the GR
rather than another nuclear receptors, such as mineralocorticoid
receptor (MR) or progesterone receptor (PR).
[0039] "Fused ring azadecalin," as used herein, means a
glucocorticoid receptor modulator as described by any of the
Formulae (I)-(XI) below. A fused ring azadecalin compound may also
be referred to herein as a "copound of the present invention."
[0040] The term "treating" refers to any indicia of success in the
treatment or amelioration of an injury, pathology or condition,
including any objective or subjective parameter such as abatement;
remission; diminishing of symptoms or making the injury, pathology
or condition more tolerable to the patient; slowing in the rate of
degeneration or decline; making the final point of degeneration
less debilitating; improving a patient's physical or mental
well-being. The treatment or amelioration of symptoms can be based
on objective or subjective parameters; including the results of a
physical examination, neuropsychiatric exams, and/or a psychiatric
evaluation. For example, the methods of the invention successfully
treat a patient's delirium by decreasing the incidence of
disturbances in consciousness or cognition.
[0041] An "additional ring heteroatom" refers to a heteroatom that
foils part of a substituted or unsubstituted ring (e.g., a
heterocycloalkyl or heteroaryl) that is not the point of attachment
of the ring toward the azadecalin core. The azadecalin core is the
fused ring portion of the compound of Formula (I), excluding ring
A.
[0042] A "substituent group," as used herein, means a group
selected from the following moieties: [0043] (A) --OH, --NH.sub.2,
--SH, --CN, --CF.sub.3, --COOH, --C(O)NH.sub.2, oxo, halogen,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,
unsubstituted heteroaryl, and [0044] (B) alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted
with at least one substituent selected from: [0045] (i) oxo, --OH,
--NH.sub.2, --SH, --CN, --CF.sub.3, --COOH, --C(O)NH.sub.2,
halogen, unsubstituted alkyl, unsubstituted heteroalkyl,
unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,
unsubstituted aryl, unsubstituted heteroaryl, and [0046] (ii)
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, substituted with at least one substituent selected
from: [0047] (a) oxo, --OH, --NH.sub.2, --SH, --CN, --CF.sub.3,
--COOH, --C(O)NH.sub.2, halogen, unsubstituted alkyl, unsubstituted
heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
[0048] (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl, substituted with at least one substituent selected
from oxo, --OH, --NH.sub.2, --SH, --CN, --CF.sub.3, halogen,
unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and
unsubstituted heteroaryl.
[0049] A "size-limited substituent" or "size-limited substituent
group," as used herein means a "substituent group" as defined
above, wherein each substituted or unsubstituted alkyl is a
substituted or unsubstituted C.sub.1-C.sub.20 alkyl, each
substituted or unsubstituted heteroalkyl is a substituted or
unsubstituted 2 to 20 membered heteroalkyl, each substituted or
unsubstituted cycloalkyl is a substituted or unsubstituted
C.sub.4-C.sub.8 cycloalkyl, and each substituted or unsubstituted
heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered
heterocycloalkyl.
[0050] A "lower substituent" or "lower substituent group," as used
herein means a "substituent group" as defined above, wherein each
substituted or unsubstituted alkyl is a substituted or
unsubstituted C.sub.1-C.sub.8 alkyl, each substituted or
unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8
membered heteroalkyl, each substituted or unsubstituted cycloalkyl
is a substituted or unsubstituted C.sub.5-C.sub.7 cycloalkyl, and
each substituted or unsubstituted heterocycloalkyl is a substituted
or unsubstituted 5 to 7 membered heterocycloalkyl.
[0051] The compounds of the present invention may exist as salts.
The present invention includes such salts. Examples of applicable
salt forms include hydrochlorides, hydrobromides, sulfates,
methanesulfonates, nitrates, maleates, acetates, citrates,
fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures
thereof including racemic mixtures, succinates, benzoates and salts
with amino acids such as glutamic acid. These salts may be prepared
by methods known to those skilled in art. Also included are base
addition salts such as sodium, potassium, calcium, ammonium,
organic amino, or magnesium salt, or a similar salt. When compounds
of the present invention contain relatively basic functionalities,
acid addition salts can be obtained by contacting the neutral form
of such compounds with a sufficient amount of the desired acid,
either neat or in a suitable inert solvent. Examples of acceptable
acid addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived organic acids like acetic, propionic,
isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric,
lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic,
citric, tartaric, methanesulfonic, and the like. Also included are
salts of amino acids such as arginate and the like, and salts of
organic acids like glucuronic or galactunoric acids and the like.
Certain specific compounds of the present invention contain both
basic and acidic functionalities that allow the compounds to be
converted into either base or acid addition salts.
[0052] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0053] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention.
[0054] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
enantiomers, racemates, diastereomers, tautomers, geometric
isomers, stereoisometric forms that may be defined, in terms of
absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for
amino acids, and individual isomers are encompassed within the
scope of the present invention. The compounds of the present
invention do not include those which are known in art to be too
unstable to synthesize and/or isolate. The present invention is
meant to include compounds in racemic and optically pure forms.
Optically active (R)- and (S)-, or (D)- and (L)-isomers may be
prepared using chiral synthons or chiral reagents, or resolved
using conventional techniques.
[0055] The term "tautomer," as used herein, refers to one of two or
more structural isomers which exist in equilibrium and which are
readily converted from one isomeric form to another.
[0056] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention.
[0057] Unless otherwise stated, structures depicted herein are also
meant to include all stereochemical forms of the structure; i.e.,
the R and S configurations for each asymmetric center. Therefore,
single stereochemical isomers as well as enantiomeric and
diastereomeric mixtures of the present compounds are within the
scope of the invention.
[0058] Unless otherwise stated, structures depicted herein are also
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of a hydrogen by
a deuterium or tritium, or the replacement of a carbon by .sup.13C-
or .sup.14C-enriched carbon are within the scope of this
invention.
[0059] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of atoms
that constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are encompassed within the scope of the
present invention.
[0060] In addition to salt forms, the present invention provides
compounds, which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0061] The terms "a," "an," or "a(n)", when used in reference to a
group of substituents or "substituent group" herein, mean at least
one. For example, where a compound is substituted with "an" alkyl
or aryl, the compound is optionally substituted with at least one
alkyl and/or at least one aryl, wherein each alkyl and/or aryl is
optionally different. In another example, where a compound is
substituted with "a" substitutent group, the compound is
substituted with at least one substituent group, wherein each
substitutent group is optionally different.
[0062] Description of compounds of the present invention are
limited by principles of chemical bonding known to those skilled in
the art. Accordingly, where a group may be substituted by one or
more of a number of substituents, such substitutions are selected
so as to comply with principles of chemical bonding and to give
compounds which are not inherently unstable and/or would be known
to one of ordinary skill in the art as likely to be unstable under
ambient conditions, such as aqueous, neutral, or physiological
conditions.
[0063] The terms "treating" or "treatment" in reference to a
particular disease includes prevention of the disease.
DESCRIPTION OF THE EMBODIMENTS
I. Glucocorticoid Receptor Modulators
[0064] It has now been discovered that fused ring azadecalin
compounds are potent modulators of glucocorticoid receptors ("GR").
GR modulators typically act as agonists, partial agonists or
antagonists of GR thereby affecting a wide array of cellular
functions, physiological functions and disease states.
[0065] Cortisol acts by binding to an intracellular glucocorticoid
receptor. In humans, glucocorticoid receptors are present in two
forms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-beta
isoform that differs in only the last fifteen amino acids. The two
types of GR have high affinity for their specific ligands, and are
considered to function through the same transduction pathways.
[0066] GR modulators are typically efficacious agents for
influencing important cellular and physiological functions such as
carbohydrate, protein and lipid metabolism; electrolyte and water
balance; and functions of the cardiovascular system, kidney,
central nervous system, immune system, skeletal muscle system and
other organ and tissue systems. GR modulators may also affect a
wide variety of disease states, such as obesity, diabetes,
cardiovascular disease, hypertension, Syndrome X, depression,
anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (AIDS), neurodegeneration (e.g.
Alzheimer's disease and Parkinson's disease), cognition
enhancement, Cushing's Syndrome, Addison's Disease, osteoporosis,
frailty, inflammatory diseases (e.g., osteoarthritis, rheumatoid
arthritis, asthma and rhinitis), adrenal function-related ailments,
viral infection, immunodeficiency, immunomodulation, autoimmune
diseases, allergies, wound healing, compulsive behavior, multi-drug
resistance, addiction, psychosis, anorexia, cachexia,
post-traumatic stress syndrome, post-surgical bone fracture,
medical catabolism, and muscle frailty.
[0067] In a first aspect, the present invention provides a compound
having the formula:
##STR00002##
[0068] In Formula (I), L.sup.1 and L.sup.2 are independently
selected from a bond, --O--, --S--, S(O)--, --S(O.sub.2)--,
--C(O)--, --C(O)O--, --C(O)NH--, substituted or unsubstituted
alkylene, and substituted or unsubstituted heteroalkylene.
[0069] The dashed line b is optionally a bond.
[0070] The ring A is selected from substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0071] R.sup.1 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.1A,
--NR.sup.1CR.sup.1D, --C(O)NR.sup.1CR.sup.1D, --C(O)OR.sup.1A.
R.sup.1A is selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. R.sup.1C and R.sup.1D are
selected from substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
Alternatively, R.sup.1C and R.sup.1D may be joined together with
the nitrogen atom to which they are attached to form a substituted
or unsubstituted ring optionally containing a second heteroatom
selected from O, N or S. In some embodiments, the substituted or
unsubstituted ring is a 4 to 8 membered ring and the second
heteroatom is a nitrogen. In other embodiments, where R.sup.1 is a
substituted or unsubstituted alkyl, the alkyl moiety is a
substituted or unsubstituted C.sub.1-C.sub.20 alkyl (e.g. a
C.sub.6-C.sub.20 alkyl).
[0072] R.sup.2 is selected from substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --S(O.sub.2)R.sup.2A,
--S(O.sub.2)NR.sup.2BR.sup.2C, --NOR.sup.2D. R.sup.2A, R.sup.2B,
R.sup.2C, or R.sup.2D are independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0073] L.sup.1 and L.sup.2 may also be independently selected from
a bond, substituted or unsubstituted (C.sub.1-C.sub.6)alkylene, and
substituted or unsubstituted 2 to 5 membered heteroalkylene. In a
related embodiment, L.sup.1 and L.sup.2 are independently selected
from a bond and --C(O)--. In another related embodiment, L.sup.1
and L.sup.2 are independently selected from a bond and
unsubstituted (C.sub.1-C.sub.6) alkylene.
[0074] In some embodiments, the ring A is selected from substituted
or unsubstituted 5 to 6 membered heterocycloalkyl, and substituted
or unsubstituted heteroaryl. A may also be selected from
unsubstituted 5 to 6 membered heterocycloalkyl including at least
one heteroatom selected from N, O and S; substituted 5 to 6
membered heterocycloalkyl having 1 to 3 substituents and at least
one ring heteroatom selected from N, O and S; unsubstituted aryl
having at least one heteroatom selected from N, O and S; and
substituted aryl having 1 to 3 substituents and at least one ring
heteroatom selected from N, O and S.
[0075] A variety of heterocycloalkyl groups are useful as A ring
groups, including substituted or unsubstituted pyrrolidinyl,
substituted or unsubstituted pyrrolyl, substituted or unsubstituted
pyrazolyl, substituted or unsubstituted imidazolyl, substituted or
unsubstituted furanyl, substituted or unsubstituted oxazolyl,
substituted or unsubstituted isoxazolyl, substituted or
unsubstituted thienyl, substituted or unsubstituted thiazolyl,
substituted or unsubstituted isothiazolyl, substituted or
unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl,
substituted or unsubstituted pyrazinyl, and substituted or
unsubstituted pyrimidinyl and substituted or unsubstituted
piperidinyl. In some embodiments, A is a substituted or
unsubstituted pyrazolyl.
[0076] Where A is substituted, the substituent may be selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--NR.sup.3AR.sup.3B, and --OR.sup.3C. The ring A substituent may
also be selected from hydrogen, substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7) cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl, --NR.sup.3AR.sup.3B, and
--OR.sup.3C. The ring A substituent may also be selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryl,
--NR.sup.3AR.sup.3B, and --OR.sup.3C. R.sup.3A and R.sup.3B are
independently selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycloalkyl, and substituted or unsubstituted
heteroaryl. R.sup.3A and R.sup.3B are optionally joined to form a
substituted or unsubstituted ring with the nitrogen to which they
are attached, wherein the ring optionally comprises an additional
ring heteroatom. R.sup.3C is a selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0077] R.sup.3A, R.sup.3B, and R.sup.3C may be selected from
substituted or unsubstituted (C.sub.1-C.sub.10) alkyl, substituted
or unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0078] In a related embodiment, A is substituted with at least two
substituents. The first substituent is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted aryl, --NR.sup.3AR.sup.3B,
and --OR.sup.3C. The second substituent is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0079] R.sup.1 may be selected from substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7) cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In some embodiments,
R.sup.1 is a substituted or unsubstituted (C.sub.6-C.sub.10)
alkyl.
[0080] In some embodiments, R.sup.1 has the formula:
##STR00003##
[0081] In Formula (III), q is an integer selected from 1 to 5. In
some embodiments, q is an integer selected from 1 to 3. The integer
q may also be 1.
[0082] The symbol R.sup.1B in Formula (III) may be selected from
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --NR.sup.1B1R.sup.1B2, --OR.sup.1B3,
--C(O)NR.sup.1B4R.sup.1B5, and --S(O.sub.2)R.sup.1B6. In another
embodiment, R.sup.1B is selected from hydrogen, substituted alkyl,
substituted or unsubstituted heteroalkyl, substituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted aryl,
and substituted or unsubstituted heteroaryl. In some embodiments,
R.sup.1B is selected from substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7) cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0083] R.sup.1B1 and R.sup.1B2 are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--COR.sup.1B10, and --S(O.sub.2)R.sup.1B9. R.sup.1B9 and R.sup.1B10
are independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. R.sup.1B1 and
R.sup.1B2 are optionally joined to form a substituted or
unsubstituted ring with the nitrogen to which they are attached.
The ring formed by R.sup.1B1 and R.sup.1B2 optionally includes an
additional ring heteroatom. R.sup.1B1 and R.sup.1B2 may also be
independently selected from substituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted
heterocycloalkyl, and substituted or unsubstituted heteroaryl.
[0084] R.sup.1B3 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In some embodiments,
R.sup.1B3 is selected from hydrogen, substituted or unsubstituted
heteroalkyl having a nitrogen; substituted or unsubstituted
heterocycloalkyl having a ring nitrogen; substituted or
unsubstituted heteroaryl having a ring nitrogen; and alkyl
substituted with a substituted or unsubstituted heteroalkyl having
a nitrogen, substituted or unsubstituted heterocycloalkyl having a
ring nitrogen, and substituted or unsubstituted heteroaryl having a
ring nitrogen.
[0085] R.sup.1B6 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, and --NR.sup.1B7R.sup.1B8.
R.sup.1B7 and R.sup.1B8 are independently selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. R.sup.1B7 and
R.sup.1B8 are optionally joined with the nitrogen to which they are
attached to form a substituted or unsubstituted ring.
[0086] In a related embodiment, R.sup.1B is selected from
--C(O)NR.sup.1B4R.sup.1B5 and substituted or unsubstituted
heteroaryl having a ring nitrogen. R.sup.1B4 and R.sup.1B5 are
independently selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In some embodiments,
R.sup.1B4 and R.sup.1B5 are independently selected from hydrogen;
substituted or unsubstituted heteroalkyl having a nitrogen;
substituted or unsubstituted heterocycloalkyl having a ring
nitrogen; substituted or unsubstituted heteroaryl having a ring
nitrogen; and alkyl substituted with a substituted or unsubstituted
heteroalkyl having a nitrogen, substituted or unsubstituted
heterocycloalkyl having a ring nitrogen, and substituted or
unsubstituted heteroaryl having a ring nitrogen. R.sup.1B4 and
R.sup.1B5 are optionally joined to form a substituted or
unsubstituted ring with the nitrogen to which they are attached.
The ring formed by R.sup.1B4 and R.sup.1B5 optionally contains an
additional heteroatom.
[0087] In another embodiment, R.sup.1B1, R.sup.1B2, R.sup.1B3,
R.sup.1B4, R.sup.1B5, R.sup.1B6, R.sup.1B7, R.sup.1B8, R.sup.1B9
and R.sup.1B10 are independently selected from R.sup.1B is selected
from substituted or unsubstituted (C.sub.1-C.sub.10) alkyl,
substituted or unsubstituted 2-10 membered heteroalkyl, substituted
or unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
some embodiments, the rings formed by R.sup.1B4 and R.sup.1B5,
R.sup.1B7 and R.sup.1B8, and R.sup.1B1 and R.sup.1B are
independently selected from, substituted or unsubstituted 3-7
membered heterocycloalkyl and substituted or unsubstituted
heteroaryl.
[0088] R.sup.1B1, R.sup.1B2, R.sup.1B3, R.sup.1B4 and R.sup.1B5 may
also be independently selected from hydrogen and a substituted or
unsubstituted ring, wherein the ring optionally contains a nitrogen
atom and at least one additional ring heteroatom.
[0089] R.sup.1 may also have the formula:
##STR00004##
[0090] In Formula (IV), R.sup.1B is selected from hydrogen,
--NR.sup.1B1R.sup.1B2, --OR.sup.1B3, substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7)cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0091] In an exemplary embodiment, R.sup.1A is selected from
hydrogen, substituted or unsubstituted C.sub.1-C.sub.10 alkyl,
substituted or unsubstituted 2 to 10 membered heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.7 membered cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. R.sup.1C and R.sup.1D are independently selected from
hydrogen, substituted or unsubstituted C.sub.1-C.sub.10 alkyl,
substituted or unsubstituted 2 to 10 membered heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.7 membered cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. R.sup.1C and R.sup.1D may be joined together with the
nitrogen atom to which they are attached to form a substituted or
unsubstituted heteroaryl of 4 to 8 membered heterocycloalkyl. In
some embodiments, R.sup.1A is hydrogen.
[0092] In some embodiments, R.sup.1 is selected from OR.sup.1A,
--NR.sup.1CR.sup.1D, --C(O)R.sup.1A, and --C(O)NR.sup.1CR.sup.1D.
In a related embodiment, L.sup.1 is a substituted or unsubstituted
(C.sub.1-C.sub.6)alkylene. In a further related embodiment, L.sup.1
is an unsubstituted (C.sub.1-C.sub.6)alkylene.
[0093] In other embodiments, R.sup.1 is selected from
--C(O)OR.sup.1A, --C(O)NR.sup.1BR.sup.1C, and L.sup.1 is selected
from a bond or substituted or unsubstituted
(C.sub.1-C.sub.6)alkylene. In a related embodiment, L.sup.1 is
selected from a bond or unsubstituted (C.sub.1-C.sub.6)alkylene
[0094] In still other embodiments, R.sup.1 has the formula of
formula (III) above, and L.sup.1 is --C(O)--.
[0095] In an exemplary embodiment, R.sup.2 is selected from
substituted or unsubstituted (C.sub.1-C.sub.10) alkyl, substituted
or unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0096] In another exemplary embodiment, R.sup.2A, R.sup.2B,
R.sup.2C, and R.sup.2D are independently selected from substituted
or unsubstituted (C.sub.1-C.sub.10) alkyl, substituted or
unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0097] R.sup.2 may also have the formula:
##STR00005##
[0098] In Formula (V), R.sup.2G is selected from halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In a related
embodiment, R.sup.2G is selected from hydrogen, substituted or
unsubstituted (C.sub.1-C.sub.10) alkyl, substituted or
unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
another related embodiment, R.sup.2G is a branched or unbranched
(C.sub.1-C.sub.10) alkyl. The symbol t is an integer selected from
0 to 5.
[0099] One of skill in the art will immediately recognize that the
value for t is limited by the number of ring members in ring J. For
example, the symbol t is an integer from 0 to 5 where J is a 6 or 7
membered substituted or unsubstituted ring. The symbol t is an
integer from 0 to 4 where J is a 5 membered substituted or
unsubstituted ring. The symbol t is an integer from 0 to 3 where J
is a 4 membered substituted or unsubstituted ring. The symbol t is
an integer from 0 to 2 where J is a 3 membered substituted or
unsubstituted ring.
[0100] In some embodiments, the symbol t is 1.
[0101] J is selected from substituted or unsubstituted ring
selected from substituted or unsubstituted (C.sub.3-C.sub.7)
cycloalkyl, substituted or unsubstituted 3-7 membered
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In some embodiments, J is
a substituted or unsubstituted ring selected from substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0102] X is selected from a bond, --S(O.sub.2)--, and
--S(O.sub.2)NR.sup.2I--. R.sup.2I is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In some
embodiments, R.sup.2I is selected from substituted or unsubstituted
(C.sub.1-C.sub.10) alkyl, substituted or unsubstituted 2-10
membered heteroalkyl, substituted or unsubstituted
(C.sub.3-C.sub.7) cycloalkyl, substituted or unsubstituted 3-7
membered heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In another embodiment,
R.sup.2I is selected from hydrogen, substituted or unsubstituted
alkyl, and substituted or unsubstituted heteroalkyl.
[0103] In another exemplary embodiment, the compound of the present
invention has the formula
##STR00006##
[0104] In Formula (II), the dashed ring represents unsaturated,
partially saturated, or fully saturated bonds within ring E. Thus,
a double bond is optionally present at any of the bonds within ring
E. The dashed line b is optionally a bond.
[0105] Z.sup.1 is selected from --NR.sup.5--, .dbd.N--, --O--, and
--S--. R.sup.5 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
heteroaryl, and substituted or unsubstituted aryl. R.sup.3 may also
be selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroaryl, and substituted or
unsubstituted aryl. Alternatively, R.sup.5 may be selected from
hydrogen and substituted or unsubstituted aryl. In another
embodiment, R.sup.5 is an substituted or unsubstituted
C.sub.1-C.sub.10 alkyl, or substituted or unsubstituted aryl. In
some embodiments, R.sup.5 is an unsubstituted C.sub.1-C.sub.10
alkyl, unsubstituted aryl, or fluoro-substituted aryl.
[0106] Z.sup.2 is selected from --CR.sup.6AR.sup.6B, --CR.sup.6A--,
--C(O)--, --NR.sup.6C--, .dbd.N--, --O--, --S--,
--CR.sup.6AR.sup.6B--NR.sup.6C--, .dbd.CR.sup.6A--NR.sup.6C--,
--CR.sup.6A.dbd.N--, --CR.sup.6AR.sup.6B--N.dbd., and
.dbd.CR.sup.6A--N.dbd.. R.sup.6C is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
heteroaryl, and substituted or unsubstituted aryl. R.sup.6C may
also be selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aryl.
[0107] R.sup.6A and R.sup.6B are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryl,
--NR.sup.6A1R.sup.6A2, and --OR.sup.6A3. R.sup.6A and R.sup.6C are
optionally joined together to form a substituted or unsubstituted
ring, wherein the ring optionally comprises an additional ring
heteroatom. R.sup.6A and R.sup.6B may also be independently
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted aryl, --NR.sup.6A1R.sup.6A2, and --OR.sup.6A3.
[0108] R.sup.6A1 and R.sup.6A2 are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
R.sup.6A1 and R.sup.6A2 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached.
The ring formed by R.sup.6A1 and R.sup.6A2 optionally contains an
additional ring heteroatom.
[0109] R.sup.6A3 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0110] Z.sup.3 is selected from --CR.sup.7AR.sup.7B--,
.dbd.CR.sup.7A--, --C(O)--, --NR.sup.7C--, .dbd.N--, --O--, and
--S--. R.sup.7C is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
heteroaryl, and substituted or unsubstituted aryl. R.sup.7C may
also be selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroaryl, and substituted or
unsubstituted aryl.
[0111] R.sup.7A and R.sup.7B are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted aryl,
--NR.sup.7A1R.sup.7A2, and --OR.sup.7A3. R.sup.7A and R.sup.7B may
also be independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted aryl, --NR.sup.7A1R.sup.7A2, and
--OR.sup.7A3.
[0112] R.sup.7A1 and R.sup.7A2 are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
R.sup.7A1 and R.sup.7A2 are optionally joined to form a substituted
or unsubstituted ring with the nitrogen to which they are attached.
The ring formed by R.sup.7A1 and R.sup.7A2 optionally contains an
additional ring heteroatom.
[0113] R.sup.7A3 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0114] In some embodiments, R.sup.5, R.sup.6A, R.sup.6B, R.sup.6C,
R.sup.6A1, R.sup.6A2, R.sup.6A3, R.sup.7A, R.sup.7B, R.sup.7C,
R.sup.7A1, R.sup.7A2, R.sup.7A3 are independently selected from
substituted or unsubstituted (C.sub.1-C.sub.10) alkyl, substituted
or unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0115] A variety of substituted or unsubstituted rings may be
formed by connecting some of the substituents described above. For
example, R.sup.5 is optionally joined with R.sup.6A or R.sup.6C to
form a substituted or unsubstituted ring optionally including an
additional ring heteroatom. In addition, R.sup.7A is optionally
joined with R.sup.6A or R.sup.6C to form a substituted or
unsubstituted ring optionally including an additional ring
heteroatom. Still further, R.sup.7C is optionally joined with
R.sup.6A or R.sup.6C to form a substituted or unsubstituted ring
optionally including an additional ring heteroatom. In some related
embodiments, where a ring is formed by R.sup.5 or R.sup.7A as
described above, the ring is selected from substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0116] In some embodiments of the Formula (II) compound, Z.sup.1 is
--NR.sup.5--, Z.sup.2 is .dbd.N--, and Z.sup.3 is .dbd.CR.sup.7A--.
In a related embodiment, R.sup.7A is hydrogen and R.sup.5 is a
member selected from hydrogen, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted arylalkyl and substituted or unsubstituted
heteroarylalkyl. In a further related embodiment, R.sup.7A is
hydrogen and R.sup.5 is a member selected from substituted or
unsubstituted alkyl and substituted or unsubstituted
cycloalkyl.
[0117] R.sup.5 may also have the formula:
##STR00007##
[0118] In Formula (VI), R.sup.5A is a member selected from
hydrogen, halogen, --OR.sup.5A1, --NR.sup.5A2R.sup.5A3,
--S(O.sub.2)NR.sup.5A2R.sup.5A3, CN, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. The symbol m is an integer
independently selected from 0 to 10. The symbol n is an integer
independently selected from 1 to 5.
[0119] R.sup.5A1 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. R.sup.5A2 and
R.sup.5A3 are independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. R.sup.5A2 and
R.sup.5A3 are optionally joined to form a substituted or
unsubstituted ring with the nitrogen to which they are joined. The
ring formed by R.sup.5A2 and R.sup.5A3 may be a substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0120] In some embodiments, R.sup.5A, R.sup.5A1, R.sup.5A2,
R.sup.5A3 are independently selected from substituted or
unsubstituted (C.sub.1-C.sub.10) alkyl, substituted or
unsubstituted 2-10 membered heteroalkyl, substituted or
unsubstituted (C.sub.3-C.sub.7) cycloalkyl, substituted or
unsubstituted 3-7 membered heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0121] In some embodiments of Formula (VI), n is 1 and m is
selected from 0 and 1. In a related embodiment, n is 1 and m is 1.
In another related embodiment, R.sup.5A1, R.sup.5A2 and R.sup.5A3
are hydrogen.
[0122] In another related embodiment, R.sup.5 and R.sup.7A are
hydrogen.
[0123] In yet another related embodiment, b is a bond.
[0124] In some embodiments of the Formula (II) compound, Z.sup.1 is
--NR.sup.5--, Z.sup.2 is .dbd.CR.sup.6A--, and Z.sup.3 is .dbd.N--.
In a related embodiment, R.sup.3 is a member selected from hydrogen
and substituted or unsubstituted aryl.
[0125] In an exemplary embodiment of the compound of Formula (I),
the dashed line b is a bond; R.sup.1 is substituted or
unsubstituted benzyl; L.sup.1 is a bond; L.sup.2 is a bond; and
R.sup.2 has the formula:
##STR00008##
[0126] In this exemplary embodiment, R.sup.2G is selected from
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. J is a substituted or unsubstituted ring selected from
substituted or unsubstituted (C.sub.3-C.sub.7) cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. X is --S(O.sub.2)--. The symbol t is an integer
selected fro 0 to 5.
[0127] In another embodiment, the compound of Formula (I) has the
formula
##STR00009##
[0128] In Formula (VII), L.sup.2 and R.sup.2 are as defined above
in the discussion of Formula (I). R.sup.1B is as defined above in
the discussion of Formula (III). R.sup.5A is as defined above in
the discussion of Formula (VI). L.sup.1 is selected from
--CH.sub.2-- and --C(O)--.
[0129] In another exemplary embodiment, the compound of Formula (I)
has the formula
##STR00010##
[0130] In Formula (VIII), L.sup.2 and R.sup.2 are as defined above
in the discussion of Formula (I). R.sup.1B is as defined above in
the discussion of Formula (III).
[0131] In another exemplary embodiment, the compound of Formula (I)
has the formula
##STR00011##
[0132] In Formula (X), L.sup.2 and R.sup.2 are as defined above in
the discussion of Formula (I). R.sup.5A is as defined above in the
discussion of Formula (VI). -L.sup.1-R.sup.1 is selected from
methyl (i.e. L.sup.1 is a bond and R.sup.1 is methyl), --OR.sup.1A,
--C(O)OR.sup.1A (i.e. L.sup.1 is a --C(O)-- and R.sup.1 is
--OR.sup.1A), --CH.sub.2--OR.sup.1A, --(CH.sub.2).sub.2--OR.sup.1A,
--NR.sup.1CR.sup.1D, --C(O)NR.sup.1CR.sup.1D,
--CH.sub.2--NR.sup.1CR.sup.1D, and
--(CH.sub.2).sub.2--NR.sup.1CR.sup.1D.
[0133] In another exemplary embodiment, the compound of Formula (I)
has the formula
##STR00012##
[0134] In Formula (X), L.sup.1, R.sup.1, L.sup.2 and R.sup.2 are as
defined above in the discussion of Formula (I). R.sup.6A is as
defined above in the discussion of Formula (II).
[0135] In another exemplary embodiment, the compound of Formula (I)
has the formula
##STR00013##
[0136] In Formula (XI), R.sup.1A, L.sup.2 and R.sup.2 are as
defined above in the discussion of Formula (I). R.sup.5 is as
defined above in the discussion of Formula (II). -L.sup.1-R.sup.1
is selected from methyl (i.e. L.sup.1 is a bond and R.sup.1 is
methyl), --OR.sup.1A, --C(O)OR.sup.1A (i.e. L.sup.1 is a --C(O)--
and R.sup.1 is --OR.sup.1A), --CH.sub.2--OR.sup.1A,
--(CH.sub.2).sub.2--OR.sup.1A, --C(O)NR.sup.1CR.sup.1D,
--CH.sub.2--NR.sup.1CR.sup.1D, and
--(CH.sub.2).sub.2--NR.sup.1CR.sup.1D. In a related embodiment,
-L.sup.1-R.sup.1 is selected from --CH.sub.2--OR.sup.1A, and
--CH.sub.2--NR.sup.1CR.sup.1D.
[0137] In an exemplary embodiment of the compound of Formula (II),
the dashed line b is a bond; R.sup.1 is substituted or
unsubstituted benzyl; L.sup.1 is a bond; L.sup.2 is a bond; Z' is
--NR.sup.5--; Z.sup.2 is .dbd.C.sup.6A--, Z.sup.3 is .dbd.N--; and
R.sup.2 has the formula:
##STR00014##
[0138] In this exemplary embodiment, R.sup.2G is selected from
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. J is a substituted or unsubstituted ring selected from
substituted or unsubstituted (C.sub.3-C.sub.7) cycloalkyl,
substituted or unsubstituted 3-7 membered heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl. The symbol t is 1. X is --S(O.sub.2)--. R.sup.5 is
hydrogen, alkyl, cycloalkyl, aryl or heteroaryl. R.sup.6A is as
defined in the description of Formula (II).
[0139] In another exemplary embodiment, the compound of Formula (I)
is selected from one of the compounds set forth in Examples 15-23,
25, 28-29, or 33-62.
[0140] In some embodiments of the compounds of Formulae (I)-(XI),
each substituted alkylene, substituted heteroalkylene, substituted
alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl,
substituted arylalkyl, substituted heteroarylalkyl, and substituted
ring structures are substituted with a substituent group. In other
embodiments of the compounds of Formulae (I)-(XI), each substituted
alkylene, substituted heteroalkylene, substituted alkyl,
substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted, substituted heteroaryl, substituted
alkylene, substituted heteroalkylene, substituted arylalkyl, and
substituted heteroarylalkyl is substituted with a size-limited
substituent group. In another embodiments of the compounds of
Formulae (I)-(XI), each substituted alkylene, substituted
heteroalkylene, substituted alkyl, substituted heteroalkyl,
substituted cycloalkyl, substituted heterocycloalkyl, substituted,
substituted heteroaryl, substituted alkylene, substituted
heteroalkylene, substituted arylalkyl, and substituted
heteroarylalkyl is substituted with a lower substituent group.
[0141] For example, where R.sup.1, R.sup.1A, R.sup.1B, R.sup.1B1,
R.sup.1B2, R.sup.1B3, R.sup.1B4, R.sup.1B5, R.sup.1B6, R.sup.1B7,
R.sup.1B8, R.sup.1B9, R.sup.1B10, R.sup.1C, R.sup.1D, R.sup.2A,
R.sup.2B3, R.sup.2C, R.sup.2D, R.sup.2G, R.sup.2I, R.sup.3A,
R.sup.3B, R.sup.3C, R.sup.5, R.sup.5A, R.sup.5A1, R.sup.5A2,
R.sup.5A3, R.sup.6A, R.sup.6B, R.sup.6C, R.sup.6A1, R.sup.6A2,
R.sup.6A3, R.sup.7A, R.sup.7B, R.sup.7C, R.sup.7A1, R.sup.7A2,
R.sup.7A3, R.sup.2A are independently selected from a substituted
alkylene, substituted heteroalkylene, substituted alkyl,
substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl,
substituted arylalkyl, substituted heteroarylalkyl, or form
substituted ring structures, the designated R group may be
substituted with a substituent group. Alternatively, the designated
R group may be substituted with a size-limited substituent group.
In some embodiments, the designated R group is substituted with a
lower substituent group.
[0142] Likewise, where L.sup.1 and L.sup.2 are independently
selected from a substituted alkyleneor substituted heteroalkylene,
L.sup.1 and/or L.sup.2 may substituted with a substituent group,
size-limited substituent group, or lower substituent group. Where A
is selected from substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, and substituted heteroaryl, A
may substituted with a substituent group, size-limited substituent
group, or lower substituent group.
II. Exemplary Syntheses
[0143] The compounds of the invention are synthesized by an
appropriate combination of generally well known synthetic methods.
Techniques useful in synthesizing the compounds of the invention
are both readily apparent and accessible to those of skill in the
relevant art. The discussion below is offered to illustrate certain
of the diverse methods available for use in assembling the
compounds of the invention. However, the discussion is not intended
to define the scope of reactions or reaction sequences that are
useful in preparing the compounds of the present invention.
Although some compounds in Schemes I-XVI may indicate relative
stereochemistry, the compounds may exist as a racemic mixture or as
either enantiomer. Compounds containing the double bond in the
azadecalin core are designated Series A. Ring-saturated compounds
are designated Series B.
##STR00015##
[0144] In SchemeI, R.sup.1B, R.sup.2, R.sup.2A, R.sup.2B, and
R.sup.2 are as defined above in the discussion of the compounds of
the present invention. R.sup.2M, R.sup.2J, and R.sup.2K are
independently selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0145] Compounds 6A-11A are prepared as illustrated in SchemeI. A
suitably N-protected piperidone-2-carboxylic acid ester 1 is
treated with a base such as sodium hydride, sodium ethoxide or
potassium tert-butoxide in a polar solvent (e.g.
N,N-dimethylformamide, ethanol, tert-butanol, dimethylsulfoxide,
N-methyl-2-pyrrolidone and the like) followed by an alkylating
agent to afford the alkylated keto ester 2. Suitable N-protecting
groups (Z) include benzyl and carbamate groups such as
tert-butoxycarbonyl (Boc) and the like. Typical alkylating agents
are primary, secondary or arylalkyl halides and are preferably
benzyl halides in which the aromatic ring can be substituted with a
R.sup.1B group.
[0146] Keto ester 2 is hydrolyzed and decarboxylated by heating in
a suitable solvent such as aqueous methanol or ethanol in the
presence of a strong acid (e.g. hydrochloric acid or sulfuric acid)
to afford ketone 3. The reaction is typically carried out at the
reflux temperature of the solvent mixture.
[0147] Ketone 3 is converted to enone 4 by a Robinson annelation
reaction involving treatment of 3 with a base (e.g. potassium or
sodium alkoxides) in an alcohol solvent (e.g. methanol, ethanol, or
tert-butanol) followed by addition of methylvinyl ketone (MVK). The
reaction is typically carried out at 0-25.degree. C. This reaction
can also be carried out with a nitrogen-containing base such as
pyrrolidine, piperidine or morpholine in an aprotic solvent (e.g.
benzene, toluene or dioxane) at reflux temperature followed by
cooling and addition of MVK.
[0148] Enone 4 is prepared in optically active form when the
nitrogen-containing base is an optical isomer of
.alpha.-methylbenzylamine as described in J. Med. Chem. 39: 2302
(1996). Alternatively, the Robinson annelation can be carried out
in an asymmetric manner with catalysis by an amino acid such as
l-proline.
[0149] Removal of the N-protecting group Z from compound 4 is
accomplished under standard conditions, such as treatment with a
chloroformate and subsequent hydrolysis when Z is benzyl, to afford
amine 5A. Suitable chloroformates include methyl chloroformate,
ethyl chloroformate and .alpha.-chloroethyl chloroformate. When Z
is a group such as Boc, deprotection is accomplished by treatment
with a strong acid such as HCl in a protic solvent (e.g., ethanol)
or with trifluoroacetic acid.
[0150] Compound 6A may be prepared by alkylation of 5A with a
primary or secondary alkyl, cycloalkyl, heterocycloalkyl,
arylalkyl, or heteroarylalkyl halide. Alternatively, 6A may be
prepared by reductive alkylation of 5A with the requisite aldehyde
in the presence of a reducing agent such as sodium borohydride or
sodium cyanoborohydride in an inert solvent (e.g.
1,2-dichloroethane).
[0151] Compound 7A where R.sup.2 is aryl or heteroaryl may be
prepared by treatment of 5A with an aryl, heteroaryl halide, or
boronic acid in the presence of a copper or palladium catalyst
(e.g., copper (II) acetate, palladium (II) chloride) and a base
such as triethylamine.
[0152] Compound 8A may be prepared by acylation of 5A with a
primary, secondary or tertiary alkyl, cycloalkyl, heterocycloalkyl,
arylalkyl, or heteroarylalkyl carbonyl halide in a suitable protic
or aprotic solvent in the presence of a base such as sodium
hydroxide, triethylamine and the like. Alternatively, 8A may be
prepared by coupling of amine 5A with the requisite carboxylic acid
in the presence of a suitable coupling agent such as
N,N-dicyclohexylcarbodiimide.
[0153] Compound 9A where R.sup.2K is hydrogen may be prepared by
treatment of 5A with a primary, secondary or tertiary alkyl,
cycloalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl
isocyanate in an inert solvent (e.g. toluene, dichloromethane,
1,2-dichloroethane or dioxane). When R.sup.2K is a group other than
hydrogen, compound 9A may be prepared by treatment of 5A with the
carbamoyl halide R.sup.2JR.sup.2KNC(O)X (where X is Cl, Br, F) in
an inert solvent (e.g. toluene, dichloromethane, 1,2-dichloroethane
or dioxane) in the presence of a base such as triethylamine.
[0154] Compound 10A is prepared by treatment of 5A with a primary,
secondary or tertiary alkyl, cycloalkyl, heterocycloalkyl,
arylalkyl, or heteroarylalkyl sulfonyl halide in an inert solvent
(e.g. toluene, dichloromethane, 1,2-dichloroethane or dioxane) in
the presence of a base such as triethylamine.
[0155] Compound 11A is prepared by treatment of 5A with the
sulfamoyl halide R.sup.2BR.sup.2CNSO.sub.2X (where X is Cl, Br, or
F) in an inert solvent (e.g. toluene, dichloromethane,
1,2-dichloroethane or dioxane) in the presence of a base such as
triethylamine.
##STR00016##
[0156] In SchemeII, R.sup.1B, R.sup.2, R.sup.2A, R.sup.2B,
R.sup.2C, R.sup.2M, R.sup.2J, and R.sup.2K are as defined above in
SchemeI.
[0157] Compounds 6B-11B are similarly prepared from saturated
ketone 5B (SchemeII) according to the reactions previously
described in SchemeI. One skilled in the art will immediately
recognize that compound 5B can also exist as the cis isomer.
SchemeII exemplifies the preparation of the trans isomers of
compounds 6B-11B. However, the reaction scheme is equally
applicable to the preparation of the corresponding cis isomers.
[0158] Reduction of enone 4 to saturated ketone 5B is accomplished
by catalytic hydrogenation using a catalyst such as palladium or
platinum catalyst in an inert solvent, such as tetrahydrofuran or
an alcohol such as ethanol. Alternatively, 5B can be prepared by
treatment of 4 with a dissolving metal, such as lithium, in liquid
ammonia.
##STR00017##
[0159] In SchemeIII, R.sup.1B, R.sup.2, R.sup.5A, R.sup.6C, and
L.sup.2 are as defined above in the discussion of the compounds of
the present invention. R.sup.6D is selected from hydrogen, halogen,
--OH, --NH.sub.2, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0160] Compounds 13A,B-17A,B are prepared as described in
SchemeIII. Treatment of ketones 6A,B-11A,B with a formylating agent
such as ethyl formate in the presence of a base such as sodium
methoxide or sodium hydride in an aprotic solvent such as toluene
affords hydroxymethylene derivatives 12A,B. Treatment of 12A,B with
hydrazine in an alcohol solvent with heating to the reflux
temperature of the mixture yields pyrazoles 13A,B. Treatment of
12A,B with an alkyl hydrazine under similar conditions affords
pyrazoles 14A,B. Treatment of 12A,B with an aryl hydrazine affords
the regioisomeric pyrazoles 15A,B. Treatment of 12A,B with
hydroxylamine in a solvent such as ethyl acetate in the presence of
acetic acid affords isoxazoles 16A,B. Pyrimidines 17A,B are
prepared by treatment of 12A,B with guanidine (R.sup.6D=NH.sub.2)
or an amidine (R.sup.6D=alkyl or aryl) in an alcohol solvent in the
presence of a base such as sodium ethoxide.
[0161] Compounds 19A,B-21A,B are prepared as shown in SchemeIV.
Bromination of ketones 6A,B-11A,B by conventional methods such as
treatment with cuprous bromide or by treatment of 6A,B-11A,B with a
strong base, such as lithium diisopropylamide, and a brominating
agent such as N-bromosuccinimide in a solvent such as
tetrahydrofuran, affords bromo derivatives 18A,B. Thiazoles 19A,B
are prepared by treatment of 18A,B with thiourea
(R.sup.6A=NH.sub.2) or a thioamide (R.sup.6A=alkyl or aryl) in a
solvent such as acetonitrile. Imidazoles 22A,B are prepared by
treatment of 18A,B with guanidine (R.sup.6A=NH.sub.2) or an amidine
(R.sup.6A=alkyl or aryl) in an alcohol solvent in the presence of a
base such as sodium ethoxide. Oxazoles 20A,B are prepared by
heating 18A,B with a primary amide in an alcohol solvent such as
ethanol. Imidazolones 21A,B are prepared by heating 18A,B with a
N,N'-disubstituted urea in an alcohol solvent such as ethanol.
##STR00018##
[0162] In SchemeIV, R.sup.1B, L.sup.2, R.sup.2, R.sup.5, R.sup.6A,
and R.sup.7C are as defined above in the discussion of the
compounds of the present invention.
##STR00019##
[0163] Substituted imidazoles 25A,B can also be prepared as shown
in Scheme V. In Scheme V, L.sup.1, L.sup.2, R.sup.1, R.sup.2 and
R.sup.6A are as defined above in the compounds of the present
invention. Compounds 24A,B may be prepared from ketones 23A,B by
treatment with manganese acetate in a suitable inert solvent such
as toluene or THF. Conversion of compounds 24A,B to compounds 25A,B
is accomplished by treatment with copper.sup.II acetate and ammonia
and a suitable aldehyde (for example where R.sup.6A is methyl, the
ketone is acetaldehyde) in a protic solvent such as methanol or
ethanol.
##STR00020##
[0164] The group R.sup.1B in compounds 27A,B-30A,B can be modified
prior to synthesis of the compounds according to Schemes III and
IV, as exemplified in Scheme VI. Thus, brominated derivatives, such
as 26A,B can be converted to amino derivatives 30A,B by conversion
to the (bis-pinacolato)diboron derivative followed by
copper-catalyzed amination. Similarly, the bromo derivative may be
converted to aryl ethers 29A,B by metal-catalyzed ether formation
or to amide derivatives 28A,B by palladium-catalyzed
carbonylation/amidation procedures. Derivatives 27A,B in which
R.sup.1B is heteroaryl can be prepared by treatment of 26A,B with a
heteroarylboronic acid in the presence of a palladium catalyst.
[0165] In Scheme VI, R.sup.1B is heteroaryl and R.sup.1B1,
R.sup.1B2, R.sup.1B3, R.sup.1B4, R.sup.1B5, L.sup.2, and R.sup.2
are as defined above in the discussion of the compounds of the
present invention.
##STR00021##
[0166] Alternatively, the group R.sup.1B in compounds 13A,B-17A,B
and 19A,B-22A,B can be modified subsequent to synthesis of the
compounds according to Schemes III and IV, as exemplified in Scheme
VII for the synthesis of pyrazole derivatives 32A,B-35A,B. Thus,
brominated derivatives, such as 31A,B can be converted to amino
derivatives 35A,B by conversion to the (bis-pinacolato)diboron
derivative followed by copper-catalyzed amination. Similarly, the
bromo derivative may be converted to aryl ethers 34A,B by
metal-catalyzed ether formation or to amide derivatives by
palladium-catalyzed carbonylation/amidation procedures. Derivatives
32A,B in which R.sup.1B is heteroaryl can be prepared by treatment
of 31A,B with a heteroarylboronic acid in the presence of a
palladium catalyst.
[0167] In Scheme VII, R.sup.1B is heteroaryl and R.sup.1B1,
R.sup.1B2, R.sup.1B3, R.sup.1B4, R.sup.1B5, L.sup.2, and R.sup.2
are as defined above in the discussion of the compounds of the
present invention.
##STR00022##
[0168] It will be appreciated by one skilled in the art that the
routes illustrated in Schemes I-IV and VI, VII wherein
L.sup.1-R.sup.1 represents a substituted benzyl group may also be
applied to compounds in which L.sup.1-R.sup.1 represents an alkyl
substituted lower alkyl group, for example a methyl group, as
described in Scheme VIII. Either enantionmer of enone 36A, in which
L.sup.2-R.sup.2 represents a benzyl group, can be prepared by
Robinson annelation when the nitrogen-containing base is an optical
isomer of .alpha.-methylbenzylamine as described in J. Med. Chem.
39: 2302 (1996). Compounds 38A,B-42A,B are prepared from 37A,B
according to the procedures described for the preparation of the
compounds in SchemeIII.
##STR00023##
[0169] Pyrazoles 44A,B, in which R.sup.5 is alkyl, substituted
alkyl, cycloalkyl or substituted cycloalkyl can be prepared by an
alternative procedure as described in SchemeIX. It will be
appreciated by one skilled in the art that these compounds are
regioisomeric with pyrazoles exemplified by compounds 14A,B and
39A,B in Scheme VIII. The preparation of 44A,B involves reaction of
43A,B with a Boc-protected hydrazine, followed by treatment with a
strong acid, such as trifluoroacetic, hydrochloric acid and the
like.
##STR00024##
[0170] Compounds 49A-53A are prepared as described in Scheme X. In
Scheme X, R.sup.5, R.sup.1A, R.sup.1C, R.sup.1D, L.sup.2 and
R.sup.2 are as defined above in the compounds of the present
invention. In Scheme X, L.sup.2-R.sup.2 can be replaced by a
suitable protecting group, such as BOC or benzyl, to facilitate the
synthesis. Keto-ester 45 is converted directly to enone 47A by a
Robinson annelation reaction involving treatment of 45 with a base
(e.g. potassium or sodium alkoxides) in an alcohol solvent (e.g.
methanol, ethanol, or tert-butanol) followed by addition of
methylvinyl ketone (MVK). The reaction is typically carried out at
0-25.degree. C.
[0171] Alternatively, compounds 47A can be prepared in optically
active form. The suitably N-protected piperidone-2-carboxylic acid
ester 45 is heated with an optically active nitrogen-containing
base (as described in J. Med. Chem. 39: 2302 (1996)) such as
(R)-(+)-.alpha.-methylbenzylamine or
(S)-2-amino-N,N-diethyl-3-methyl-butyramide, in a suitable solvent
(such as toluene, benzene or dioxane) under dehydrating conditions
(concentrated HCl, molecular sieves or Dean-Stark trap). The
intermediate enamine is then treated with methylvinyl ketone in an
apolar solvent such as acetone in the presence of copper.sup.II
acetate to afford the optically active methylvinyl ketone adduct
46. Suitable N-protecting groups (Z) include benzyl and carbamate
groups such as tert-butoxycarbonyl (Boc) and the like.
[0172] Optically active ketone 46 is converted to enone 47A by
treatment with a base (e.g. potassium or sodium alkoxides) in an
alcohol solvent (e.g. methanol, ethanol, or tert-butanol) or by
addition of a nitrogen-containing base such as pyrrolidine,
piperidine or morpholine in an aprotic solvent (e.g. benzene,
toluene or dioxane).
[0173] Treatment of ketones 47A with a formylating agent such as
ethyl formate or trifluoroethyl formate, as described for example
in Organic Letters, 1 (7), 989, (1999), in the presence of a base
such as sodium methoxide, LDA or sodium hydride in an aprotic
solvent such as toluene affords hydroxymethylene derivatives 48A.
Treatment of 48A with hydrazine, a protected alkyl hydrazine (as in
SchemeIX) or an aryl hydrazine in an alcohol solvent or acetic acid
with heating to the reflux temperature of the mixture affords
pyrazoles 49A.
[0174] Alcohols 50A are prepared by treatment of ester 49A with a
reducing agent such as DIBAL-H, LiAlH.sub.4 or RED-AL in an inert
solvent such as THF, benzene or toluene.
[0175] Alcohols 50A are converted into ether derivatives 51A by
treatment with a base (e.g. sodium hydride) in an aprotic solvent
(e.g. tetrahydrofuran, N,N-dimethylformamide) followed by addition
of a substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heterocycylalkyl halide.
[0176] Aldehyde intermediate 52A is prepared by reduction of ester
49A with a reducing agent such as DIBAL-H in toluene or
dimethoxyethanol or sodium borohydride in ethanol or diglyme.
Alternatively, compounds 52A are prepared from alcohols 50A by
treatment with an oxidizing agent (e.g. chromium (VI) reagents such
as pyridinium chlorochromate and pyridinium dichromate) in an
aprotic solvent (e.g. dichloromethane); or using the Swern
oxidation method (oxalyl chloride and dimethyl sulfoxide followed
by addition of an organic base such as triethylamine).
[0177] Compounds 53A are prepared by reductive amination of
aldehydes 52A with ammonia, a secondary amine, or a tertiary amine.
The reaction is carried out by treatment of 52A with the amino
component and a reducing agent (e.g. hydrogen, sodium borohydride
or sodium cyanoborohydride) in a solvent such as tetrahydrofuran,
ethanol, 1,2-dichloroethane and the like.
##STR00025##
[0178] Saturated compounds 49B-53B are prepared as described in
Scheme XI. It will be appreciated that Scheme XI exemplifies the
synthesis of pyrazole derivatives; however, the synthesis of other
heterocyclic examples such as those shown in Schemes III, IV and V
can proceed analogously. Reduction of enone 47A to saturated ketone
47B is accomplished by catalytic hydrogenation using a catalyst
such as palladium or platinum catalyst in an inert solvent, such as
tetrahydrofuran or an alcohol such as ethanol, or using Raney
nickel with hydrogen.
##STR00026##
[0179] In Scheme XII, R.sup.5, R.sup.1C, R.sup.1D, L.sup.2 and
R.sup.2 are as defined above in the compounds of the present
invention. Compounds 54A,B may be prepared from 49A,B by hydrolysis
of the ester using aqueous solutions of lithium hydroxide or sodium
hydroxide in alcoholic solvents such as ethanol or methanol. Amides
55A,B may be prepared from 54A,B and an amine using standard
methods of amide bond formation, for example, EDC or HATU with an
organic base such as diisopropylethylamine or triethylamine in an
inert solvent such as dichloromethane.
##STR00027##
[0180] In Scheme XIII, R.sup.5, L.sup.2, R.sup.1 and R.sup.2 are as
defined above in the compounds of the present invention.
[0181] Compounds 56A,B may be prepared from aldehydes 52A,B by
treatment with a suitable organometallic species, such as a
Grignard reagent, an organocerium reagent or an organozinc reagent,
in a solvent such as ether, THF or a similar aprotic solvent.
Compounds 57A,B may be prepared from 56A,B using, for example,
Swern oxidation conditions or an oxidizing agent such as MnO.sub.2
in an inert solvent such as dichloromethane.
##STR00028##
[0182] In Scheme XIV, R.sup.5, L.sup.2, R.sup.1A, R.sup.1C,
R.sup.1D and R.sup.2 are as defined above in the compounds of the
present invention.
[0183] Thioketene acetals 58A,B may be prepared from acids 54A,B by
treatment with 2-trimethylsilyl-1,3-dithiane and n-butyl lithium in
an aprotic solvent such as THF. Typically, the chemistry is
performed at -78.degree. C. Esters 59A,B are formed by the
treatment of 58A,B with mercury.sup.II chloride and perchloric acid
in methanol.
[0184] Reduction of the ester in compounds 59A,B is achieved with a
reducing agents such as DIBAL-H, LiAlH.sub.4 or RED-AL in an inert
solvent such as THF, benzene or toluene to afford alcohols 60A,B.
Alcohols 60A,B are converted into ether derivatives 61A,B by
treatment with a base (e.g. sodium hydride) in an aprotic solvent
(e.g. tetrahydrofuran, N,N-dimethylformamide) followed by addition
of a substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heterocycylalkyl halide.
[0185] Aldehydes 62A,B are prepared by reduction of esters 59A,B
with a reducing agent such as DIBAL-H in toluene or
dimethoxyethanol or sodium borohydride in ethanol or diglyme.
Alternatively, compounds 62A,B are prepared from alcohols 60A,B by
oxidation with an oxidizing agent (e.g. chromium (VI) reagents such
as pyridinium chlorochromate and pyridinium dichromate) in an
aprotic solvent (e.g. dichloromethane); or using the Swern
oxidation method (oxalyl chloride and dimethyl sulfoxide followed
by addition of an organic base such as triethylamine).
[0186] Amines 63A,b are prepared by reductive amination of
aldehydes 62A,B with ammonia, a secondary amine, or a tertiary
amine. The reaction is carried out by treatment of 62A,B with the
amine component and a reducing agent (e.g. hydrogen, sodium
borohydride or sodium cyanoborohydride) in a solvent such as
tetrahydrofuran, ethanol, 1,2-dichloroethane and the like. Amines
63A,B could also be prepared by conversion of the alcohol group in
60A,B to a leaving group, such as a sulfonate or halide, followed
by displacement of the leaving group with an amine.
##STR00029##
[0187] Saturated compounds 44B can also prepared as described in
Scheme XV. It will be appreciated that Scheme XV exemplifies the
synthesis of pyrazole derivatives; however, the synthesis of other
heterocyclic examples such as those shown in Schemes III, IV and V
can proceed analogously. Reduction of enone 44A to saturated ketone
44B is accomplished by catalytic hydrogenation using a catalyst
such as palladium or platinum catalyst in an inert solvent, such as
tetrahydrofuran or an alcohol such as ethanol, or using Raney
nickel with hydrogen.
##STR00030##
[0188] Compounds 44A,B can also be prepared as shown in Scheme XVI
by introducing the grouping L.sup.2-R.sup.2 into intermediates
65A,B which can be prepared from a protected amine of the type
64A,B. The conditions and procedures for these conversions are the
same as those described for the preparations in Schemes I and
II.
III. Assays and Methods for Modulating Glucocorticoid Receptor
Activity
[0189] The compounds of the present invention can be tested for
their antiglucocorticoid properties. Methods of assaying compounds
capable of modulating glucocorticoid receptor activity are
presented herein. Typically, compounds of the current invention are
capable of modulating glucocorticoid receptor activity by
selectively binding to the GR or by preventing GR ligands from
binding to the GR. In some embodiments, the compounds exhibit
little or no cytotoxic effect. Therefore, exemplary assays
disclosed herein may test the ability of compounds to (1) bind to
the GR; (2) selectively bind to the GR; (3) prevent GR ligands from
binding to the GR; (4) modulate the activity of the GR in a
cellular system; and/or (5) exhibit non-cytotoxic effects.
[0190] Binding Assays
[0191] In some embodiments, GR modulators are identified by
screening for molecules that compete with a ligand of GR, such as
dexamethasone. Those of skill in the art will recognize that there
are a number of ways to perform competitive binding assays. In some
embodiments, GR is pre-incubated with a labeled GR ligand and then
contacted with a test compound. This type of competitive binding
assay may also be referred to herein as a binding displacement
assay. Alteration (e.g., a decrease) of the quantity of ligand
bound to GR indicates that the molecule is a potential GR
modulator. Alternatively, the binding of a test compound to GR can
be measured directly with a labeled test compound. This latter type
of assay is called a direct binding assay.
[0192] Both direct binding assays and competitive binding assays
can be used in a variety of different formats. The formats may be
similar to those used in immunoassays and receptor binding assays.
For a description of different formats for binding assays,
including competitive binding assays and direct binding assays, see
Basic and Clinical Immunology 7th Edition (D. Stites and A. Ten
ed.) 1991; Enzyme Immunoassay, E. T. Maggio, ed., CRC Press, Boca
Raton, Fla. (1980); and "Practice and Theory of Enzyme
Immunoassays," P. Tijssen, Laboratory Techniques in Biochemistry
and Molecular Biology, Elsevier Science Publishers B.V. Amsterdam
(1985), each of which is incorporated herein by reference.
[0193] In solid phase competitive binding assays, for example, the
sample compound can compete with a labeled analyte for specific
binding sites on a binding agent bound to a solid surface. In this
type of format, the labeled analyte can be a GR ligand and the
binding agent can be GR bound to a solid phase. Alternatively, the
labeled analyte can be labeled GR and the binding agent can be a
solid phase GR ligand. The concentration of labeled analyte bound
to the capture agent is inversely proportional to the ability of a
test compound to compete in the binding assay.
[0194] Alternatively, the competitive binding assay may be
conducted in liquid phase, and any of a variety of techniques known
in the art may be used to separate the bound labeled protein from
the unbound labeled protein. For example, several procedures have
been developed for distinguishing between bound ligand and excess
bound ligand or between bound test compound and the excess unbound
test compound. These include identification of the bound complex by
sedimentation in sucrose gradients, gel electrophoresis, or gel
isoelectric focusing; precipitation of the receptor-ligand complex
with protamine sulfate or adsorption on hydroxylapatite; and the
removal of unbound compounds or ligands by adsorption on
dextran-coated charcoal (DCC) or binding to immobilized antibody.
Following separation, the amount of bound ligand or test compound
is determined.
[0195] Alternatively, a homogenous binding assay may be performed
in which a separation step is not needed. For example, a label on
the GR may be altered by the binding of the GR to its ligand or
test compound. This alteration in the labeled GR results in a
decrease or increase in the signal emitted by label, so that
measurement of the label at the end of the binding assay allows for
detection or quantitation of the GR in the bound state. A wide
variety of labels may be used. The component may be labeled by any
one of several methods. Useful radioactive labels include those
incorporating .sup.3H, .sup.125I, .sup.35S, .sup.14C, or .sup.32P.
Useful non-radioactive labels include those incorporating
fluorophores, chemiluminescent agents, phosphorescent agents,
electrochemiluminescent agents, and the like. Fluorescent agents
are especially useful in analytical techniques that are used to
detect shifts in protein structure such as fluorescence anisotropy
and/or fluorescence polarization. The choice of label depends on
sensitivity required, ease of conjugation with the compound,
stability requirements, and available instrumentation. For a review
of various labeling or signal producing systems which may be used,
see U.S. Pat. No. 4,391,904, which is incorporated herein by
reference in its entirety for all purposes. The label may be
coupled directly or indirectly to the desired component of the
assay according to methods well known in the art.
[0196] For competitive binding assays, the amount of inhibition may
be detei mined using the techniques disclosed herein. The amount of
inhibition of ligand binding by a test compound depends on the
assay conditions and on the concentrations of ligand, labeled
analyte, and test compound that are used. In an exemplary
embodiment, a compound is said to be capable of inhibiting the
binding of a GR ligand to a GR in a competitive binding assay if
the inhibition constant (K.sub.i) is less than 5 .mu.M using the
assay conditions presented in Example 63. In another exemplary
embodiment, a compound is said to be capable of inhibiting the
binding of a GR ligand to a GR in a competitive binding assay if
the K.sub.i is less than 1 .mu.M using the assay conditions
presented in Example 63. In another exemplary embodiment, a
compound is said to be capable of inhibiting the binding of a GR
ligand to a GR in a competitive binding assay if the K.sub.i is
less than 100 nM using the assay conditions presented in Example
63. In another exemplary embodiment, a compound is said to be
capable of inhibiting the binding of a GR ligand to a GR in a
competitive binding assay if the K.sub.i is less than 10 nM using
the assay conditions presented in Example 63. In another exemplary
embodiment, a compound is said to be capable of inhibiting the
binding of a GR ligand to a GR in a competitive binding assay if
the K.sub.i is less than 1 nM using the assay conditions presented
in Example 63. In another exemplary embodiment, a compound is said
to be capable of inhibiting the binding of a GR ligand to a GR in a
competitive binding assay if the K.sub.i is less than 100 pM using
the assay conditions presented in Example 63. In another exemplary
embodiment, a compound is said to be capable of inhibiting the
binding of a GR ligand to a GR in a competitive binding assay if
the K.sub.i is less than 10 pM using the assay conditions presented
in Example 63.
[0197] High-throughput screening methods may be used to assay a
large number of potential modulator compounds. Such "compound
libraries" are then screened in one or more assays, as described
herein, to identify those library members (particular chemical
species or subclasses) that display a desired characteristic
activity. Preparation and screening of chemical libraries is well
known to those of skill in the art. Devices for the preparation of
chemical libraries are commercially available (see, e.g., 357 MPS,
390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin,
Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050
Plus, Millipore, Bedford, Mass.).
[0198] Cell-Based Assays
[0199] Cell-based assays involve whole cells or cell fractions
containing GR to assay for binding or modulation of activity of GR
by a compound of the present invention. Exemplary cell types that
can be used according to the methods of the invention include,
e.g., any mammalian cells including leukocytes such as neutrophils,
monocytes, macrophages, eosinophils, basophils, mast cells, and
lymphocytes, such as T cells and B cells, leukemias, Burkitt's
lymphomas, tumor cells (including mouse mammary tumor virus cells),
endothelial cells, fibroblasts, cardiac cells, muscle cells, breast
tumor cells, ovarian cancer carcinomas, cervical carcinomas,
glioblastomas, liver cells, kidney cells, and neuronal cells, as
well as fungal cells, including yeast. Cells can be primary cells
or tumor cells or other types of immortal cell lines. Of course, GR
can be expressed in cells that do not express an endogenous version
of GR.
[0200] In some cases, fragments of GR, as well as protein fusions,
can be used for screening. When molecules that compete for binding
with GR ligands are desired, the GR fragments used are fragments
capable of binding the ligands (e.g., dexamethasone).
Alternatively, any fragment of GR can be used as a target to
identify molecules that bind GR. GR fragments can include any
fragment of, e.g., at least 20, 30, 40, 50 amino acids up to a
protein containing all but one amino acid of GR. Typically,
ligand-binding fragments will comprise transmembrane regions and/or
most or all of the extracellular domains of GR.
[0201] In some embodiments, signaling triggered by GR activation is
used to identify GR modulators. Signaling activity of GR can be
determined in many ways. For example, downstream molecular events
can be monitored to determine signaling activity. Downstream events
include those activities or manifestations that occur as a result
of stimulation of a GR receptor. Exemplary downstream events useful
in the functional evaluation of transcriptional activation and
antagonism in unaltered cells include upregulation of a number of
glucocorticoid response element (GRE)-dependent genes (PEPCK,
tyrosine amino transferase, aromatase). In addition, specific cell
types susceptible to GR activation may be used, such as osteocalcin
expression in osteoblasts which is downregulated by
glucocorticoids; primary hepatocytes which exhibit glucocorticoid
mediated upregulation of PEPCK and glucose-6-phosphate (G-6-Pase)).
GRE-mediated gene expression has also been demonstrated in
transfected cell lines using well-known GRE-regulated sequences
(e.g. the mouse mammary tumor virus promoter (MMTV) transfected
upstream of a reporter gene construct). Examples of useful reporter
gene constructs include luciferase (luc), alkaline phosphatase
(ALP) and chloramphenicol acetyl transferase (CAT). The functional
evaluation of transcriptional repression can be carried out in cell
lines such as monocytes or human skin fibroblasts. Useful
functional assays include those that measure IL-1beta stimulated
IL-6 expression; the downregulation of collagenase,
cyclooxygenase-2 and various chemokines (MCP-1, RANTES); or
expression of genes regulated by NFkB or AP-1 transcription factors
in transfected cell-lines. An example of a cell-based assay
measuring gene transcription is presented in Example 65.
[0202] Typically, compounds that are tested in whole-cell assays
are also tested in a cytotoxicity assay. Cytotoxicity assays are
used to determine the extent to which a perceived modulating effect
is due to non-GR binding cellular effects. In an exemplary
embodiment, the cytotoxicity assay includes contacting a
constitutively active cell with the test compound. Any decrease in
cellular activity indicates a cytotoxic effect. An exemplary
cytotoxicity assay is presented in Example 66.
[0203] Specificity
[0204] The compounds of the present invention may be subject to a
specificity assay (also referred to herein as a selectivity assay).
Typically, specificity assays include testing a compound that binds
GR in vitro or in a cell-based assay for the degree of binding to
non-GR proteins. Selectivity assays may be performed in vitro or in
cell based systems, as described above. GR binding may be tested
against any appropriate non-GR protein, including antibodies,
receptors, enzymes, and the like. In an exemplary embodiment, the
non-GR binding protein is a cell-surface receptor or nuclear
receptor. In another exemplary embodiment, the non-GR protein is a
steroid receptor, such as estrogen receptor, progesterone receptor,
androgen receptor, or mineralocorticoid receptor. An exemplary
specificity assay is presented in Example 64.
[0205] Methods of Modulating GR Activity
[0206] In another aspect, the present invention provides methods of
modulating glucocorticoid receptor activity using the techniques
described above. In an exemplary embodiment, the method includes
contacting a GR with an effective amount of a compound of the
present invention, such as the compound of Formula (I), and
detecting a change in GR activity.
[0207] In an exemplary embodiment, the GR modulator is an
antagonist of GR activity (also referred to herein as "a
glucocorticoid receptor antagonist"). A glucocorticoid receptor
antagonist, as used herein, refers to any composition or compound
which partially or completely inhibits (antagonizes) the binding of
a glucocorticoid receptor (GR) agonist (e.g. cortisol and synthetic
or natural cortisol analog) to a GR thereby inhibiting any
biological response associated with the binding of a GR to the
agonist.
[0208] In a related embodiment, the GR modulator is a specific
glucocorticoid receptor antagonist. As used herein, a specific
glucocorticoid receptor antagonist refers to a composition or
compound which inhibits any biological response associated with the
binding of a GR to an agonist by preferentially binding to the GR
rather than another nuclear receptor (NR). In some embodiments, the
specific glucocorticoid receptor antagonist binds preferentially to
GR rather than the mineralocorticoid receptor (MR) or progesterone
receptor (PR). In an exemplary embodiment, the specific
glucocorticoid receptor antagonist binds preferentially to GR
rather than the mineralocorticoid receptor (MR). In another
exemplary embodiment, the specific glucocorticoid receptor
antagonist binds preferentially to GR rather than the progesterone
receptor (PR).
[0209] In a related embodiment, the specific glucocorticoid
receptor antagonist binds to the GR with an association constant
(K.sub.d) that is at least 10-fold less than the K.sub.d for the
NR. In another embodiment, the specific glucocorticoid receptor
antagonist binds to the GR with an association constant (K.sub.d)
that is at least 100-fold less than the K.sub.d for the NR. In
another embodiment, the specific glucocorticoid receptor antagonist
binds to the GR with an association constant (K.sub.d) that is at
least 1000-fold less than the K.sub.d for the NR.
[0210] In an exemplary embodiment, the present invention provides a
method of treating a disorder or condition. The method includes
modulating a glucocorticoid receptor by administering to a subject
in need of such treatment, an effective amount of a compound of the
present invention.
[0211] Methods of treating a disorder or condition through
antagonizing a glucocorticoid receptor are also provided. The
method includes administering to a subject in need of such
treatment, an effective amount of a compound of the present
invention.
[0212] In other embodiments, a method of modulating a
glucocorticoid receptor is provided. The method includes the steps
of contacting a glucocorticoid receptor with an effective amount of
a compound of the present invention and detecting a change in the
activity of the glucocorticoid receptor.
IV. Pharmaceutical Compositions of Glucocorticoid Receptor
Modulators
[0213] In another aspect, the present invention provides
pharmaceutical compositions including a pharmaceutically acceptable
excipient and a compound of the present invention, such as the
compound of Formula (I) provided above.
[0214] The compounds of the present invention can be prepared and
administered in a wide variety of oral, parenteral and topical
dosage forms. Oral preparations include tablets, pills, powder,
dragees, capsules, liquids, lozenges, gels, syrups, slurries,
suspensions, etc., suitable for ingestion by the patient. The
compounds of the present invention can also be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. Also, the compounds described herein can be
administered by inhalation, for example, intranasally.
Additionally, the compounds of the present invention can be
administered transdermally. The GR modulators of this invention can
also be administered by in intraocular, intravaginal, and
intrarectal routes including suppositories, insufflation, powders
and aerosol formulations (for examples of steroid inhalants, see
Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann.
Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present
invention also provides pharmaceutical compositions including a
pharmaceutically acceptable carrier or excipient and either a
compound of Formula (I), or a pharmaceutically acceptable salt of a
compound of Formula (I).
[0215] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances, which may
also act as diluents, flavoring agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material. Details
on techniques for formulation and administration are well described
in the scientific and patent literature, see, e.g., the latest
edition of Remington's Pharmaceutical Sciences, Maack Publishing
Co, Easton Pa. ("Remington's").
[0216] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0217] The powders and tablets preferably contain from 5% or 10% to
70% of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as a carrier
providing a capsule in which the active component with or without
other carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid dosage forms suitable for oral administration.
[0218] Suitable solid excipients are carbohydrate or protein
fillers include, but are not limited to sugars, including lactose,
sucrose, mannitol, or sorbitol; starch from corn, wheat, rice,
potato, or other plants; cellulose such as methyl cellulose,
hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose;
and gums including arabic and tragacanth; as well as proteins such
as gelatin and collagen. If desired, disintegrating or solubilizing
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium
alginate.
[0219] Dragee cores are provided with suitable coatings such as
concentrated sugar solutions, which may also contain gum arabic,
talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol,
and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures. Dyestuffs or pigments may be added to
the tablets or dragee coatings for product identification or to
characterize the quantity of active compound (i.e., dosage).
Pharmaceutical preparations of the invention can also be used
orally using, for example, push-fit capsules made of gelatin, as
well as soft, sealed capsules made of gelatin and a coating such as
glycerol or sorbitol. Push-fit capsules can contain GR modulator
mixed with a filler or binders such as lactose or starches,
lubricants such as talc or magnesium stearate, and, optionally,
stabilizers. In soft capsules, the GR modulator compounds may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycol with or without
stabilizers.
[0220] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0221] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water/propylene glycol solutions.
For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[0222] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizers, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material,
such as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and
dispersing or wetting agents such as a naturally occurring
phosphatide (e.g., lecithin), a condensation product of an alkylene
oxide with a fatty acid (e.g., polyoxyethylene stearate), a
condensation product of ethylene oxide with a long chain aliphatic
alcohol (e.g., heptadecaethylene oxycetanol), a condensation
product of ethylene oxide with a partial ester derived from a fatty
acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or
a condensation product of ethylene oxide with a partial ester
derived from fatty acid and a hexitol anhydride (e.g.,
polyoxyethylene sorbitan mono-oleate). The aqueous suspension can
also contain one or more preservatives such as ethyl or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents and one or more sweetening agents, such as
sucrose, aspartame or saccharin. Formulations can be adjusted for
osmolarity.
[0223] Also included are solid form preparations, which are
intended to be converted, shortly before use, to liquid form
preparations for oral administration. Such liquid forms include
solutions, suspensions, and emulsions. These preparations may
contain, in addition to the active component, colorants, flavors,
stabilizers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilizing agents, and the like.
[0224] Oil suspensions can be formulated by suspending a GR
modulator in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin; or a mixture of these. The oil suspensions can contain a
thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
Sweetening agents can be added to provide a palatable oral
preparation, such as glycerol, sorbitol or sucrose. These
formulations can be preserved by the addition of an antioxidant
such as ascorbic acid. As an example of an injectable oil vehicle,
see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The
pharmaceutical formulations of the invention can also be in the
form of oil-in-water emulsions. The oily phase can be a vegetable
oil or a mineral oil, described above, or a mixture of these.
Suitable emulsifying agents include naturally-occurring gums, such
as gum acacia and gum tragacanth, naturally occurring phosphatides,
such as soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan mono-oleate,
and condensation products of these partial esters with ethylene
oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion
can also contain sweetening agents and flavoring agents, as in the
formulation of syrups and elixirs. Such formulations can also
contain a demulcent, a preservative, or a coloring agent.
[0225] The GR modulators of the invention can be delivered by
transdermally, by a topical route, formulated as applicator sticks,
solutions, suspensions, emulsions, gels, creams, ointments, pastes,
jellies, paints, powders, and aerosols.
[0226] The GR modulators of the invention can also be delivered as
microspheres for slow release in the body. For example,
microspheres can be administered via intradermal injection of
drug-containing microspheres, which slowly release subcutaneously
(see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as
biodegradable and injectable gel formulations (see, e.g., Gao
Pharm. Res. 12:857-863, 1995); or, as microspheres for oral
administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,
1997). Both transdermal and intradermal routes afford constant
delivery for weeks or months.
[0227] The GR modulator pharmaceutical formulations of the
invention can be provided as a salt and can be formed with many
acids, including but not limited to hydrochloric, sulfuric, acetic,
lactic, tartaric, malic, succinic, etc. Salts tend to be more
soluble in aqueous or other protonic solvents that are the
corresponding free base forms. In other cases, the preparation may
be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose,
2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with
buffer prior to use
[0228] In another embodiment, the GR modulator formulations of the
invention are useful for parenteral administration, such as
intravenous (IV) administration or administration into a body
cavity or lumen of an organ. The formulations for administration
will commonly comprise a solution of the GR modulator dissolved in
a pharmaceutically acceptable carrier. Among the acceptable
vehicles and solvents that can be employed are water and Ringer's
solution, an isotonic sodium chloride. In addition, sterile fixed
oils can conventionally be employed as a solvent or suspending
medium. For this purpose any bland fixed oil can be employed
including synthetic mono- or diglycerides. In addition, fatty acids
such as oleic acid can likewise be used in the preparation of
injectables. These solutions are sterile and generally free of
undesirable matter. These formulations may be sterilized by
conventional, well known sterilization techniques. The formulations
may contain pharmaceutically acceptable auxiliary substances as
required to approximate physiological conditions such as pH
adjusting and buffering agents, toxicity adjusting agents, e.g.,
sodium acetate, sodium chloride, potassium chloride, calcium
chloride, sodium lactate and the like. The concentration of GR
modulator in these formulations can vary widely, and will be
selected primarily based on fluid volumes, viscosities, body
weight, and the like, in accordance with the particular mode of
administration selected and the patient's needs. For IV
administration, the formulation can be a sterile injectable
preparation, such as a sterile injectable aqueous or oleaginous
suspension. This suspension can be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can also be a
sterile injectable solution or suspension in a nontoxic
parenterally-acceptable diluent or solvent, such as a solution of
1,3-butanediol.
[0229] In another embodiment, the GR modulator formulations of the
invention can be delivered by the use of liposomes which fuse with
the cellular membrane or are endocytosed, i.e., by employing
ligands attached to the liposome, or attached directly to the
oligonucleotide, that bind to surface membrane protein receptors of
the cell resulting in endocytosis. By using liposomes, particularly
where the liposome surface carries ligands specific for target
cells, or are otherwise preferentially directed to a specific
organ, one can focus the delivery of the GR modulator into the
target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.
13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995;
Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).
[0230] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0231] The quantity of active component in a unit dose preparation
may be varied or adjusted from 0.1 mg to 10000 mg, more typically
1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the
particular application and the potency of the active component. The
composition can, if desired, also contain other compatible
therapeutic agents.
V. Methods for Treating Conditions Mediated by Glucocorticoid
Receptors
[0232] In another aspect, the present invention provides a method
for the treatment of a disorder or condition through modulation of
a glucocorticoid receptor. In this method, a subject in need of
such treatment is administered an effective amount of a compound of
the present invention. The amount is effective in modulating the
glucocorticoids receptor.
[0233] A variety of disease states are capable of being treated
with glucocorticoid receptor modulators of the present invention.
Exemplary disease states include major psychotic depression, mild
cognitive impairment, psychosis, dementia, hyperglycemia, stress
disorders, antipsychotic induced weight gain, delirium, cognitive
impairment in depressed patients, cognitive deterioration in
individuals with Down's syndrome, psychosis associated with
interferon-alpha therapy, chronic pain (e.g. pain associate with
gastroesophageal reflux disease), postpartum psychosis, postpartum
depression, neurological disorders in premature infants, migraine
headaches, obesity, diabetes, cardiovascular disease, hypertension,
Syndrome X, depression, anxiety, glaucoma, human immunodeficiency
virus (HIV) or acquired immunodeficiency syndrome (AIDS),
neurodegeneration (e.g. Alzheimer's disease and Parkinson's
disease), cognition enhancement, Cushing's Syndrome, Addison's
Disease, osteoporosis, frailty, inflammatory diseases (e.g.,
osteoarthritis, rheumatoid arthritis, asthma and rhinitis), adrenal
function-related ailments, viral infection, immunodeficiency,
immunomodulation, autoimmune diseases, allergies, wound healing,
compulsive behavior, multi-drug resistance, addiction, psychosis,
anorexia, cachexia, post-traumatic stress syndrome post-surgical
bone fracture, medical catabolism, and muscle frailty. The methods
of treatment includes administering to a patient in need of such
treatment, a therapeutically effective amount of a compound of the
present invention, or a pharmaceutically acceptable salt
thereof.
[0234] Thus, in an exemplary embodiment, the present invention
provides a method of treating a disorder or condition through
modulating a GR, the method includes administering to a subject in
need of such treatment, an effective amount of a compound of the
present invention, such as a compound of Formula (I).
[0235] The amount of GR modulator adequate to treat a disease
through modulating the GR is defined as a "therapeutically
effective dose." The dosage schedule and amounts effective for this
use, i.e., the "dosing regimen," will depend upon a variety of
factors, including the stage of the disease or condition, the
severity of the disease or condition, the general state of the
patient's health, the patient's physical status, age and the like.
In calculating the dosage regimen for a patient, the mode of
administration also is taken into consideration.
[0236] The dosage regimen also takes into consideration
pharmacokinetics parameters well known in the art, i.e., the rate
of absorption, bioavailability, metabolism, clearance, and the like
(see, e.g., Hidalgo-Aragones (1996) J Steroid Biochem. Mol. Biol.
58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996)
Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146;
Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin.
Pharmacol. 24:103-108; the latest Remington's, supra). The state of
the art allows the clinician to determine the dosage regimen for
each individual patient, GR modulator and disease or condition
treated.
[0237] Single or multiple administrations of GR modulator
formulations can be administered depending on the dosage and
frequency as required and tolerated by the patient. The
formulations should provide a sufficient quantity of active agent
to effectively treat the disease state. Thus, in one embodiment,
the pharmaceutical formulations for oral administration of GR
modulator is in a daily amount of between about 0.5 to about 20 mg
per kilogram of body weight per day. In an alternative embodiment,
dosages are from about 1 mg to about 4 mg per kg of body weight per
patient per day are used. Lower dosages can be used, particularly
when the drug is administered to an anatomically secluded site,
such as the cerebral spinal fluid (CSF) space, in contrast to
administration orally, into the blood stream, into a body cavity or
into a lumen of an organ. Substantially higher dosages can be used
in topical administration. Actual methods for preparing
parenterally administrable GR modulator formulations will be known
or apparent to those skilled in the art and are described in more
detail in such publications as Remington's, supra. See also Nieman,
In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds.,
De Gruyter, New York (1987).
[0238] After a pharmaceutical composition including a GR modulator
of the invention has been formulated in an acceptable carrier, it
can be placed in an appropriate container and labeled for treatment
of an indicated condition. For administration of GR modulators,
such labeling would include, e.g., instructions concerning the
amount, frequency and method of administration. In one embodiment,
the invention provides for a kit for the treatment of delirium in a
human which includes a GR modulator and instructional material
teaching the indications, dosage and schedule of administration of
the GR modulator.
[0239] The terms and expressions which have been employed herein
are used as teams of description and not of limitation, and there
is no intention in the use of such terms and expressions of
excluding equivalents of the features shown and described, or
portions thereof, it being recognized that various modifications
are possible within the scope of the invention claimed. Moreover,
any one or more features of any embodiment of the invention may be
combined with any one or more other features of any other
embodiment of the invention, without departing from the scope of
the invention. For example, the features of the GR modulator
compounds are equally applicable to the methods of treating disease
states and/or the pharmaceutical compositions described herein. All
publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
EXAMPLES
[0240] The following examples are provided solely to illustrate the
present invention and are not intended to limit the scope of the
invention, as described herein.
[0241] High Pressure Liquid Chromatography--Mass Spectrometry
(LCMS) experiments to determine retention times (RT) and associated
mass ions were performed using one of the following methods.
Solvent A is water and solvent B is acetonitrile.
[0242] Method A: Experiments performed on a Micromass Platform LC
spectrometer with positive and negative ion electrospray and
ELS/Diode array detection using a Phenomenex Luna C18(2)
30.times.4.6 mm column and a 2 mL/minute flow rate. The solvent
system was 95% solvent A and 5% solvent B for the first 0.50
minutes followed by a gradient up to 5% solvent A and 95% solvent B
over the next 4 minutes. The final solvent system was held constant
for a further 0.50 minutes.
[0243] Method B: Experiments performed on a Micromass Platform LCT
spectrometer with positive ion electrospray and single wavelength
UV 254 nm detection using a Higgins Clipeus C18 5 .mu.m
100.times.3.0 mm column and a 2 mL/minute flow rate. The initial
solvent system was 95% water containing 0.1% formic acid (solvent
A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for
the first minute followed by a gradient up to 5% solvent A and 95%
solvent B over the next 14 minutes. The final solvent system was
held constant for a further 2 minutes.
Example 1
1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (2:
R.sup.1B=H, Z=benzyl)
##STR00031##
[0245] 1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester
hydrochloride salt (1, Z=benzyl) (15 g, 52.9 mmol) was suspended in
DMF (150 mL) and cooled to 0.degree. C. Sodium hydride (4.23 g,
105.8 mmol) was added portionwise over 1 h and the contents were
allowed to warm to ambient temperature and stir for a further 1 h.
Benzyl bromide (6.3 mL, 53.0 mmol) was added over 15 min and the
contents were stirred for a further 68 h at ambient temperature. 10
mL of water were added and the contents were diluted with 400 mL of
ethyl acetate, washed with water (200 mL), saturated sodium
bicarbonate (200 mL) and brine (200 mL). The organic layer was
dried over magnesium sulfate, filtered and concentrated to give
20.5 g yellow oil that was purified by flash column chromatography
(3:2 cyclohexane/CH.sub.2Cl.sub.2 to 100% CH.sub.2Cl.sub.2) to give
17.52 g (98%) of the title compound as a colorless oil. LC-MS:
RT=2.80 min. (M+H).sup.+ 338, (M-OMe).sup.+ 306.
Example 2
1,3-Dibenzylpiperidin-4-one (3: R.sup.1B=H, Z=benzyl)
##STR00032##
[0247] 1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl
ester, (2, R.sup.1B=H, Z=benzyl) (17.52 g, 51.92 mmol) was
suspended in 150 mL of 6N HCl:MeOH (5:1) and the mixture was heated
to reflux temperature with stirring for 48 h. After cooling the
mixture was basified to pH 10 with 6N NaOH and extracted with
3.times.200 mL dichloromethane. The combined organics were dried
(MgSO.sub.4) and concentrated to give 11.60 g of the title compound
as a colorless oil, 80%. LC-MS: RT=0.38 min. (M+H).sup.+ 280.
Example 3
2,8a-Dibenzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (4:
R.sup.1B=H, Z=benzyl)
##STR00033##
[0249] 1,3-Dibenzylpiperidin-4-one (3, R.sup.1B=H, Z=benzyl) (3.98
g, 13.96 mmol) was added to a solution of sodium methoxide (0.83 g,
15.36 mmol) in 80 mL of methanol and stirred at ambient temperature
for 45 min. The contents were cooled to 0.degree. C. and
methylvinyl ketone (1.74 mL, 20.94 mmol) was added over 30 min. The
contents were allowed to warm to ambient temperature and stir for
18 h. Concentrated HCl (1.55 mL) was added, the contents were
stirred for a further 5 min and the solvents were evaporated to
give a brown oil which was triturated in diethyl ether to give the
title compound, 1.90 g. LC-MS: RT=2.26 min. (M+H).sup.+ 332.
Example 4
(R)-8a-Benzyl-6-oxo-3,4,6,7,8,8a-hexahydro-1H-isoquinoline-2-carboxylic
acid tert-butyl ester (4: R.sup.1B=H, Z=t-Butoxycarbonyl)
##STR00034##
[0251] 3-Benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester
(1, Z=t-butoxycarbonyl) (11.50 g, 39.79 mmol) was dissolved in
toluene (30 mL) and (R)-(+)-.alpha.-methylbenzylamine (6.15 mL,
47.75 mmol) was added. The contents were heated to reflux for 20 h
(with a Dean-Stark trap) and then cooled to room temperature. The
mixture was concentrated in vacuo and the resultant colorless oil
(16.5 g, 39.79 mmol) was dissolved in toluene and cooled to
0.degree. C. and methylvinyl ketone (4.0 mL, 47.45 mmol) was added
dropwise. After 30 min the temperature was raised to 45.degree. C.
After 6 days at 45.degree. C., acetic acid (20 mL) and water (20
mL) were added and the contents were stirred at ambient temperature
for 1 h. The organics were extracted with CH.sub.2Cl.sub.2 (50 mL),
washed with water, dried with MgSO.sub.4, concentrated and purified
by flash chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) to afford 8.6 g of the intermediate diketone
3-benzyl-5-(1-hydroxy-1-methyl-propyl)-3-methyl-4-oxo-piperidine-1-carbox-
ylic acid tert-butyl ester as a colorless oil. The intermediate
diketone (900 mg, 2.50 mmol) was dissolved in methanol (14 mL) and
sodium methoxide (20 mg, 1.30 mmol) was added and the contents were
heated at 75.degree. C. for 3 h. The contents were cooled to
0.degree. C. and acetic acid (135 .mu.L) was added. The volatiles
were removed and the residue was partitioned between EtOAc (10 mL)
and saturated NaHCO.sub.3 solution. The organic phase was washed
with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 15% EtOAc in
CH.sub.2Cl.sub.2) afforded 1.10 g of the title compound as a
colorless oil. LC-MS (Method A): RT=3.84 mm, (M+H).sup.+ no
molecular ion seen.
Example 5
8a-Benzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (5A:
R.sup.1B=H)
##STR00035##
[0253] Compound 4 (R.sup.1B=H, Z=benzyl) (3.0 g (9.05 mmol) and
.alpha.-chloroethyl chloroformate (1.22 mL, 11.3 mmol) in
dichloroethane (50 mL) were heated to reflux under nitrogen for 18
h. After cooling, the mixture was concentrated in vacuo. Methanol
(50 mL) was added and the contents heated to reflux for 6 h. The
solvents were removed by evaporation and the residue was purified
by flash column chromatography (100% CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2/MeOH 9:1) to give the title compound as a pale
brown solid, 1.51 g. LC-MS: RT=1.67 min. (M+H).sup.+ 242
[0254] The following compounds were prepared according to the
procedures described in Examples 1 to 4:
8a-(3-Methoxybenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one
##STR00036##
[0255]
8a-(4-Methoxybenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one
##STR00037##
[0256]
8a-(4-Bromobenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one
##STR00038##
[0257] and
8a-(4-Nitrobenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one
##STR00039##
[0258] Example 6
2-Benzenesulfonyl-8a-benzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one
(10A: R.sup.1B=H, R.sup.2A=Ph)
##STR00040##
[0260] Benzenesulfonyl chloride (90.0 mmol) was added to a stirred
solution of compound 5 (R.sup.1B=H) (25.0 mg, 90.0 mmol),
triethylamine (25.0 .mu.L, 180 mmol) in 1,2-dichloroethane (3 mL).
The resulting mixture was then stirred at room temperature for 18
h. PS-Trisamine resin (33.0 mg, loading=4.11 mmol/g) was added and
the mixture was agitated at room temperature for a further 24 h.
The mixture was filtered and the filtrate was purified by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) to afford the title compound 1 as a yellow oil,
which solidified on standing. LC-MS: RT=3.68 min (M+H).sup.+
382.
Example 7
(R)-8a-Benzyl-2-(4-tert-butyl-benzenesulfonyl)-1,3,4,7,8,8a-hexahydro-2H-i-
soquinolin-6-one (10A: R.sup.1B=H, R.sup.2A=(4-t-Butyl)phenyl)
##STR00041##
[0262] To compound (R)-5A (R.sup.1B=H, Z=t-butoxycarbonyl) (598 mg,
1.75 mmol) was added a 20% solution of TFA in CH.sub.2Cl.sub.2 and
the contents were stirred at ambient temperature for 2.5 h. The
solvents were then removed in vacuo. The residue was dissolved in
CH.sub.2Cl.sub.2 (5 mL) and diisopropylethylamine (670 .mu.L, 3.86
mmol) and 4-t-butylphenylsulfonyl chloride (526 mg, 1.93 mmol) were
added and the contents were stirred for 18 h. Water (10 mL) was
added and the organics were extracted with EtOAc (15 mL), washed
with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) afforded 600 mg of the title compound as an
orange oil. LC-MS (Method A): RT=4.06 min, (M+H).sup.+ 438.
Example 8
2,8a.beta.-Dibenzyl-1,3,4,4a.alpha.,5,7,8,8a-octahydro-2H-isoquinolin-6-on-
e (6B: R.sup.1B=H, R.sup.2=Phenyl)
##STR00042##
[0264] Lithium metal (150 mg) was added to a flask charged with 75
mL of liquid ammonia.
2,8a-Dibenzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (4,
R.sup.1B=H, Z=benzyl) (2.0 g) was added and the contents were
stirred at -78.degree. C. for 20 min. A further 150 mg of lithium
metal was added and stirring continued for a further 15 min. Solid
ammonium chloride was added until the blue color was discharged.
The contents were warmed to ambient temperature and extracted with
dichloromethane. The organic phase was washed with saturated.
ammonium chloride, dried and concentrated to give a residue that
was purified by flash column chromatography (10% EtOAc in
CH.sub.2Cl.sub.2) to give 0.60 g of the title compound. LC-MS:
RT=2.15 min. (M+H).sup.+ 334.
Example 9
8a.beta.-Benzyl-1,3,4,4a.alpha.,5,7,8,8a-octahydro-2H-isoquinolin-6-one
(5B: R.sup.1B=H)
##STR00043##
[0266] Compound 6B (R.sup.1B=H, R.sup.2=Ph) (1.14 g, 3.42 mmol) and
palladium hydroxide (0.35 g, 0.342 mmol) were suspended in 40 mL of
acetic acid and hydrogenated at atmospheric pressure for 21 h. The
reaction mixture was filtered, concentrated and dissolved in
CH.sub.2Cl.sub.2 and treated with 1M HCl in diethyl ether to give
the title compound as its hydrochloride salt, a beige solid, 0.96
g. LC-MS RT=1.67 min. (M+H).sup.+ 244.
Example 10
2-Benzenesulfonyl-8a.beta.-benzyl-1,3,4,4a,.alpha.,5,7,8,8a-octahydro-2H-i-
soquinolin-6-one (10B: R.sup.1B=H, R.sup.2A=Phenyl)
##STR00044##
[0268]
8a.beta.-Benzyl-1,3,4,4a.alpha.,5,7,8,8a-octahydroisoquinolin-6-one
(5B: R.sup.1B=H) (84 mg, 0.348 mmol) and benzenesulfonyl chloride
(49 .mu.L, 0.383 mmol) were stirred in CH.sub.2Cl.sub.2 and
diisopropylethylamine (73 .mu.L) was added. The contents were
stirred for 18 h, diluted with CH.sub.2Cl.sub.2, washed with water,
brine, dried, concentrated and purified by flash column
chromatography (10% EtOAc in CH.sub.2Cl.sub.2) to give the title
compound as a waxy pale yellow solid (83 mg). LC-MS: RT=3.24 min.
(M+H).sup.+ 384.
[0269] The following compound was similarly prepared:
8a.beta.-Benzyl-2-(4-tert-butylbenzenesulfonyl)-1,3,4,4a.alpha.,5,7,8,8a-o-
ctahydro-2H-isoquinolin-6-one
##STR00045##
[0270] Example 11
2,8a-Dibenzyl-7-[1-hydroxy-meth-(Z)-ylidene]-1,3,4,7,8,8a-hexahydro-2H-iso-
quinolin-6-one (12A: R.sup.1B=H, L.sup.2-R.sup.2=Benzyl)
##STR00046##
[0272] Compound 6A (R.sup.1B=H, L.sup.2-R.sup.2=benzyl) (0.31 g,
0.94 mmol) was dissolved in toluene (2.5 mL). Ethyl formate (152
.mu.L, 1.88 mmol) was added followed by sodium methoxide (102 mg,
1.88 mmol). The contents were heated to reflux for 90 min, then
cooled, poured into water and extracted with CH.sub.2Cl.sub.2. The
organic phase was washed with brine and dried (MgSO.sub.4). Removal
of solvent gave 334 mg of the title compound as an orange oil which
was used in subsequent examples without further purification. LC-MS
(Method A): RT=2.33 min, (M+H).sup.+ 360.
Example 12
8a-Benzyl-2-(4-tert-butylbenzenesulfonyl-7-hydroxymethylene-1,3,4,7,8,8a-h-
exahydro-2H-isoquinolin-6-one (12A: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00047##
[0274] Compound 10A (R.sup.1B=H; R.sup.2A=(4-t-butyl)phenyl) (100
mg, 0.229 mmol) was dissolved in toluene (1 mL). Ethyl formate (37
.mu.L, 0.46 mmol) was added followed by sodium methoxide (25 mg,
0.46 mmol). The contents were heated to reflux for 35 min, then
cooled, poured into water and extracted with CH.sub.2Cl.sub.2. The
organic phase was washed with brine and dried (MgSO.sub.4). Removal
of solvent gave 113 mg of the title compound as an orange glass
which was used in subsequent examples without further purification.
LC-MS: RT=4.36 min. (M+H).sup.+ 466, (M-H).sup.- 464.
Example 13
(S)-8a-Benzyl-2-(4-tert-butyl-benzenesulfonyl)-7-[1-hydroxy-meth-(Z)-ylide-
ne]-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (12A: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00048##
[0276] Compound (R)-10A (R.sup.1B=H, R.sup.2A=(4-t-butyl)phenyl)
(665 mg, 1.52 mmol) was dissolved in methanol (5 mL) and sodium
methoxide (234 mg, 4.35 mmol) and ethyl formate (450 .mu.L, 7.60
mmol) were added. After 1 h, water (5 mL) was added and the
organics were extracted with EtOAc, washed with brine and dried
(MgSO.sub.4). Removal of solvent gave 532 mg of the title compound
as an orange foam which was used in subsequent examples without
further purification. LC-MS (Method A): RT=4.40 min, (M+H).sup.+
466.
Example 14
8a-Benzyl-2-(4-tert-butylbenzenesulfonyl)-7-hydroxymethylene-octahydroisoq-
uinolin-6-one. (12B: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00049##
[0278] Compound 10B (R.sup.1B=H; R.sup.2A=(4-t-butylphenyl)) (100
mg, 0.228 mmol) was dissolved in toluene (1 mL) and ethyl formate
(25 mg, 0.46 mmol) was added followed by sodium methoxide (25 mg,
0.46 mmol). The contents were heated to reflux for 35 min, then
cooled, poured into water and extracted with CH.sub.2Cl.sub.2. The
organics were washed with brine, dried (MgSO.sub.4) and
concentrated to give the title compound together with the
5-hydroxymethylene regioisomer which were used directly in the
following Examples without further purification. LC-MS: RT=4.46
min. (M+H).sup.+ 468.
Example 15
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6--
triazacyclopenta[b]naphthalene. (13A: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00050##
[0280] Compound 12A (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)Ph) (23 mg, 49.5 .mu.mol) was
suspended in ethanol (1 mL) and hydrazine hydrate (10 .mu.L, 0.32
mmol) was added and the contents were heated to reflux for 1.5 h.
The volatiles were removed under vacuum to give 40 mg of an orange
glass that was purified by preparative HPLC to yield the title
compound as a colorless glass, 10 mg. LC-MS: RT=4.12 min.
(M+H).sup.+ 462.
[0281] The following compounds were similarly prepared:
4a-Benzyl-6-(4-morpholin-4-yl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1-
,2,6-triaza-cyclopenta[b]naphthalene
##STR00051##
[0283] LC-MS (Method A): RT=3.15 min, (M+H).sup.+ 491.
4a-Benzyl-6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00052##
[0285] LC-MS (Method A): RT=3.51 min, (M+H).sup.+ 477.
Example 16
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-2-methyl-4,4a,5,6,7,8-hexahydro--
2H-1,2,6-triazacyclopenta[b]naphthalene. (14A: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl, R.sup.6C=Me)
##STR00053##
[0287] Compound 12A (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) (20 mg, 43 .mu.mol) was
suspended in ethanol (1 mL) and methyl hydrazine (15 .mu.L, 0.28
mmol) was added. The contents were heated to 90.degree. C. for 1.5
h, then cooled and evaporated to give 22 mg of an orange glass.
Purification by preparative HPLC yielded the title compound: 3.5 mg
as a yellow glass. LC-MS: RT=4.39 min. (M+H).sup.+ 476.
Example 17
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8--
hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene. (15A:
R.sup.1B=H, L.sup.2-R.sup.2.dbd.SO.sub.2(4-t-Butyl)phenyl)
##STR00054##
[0289] Compound 12A (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) (28 mg, 60.2 mmol),
4-fluorophenylhydrazine hydrochloride (10.8 mg, 66.2 mmol) and
sodium acetate (5.4 mg, 66.2 .mu.mol) were dissolved in acetic acid
(0.8 mL) and heated to 90.degree. C. for 18 h. The contents were
cooled, poured into water, extracted with CH.sub.2Cl.sub.2, dried
(MgSO.sub.4) and concentrated to give 41 mg of red-brown oil that
was purified by preparative HPLC to give the title compound as an
orange-brown glass, 8 mg. LC-MS: RT=4.85 min. (M+H).sup.+ 556.
[0290] The following compounds were similarly prepared:
(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00055##
[0291]
(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-methoxy-phenyl)-
-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00056##
[0293] LC-MS (Method A): RT=4.78 min, (M+H).sup.+ 568.
(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-p-tolyl-4,4a,5,6,7,8-hexa-
hydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00057##
[0295] LC-MS (Method A): RT=4.96 min, (M+H).sup.+ 552.
1,4a-Dibenzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1-
,2,6-triaza-cyclopenta[b]naphthalene
##STR00058##
[0297] LC-MS (Method A): RT=4.73 min, (M+H).sup.+ 552.
4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-trifluoromethyl-phenyl)-4,-
4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00059##
[0299] LC-MS (Method A): RT=5.03 min, (M+H).sup.+ 606.
4-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-
-triaza-cyclopenta[b]naphthalen-1-yl]-benzonitrile
##STR00060##
[0301] LC-MS (Method A): RT=4.74 min, (M+H).sup.+ 563.
4-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-
-triaza-cyclopenta[b]naphthalen-1-yl]-benzenesulfonamide
##STR00061##
[0303] LC-MS (Method A): RT=4.25 min, (M+H).sup.+ 617.
3-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-
-triaza-cyclopenta[b]naphthalen-1-ylmethyl]-phenol
##STR00062##
[0305] LC-MS (Method A): RT=4.33 min, (M+H).sup.+ 568.
Example 18
4a,6-Dibenzyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-c-
yclopenta[b]naphthalene (15A: R.sup.1B=H,
L.sup.2-R.sup.2=benzyl)
##STR00063##
[0307] Compound 12A (R.sup.1B=H, L.sup.2-R.sup.2=benzyl) (167 mg,
0.47 mmol) and 4-fluorophenylhydrazine hydrochloride (163 mg, 2.79
mmol) were dissolved in acetic acid (2.5 mL) and heated to
90.degree. C. for 2 hours. The contents were cooled, poured into
water, extracted with CH.sub.2Cl.sub.2, dried (MgSO.sub.4) and
concentrated. Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 15% EtOAc in CH.sub.2Cl.sub.2) afforded
41 mg of the title compound as an orange oil. LC-MS (Method A):
RT=2.75 min, (M+H).sup.+ 450.
[0308] The following compounds were similarly prepared:
6-Benzyl-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1-
H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00064##
[0310] LC-MS (Method A): RT=2.80 min, (M+H).sup.+ 468.
6-Benzyl-1-(4-fluoro-phenyl)-4a-(4-methoxy-benzyl)-4,4a,5,6,7,8-hexahydro--
1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00065##
[0312] LC-MS (Method A): RT=2.69 min, (M+H).sup.+ 480.
Example 19
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1-oxa-2,6-
-diazacyclopenta[b]naphthalene. (16A: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00066##
[0314] Compound 12A (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) (21 mg, 45 .mu.mol) and
hydroxylamine sulfate (4 mg, 22.5 .mu.mol) were dissolved in ethyl
acetate (1 mL), acetic acid (0.2 mL) and water (0.1 mL) and heated
to 90.degree. C. for 19 h. The contents were evaporated to dryness
and purified by preparative HPLC to yield the title compound, 0.9
mg. LC-MS: RT=4.49 min. (M+H).sup.+ 463.
Example 20
10a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-2-methyl-5,6,7,8,10,10a-hexahy-
dro-1,3,6-triaza-anthracene (17A: R.sup.5D=Methyl; R.sup.1B=H;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00067##
[0316] Compound 12A (R.sup.1B=H;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (50 mg, 0.11 mmol) was
heated with acetamidine hydrochloride (61 mg, 0.65 mmol) in DMF
(0.5 mL) at 180.degree. C. using microwave irradiation for 10 min.
Water (5 mL) was added and the organics were extracted with
CH.sub.2Cl.sub.2 (3.times.5 mL) and washed with brine and dried
(MgSO.sub.4). Purification by preparative HPLC afforded 6 mg of the
title compound as a yellow oil. LC-MS (Method A): RT=4.01 min,
(M+H).sup.+ 488.
Example 21
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-2H-1-
,2,6-triazacyclopenta[b]naphthalene. (13B: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00068##
[0318] The mixture of compound 12B (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) and its regioisomer (29
mg, 42.8 .mu.mol), hydrazine hydrate (9 .mu.L, 0.278 mmol) and
ethanol (1 mL) were heated at 90.degree. C. for 1.5 h. The
volatiles were removed under vacuum to give 21 mg of a glass that
was purified by preparative HPLC to give the title compound as an
off-white solid, 16 mg. LC-MS: RT=4.03 min. ((M+H).sup.+ 464.
Example 22
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,-
8a,9-octahydro-1H-1,2,6-triazacyclopenta[b]naphthalene. (15B:
R.sup.1B=H, L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00069##
[0320] The mixture of compound 12B (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) and its regioisomer (20
mg, 42.8 .mu.mol) and 4-fluorophenylhydrazine hydrochloride (7.6
mg, 47.1 .mu.mol)) were dissolved in acetic acid and sodium acetate
(4 mg, 47.1 mmol) added. The contents were heated to 90.degree. C.
for 16 h, then cooled and poured into water and extracted with
CH.sub.2Cl.sub.2. The organics were washed with brine, dried
(MgSO.sub.4) and concentrated to give 22 mg crude product which was
purified by preparative HPLC to yield the title compound as a brown
glass, 11 mg. LC-MS: RT=4.93 mins. (M+H).sup.+ 558.
Example 23
4a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1-ox-
a-2,6-diazacyclopenta[b]naphthalene. (16B: R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00070##
[0322] The mixture of compound 12B (R.sup.1B=H,
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) and its regioisomer (20
mg, 42.8 .mu.mol) were dissolved in ethanol (0.6 mL) and acetic
acid (0.2 mL) and water (0.1 mL) were added, followed by
hydroxylamine hydrochloride (3.8 mg, 54.6 .mu.mol). The contents
were heated to 90.degree. C. for 19 h, the volatiles were removed
and the residue was purified by preparative HPLC to yield the title
compound as an off-white solid, 7 mg. LC-MS: RT=4.47 min. (M+H)+
465
Example 24
(R)-7-Acetoxy-2-(4-tert-butyl-benzenesulfonyl)-6-oxo-2,3,4,6,7,8-hexahydro-
-1H-isoquinoline-8a-carboxylic acid methyl ester (24A:
L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00071##
[0324] To a solution of compound (R)-23A
(L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl)) (1.00 g, 2.47 mmol) in
toluene (50 mL) was added manganese acetate dihydrate (3.69 g,
13.79 mmol). The contents were heated for 18 h at reflux under a
Dean-Stark trap. The solvents were removed and the residue was
purified by flash chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc
in CH.sub.2Cl.sub.2) to afford 775 mg of the title compound as an
off white solid. LC-MS (Method A): RT=3.82 min, (M+H).sup.+
464.
Example 25
(R)-6-(4-tert-Butyl-benzenesulfonyl)-2-methyl-1,4,5,6,7,8-hexahydro-1,3,6--
triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester
(25A: L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00072##
[0326] To a solution of compound 24A (L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl)) (600 mg, 1.29 mmol) in
ethanol (4 mL) was added copper.sup.II acetate (470 mg, 2.59 mmol),
aqueous ammonia (3 mL) and acetaldehyde (5 mL) and the contents
were heated for 5 h at reflux. The solvents were removed,
NaHCO.sub.3 (20 mL) was added, and the organics were extracted with
CH.sub.2Cl.sub.2 (20 mL), washed with brine and dried (MgSO.sub.4).
Purification by flash chromatography (CH.sub.2Cl.sub.2 100% to 5%
EtOAc in CH.sub.2Cl.sub.2) afforded 432 mg of the title compound as
an off white solid. LC-MS (Method A): RT=2.53 min, (M+H).sup.+
444.
Example 26
(S)-8a-Methyl-6-oxo-3,4,6,7,8,8a-hexahydro-1H-isoquinoline-2-carboxylic
acid tert-butyl ester (36A: L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00073##
[0328] 1-Benzyl-3-methyl-piperidin-4-one (15.0 g, 73.89 mmol) was
dissolved in toluene (150 mL) and (R)-(+)-.alpha.-methylbenzylamine
(11.4 mL, 88.67 mmol) was added. The contents were heated to reflux
for 20 h (Dean-Stark trap) and then cooled to room temperature. The
resultant colorless oil was dissolved in THF and methylvinylketone
(7.40 mL, 88.67 mmol) and hydroquinone (150 mg, catalytic) were
added and the contents were stirred in the dark. After 2 days 1N
HCl (90 mL) was added and the contents stirred at ambient
temperature for 30 min, the organics were extracted with diethyl
ether (100 mL), washed with water, dried with MgSO.sub.4,
concentrated and purified by flash chromatography (CH.sub.2Cl.sub.2
100% to 20% EtOAc in CH.sub.2Cl.sub.2) to afford 6.51 g of
((R)-1-benzyl-3-methyl-3-(3-oxo-butyl)-piperidin-4-one as a
colorless oil. LC-MS (Method A): RT=0.32 min, (M+H).sup.+ 274.
[0329] This material (6.5 g, 23.80 mmol) was dissolved in ethanol
(100 mL) and 20% palladium hydroxide on carbon (500 mg) and
di-tort-butyl dicarbonate (7.8 g, 35.71 mmol) were added. The
contents were stirred under a hydrogen atmosphere for 18 h. The
catalyst was removed by filtration and filtrate evaporated to
dryness. Purification by flash chromatography (20% tert-butyl
methylether in cyclohexanone) afforded 6.16 g of
(R)-3-methyl-4-oxo-3-(3-oxo-butyl)-piperidine-1-carboxylic acid
tert-butyl ester as a colorless oil. LC-MS (Method A): RT=3.03 min,
(M+H).sup.+=284. To a solution of this material (6.10 g, 21.55
mmol) in methanol (100 mL) was added sodium methoxide (3.84 g,
43.10 mmol) and the contents heated at 50.degree. C. for 18 hours.
The volatiles were removed and the residue partitioned between
EtOAc (50 mL) and water then the organic phase washed with brine
and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 10% EtOAc in CH.sub.2Cl.sub.2) afforded
3.33 g of the title compound as a colorless oil. LC-MS (Method A):
RT=3.15 min, (M+H).sup.+ 266.
Example 27
(S)-7-[1-Hydroxy-meth-(Z)-ylidene]-8a-methyl-6-oxo-3,4,6,7,8,8a-hexahydro--
1H-isoquinoline-2-carboxylic acid tert-butyl ester (37A:
R.sup.5=4-F-Phenyl, L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00074##
[0331] To a solution of diisopropylamine (3.05 mL, 21.79 mmol) in
diethyl ether (50 mL) at -78.degree. C. was added n-butyl lithium
(12.45 mL, 1.6 M solution, 19.92 mmol). Compound (S)-36A
(L.sup.2-R.sup.2=CO.sub.2-t-butyl) (665 mg, 1.52 mmol) in diethyl
ether (10 mL) was then added followed by the addition of
trifluorethyl orthoformate (6.00 g, 46.81 mmol) after 20 min. After
a further 90 min, 2N HCl (30 mL) was added and the contents were
warmed to ambient temperature. Water (15 mL) and EtOAc (50 mL) were
added and the organic phase was separated, washed with brine and
dried (MgSO.sub.4). Removal of solvent gave 1.45 g of the title
compound as a yellow powder that was used in subsequent examples
without further purification. LC-MS (Method A): RT=3.56 min,
(M+H).sup.+ no molecular ion seen.
Example 28
(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cycl-
openta[b]naphthalene-6-carboxylic acid tert-butyl ester (40A:
R.sup.5=4-F-Phenyl, L.sup.2-R.sup.2=CO.sub.7-t-Butyl)
##STR00075##
[0333] Compound 37A (L.sup.2-R.sup.2=CO.sub.2-t-butyl) (2.50 g,
8.53 mmol) was suspended in acetic acid (25 mL) and sodium acetate
(1.05 g, 12.80 mmol) and 4-fluorophenylhydrazine hydrochloride
(2.08 g, 12.80 mmol) were added. After 2 h water (40 mL) was added
and the organics were extracted with EtOAc (40 mL), washed with
brine and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) to afford
2.21 g of the title compound as a cream colored solid. LC-MS
(Method A): RT=3.52, (M+H).sup.+=384.
Example 29
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene (40A:
L2-R2=SO2(4-t-Butyl)phenyl)
##STR00076##
[0335] To compound 37A (L.sup.2-R.sup.2=CO.sub.2-t-butyl) (290 mg,
0.78 mmol) was added a 20% solution of TFA in CH.sub.2Cl.sub.2 (3
mL) and the contents were stirred at ambient temperature for 2.5 h.
The solvents were then removed. The residue was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and diisopropylethyl amine (540 .mu.L, 3.88
mmol) and 4-tert-butylphenylsulfonyl chloride (199 mg, 0.85 mmol)
were added and the contents were stirred for 18 h. Water (10 mL)
was added and the organics were extracted with EtOAc (15 mL),
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) afforded 600 mg of the title compound as white
solid. LC-MS (Method A): RT=4.57 min, (M+H).sup.+ 480.
[0336] The following compounds were similarly prepared:
(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-
-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00077##
[0338] LC-MS (Method A): RT=3.93 min, (M+H).sup.+ 424.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexa-
hydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00078##
[0340] LC-MS (Method A): RT=4.11 min, (M+H).sup.+ 438.
(S)-1-(4-Trifluoromethyl-phenyl)-4a-methyl-6-(toluene-4-sulfonyl)-4,4a,5,6-
,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00079##
[0342] LC-MS (Method A): (M+H).sup.+ 492.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(4-morpholin-4-yl-benzenesulfonyl)-4,4-
a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00080##
[0344] LC-MS (Method A): RT=3.81 min, (M+H).sup.+ 509.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxa-
zine-7-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]napht-
halene
##STR00081##
[0346] LC-MS (Method A): RT=4.01 min, (M+H).sup.+ 495.
4-[(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-c-
yclopenta[b]naphthalene-6-sulfonyl]-benzonitrile
##STR00082##
[0348] LC-MS (Method A): RT=3.85 min, (M+H).sup.+ 449.
(S)-1-(4-Fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-4a-methyl-4,4a,5,6,7-
,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00083##
[0350] LC-MS (Method A): RT=3.86 min, (M+H).sup.+ 454.
(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,-
8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00084##
[0352] LC-MS (Method A): RT=3.90 min, (M+H).sup.+ 442.
(S)-6-(2-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,-
8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00085##
[0354] LC-MS (Method A): RT=3.87 min, (M+H).sup.+ 442
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(toluene-2-sulfonyl)-4,4a,5,6,7,8-hexa-
hydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00086##
[0356] LC-MS (Method A): RT=4.02 min, (M+H).sup.+ 438.
(S)-6-Benzyl-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-
-triaza-cyclopenta[b]naphthalene
##STR00087##
[0358] LC-MS (Method A): RT=2.34 min, (M+H).sup.+ 374.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cycl-
openta[b]naphthalene-6-sulfonic acid phenylamide
##STR00088##
[0360] LC-MS (Method A): RT=3.82 min, (M+H).sup.+ 439.
(S)-6-(4,4-Dimethyl-piperidine-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4-
,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00089##
[0362] LC-MS (Method A): RT=4.38 min, (M+H).sup.+ 459.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(piperidine-1-sulfonyl)-4,4a,5,6,7,8-h-
exahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00090##
[0364] LC-MS (Method A): RT=3.85 min, (M+H).sup.+ 431.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-methyl-1-pyridin-4-yl-4,4a,5,6,7,8-
-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00091##
[0366] LC-MS (Method A): RT=3.11 min, (M+H).sup.+ 463.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-methyl-1-pyridin-2-yl-4,4a,5,6,7,8-
-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00092##
[0368] LC-MS (Method A): RT=3.10 min, (M+H).sup.+ 463.
4-[(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-c-
yclopenta[b]naphthalene-6-sulfonyl]-phenylamine
##STR00093##
[0370] LC-MS (Method A): RT=3.53 min, (M+H).sup.+ 439.
(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-trimethylacetyl)-4,4a,5,6,7,8-hexahydr-
o-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00094##
[0372] LC-MS (Method A): (M+H).sup.+ 368.
Example 30
(S)-4-Oxo-3-(3-oxo-butyl)-piperidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-methyl ester (46:
L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00095##
[0374] (S)-4-Oxo-3-(3-oxo-butyl)-piperidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-methyl ester (35.0 g, 0.14 mol) was dissolved
in toluene (150 mL) and (S)-2-amino-N,N-diethyl-3-methyl-butyramide
(27.7 g, 0.16 mol) and concentrated HCl (2 mL) were added. The
contents were heated to reflux for 3 h over 4 .ANG. molecular
sieves. The resultant colorless oil was dissolved in acetone (300
mL) and copper.sup.II acetate (2.19 g, catalytic) were added and
the mixture was heated at reflux for 20 min. Methylvinylketone
(27.3 mL, 0.48 mmol) mmol) was added via the condenser and the
contents were heated at reflux. After 2 h the mixture was cooled to
ambient temperature and 2N HCl (200 mL) was added and the contents
were stirred at ambient temperature for 10 min. The organics were
extracted with EtOAc (100 mL), washed with water, dried with
MgSO.sub.4, concentrated and purified by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% acetone in CH.sub.2Cl.sub.2) to afford
30.58 g of the title compound as an off-white solid. LC-MS (Method
A): RT=3.86 min, (M+H).sup.+ 314.
Example 31
(R)-6-Oxo-4,6,7,8-tetrahydro-3H-isoquinoline-2,8a-dicarboxylic acid
2-tert-butyl ester 8a-methyl ester (47A:
L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00096##
[0376] Compound 46 (L.sup.2-R.sup.2=CO.sub.2-t-butyl) (30.0 g,
91.74 mmol) was dissolved in CH.sub.2Cl.sub.2 (300 mL) and
pyrrolidine (6.5 mL, 77.98 mmol) and acetic acid (4.5 mL, 77.98
mmol) were added. The contents were stirred for 18 h at ambient
temperature. The solvent was removed and the residue was dissolved
in EtOAc, washed with water, 2M HCl, and brine, dried (MgSO.sub.4)
and concentrated in vacuo. Trituration with 50% diethyl ether in
cyclohexane afforded 19.48 g of the title compound as a cream
colored solid. LC-MS (Method A): RT=3.26 min, (M+H).sup.+=310.
Example 32
(R)-7-[1-Hydroxymeth-(Z)-ylidene]-6-oxo-4,6,7,8-tetrahydro-3H-isoquinoline-
-2,8a-dicarboxylic acid 2-tert-butyl ester 8a-methyl ester (48A:
L.sup.2-R.sup.2=CO.sub.7-t-Butyl)
##STR00097##
[0378] To a solution of diisopropylamine (0.79 mL, 5.66 mmol) in
diethyl ether (20 mL) at -78.degree. C. was added n-butyl lithium
(3.20 mL, 1.6 M solution, 5.17 mmol). Compound 47A
(L.sup.2-R.sup.2=CO.sub.2-t-butyl) (1.0 g, 3.23 mmol) in diethyl
ether (5 mL) was added followed by the addition of trifluorethyl
orthoformate (1.20 mL, 12.92 mmol) after 20 min. After a further 90
min, 2N HCl (10 mL) was added and the contents were allowed to warm
to ambient temperature. Water (10 mL) and EtOAc (20 mL) were added
and the organic phase was separated, washed with brine and dried
(MgSO.sub.4). Removal of solvent gave 0.77 g of the title compound
as a yellow powder, which was used in subsequent examples without
further purification. LC-MS (Method A): RT=3.65 min, (M+H).sup.+
338.
Example 33
(R)-1-(4-Fluoro-phenyl)-1,4,7,8-tetrahydro-1,2,6-triaza-cyclopenta[b]napht-
halene-4a,6-dicarboxylic acid 6-tert-butyl ester 4a-methyl ester
(49A: R.sup.5=4-F-Ph; L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00098##
[0380] Compound 48A (L.sup.2-R.sup.2=CO.sub.2-t-butyl) (7.90 g,
23.44 mmol) was suspended in acetic acid (75 mL) and sodium acetate
(2.90 g, 35.16 mmol) and 4-fluorophenylhydrazine hydrochloride
(5.70 g, 35.16 mmol) were added. After 1 h water (60 mL) was added
and the organics were extracted with EtOAc (60 mL) and washed with
brine and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% acetone in CH.sub.2Cl.sub.2) to afford
3.05 g of the title compound as a cream colored solid. LC-MS
(Method A): RT=3.72 min, (M+H).sup.+=428.
Example 34
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid
methyl ester (49A: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00099##
[0382] To compound 48A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=CO.sub.2-t-Butyl) (2.0 g, 4.68 mmol) was added a
20% solution of TFA in CH.sub.2Cl.sub.2 (15 mL) and the contents
were stirred at ambient temperature for 1. The solvents were then
removed in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (2
mL) and diisopropylethyl amine (3.38 mL, 7.03 mmol) and
4-t-butylphenylsulfonyl chloride (2.26 mg, 7.03 mmol) were added
and the contents were stirred for 2 h. Water (50 mL) was added and
the organics were extracted with EtOAc (50 mL) and washed with
brine and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded
2.05 g of the title compound as white solid. LC-MS (Method A):
RT=4.34 min, (M+H).sup.+ 524.
[0383] The following compounds were similarly prepared:
(R)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-t-
riaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester
##STR00100##
[0385] LC-MS (Method A): RT=4.24 min, (M+H).sup.+ 486.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-1,4,5,6,7,8-hexahydro-1,2-
,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl
ester
##STR00101##
[0387] LC-MS (Method A): RT=3.88 min, (M+H).sup.+ 472.
Example 35
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol (50A:
R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-Butyl)phenyl)
##STR00102##
[0389] To compound 49A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butyl)phenyl) (100 mg, 0.19 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added DIBAL-H (420 .mu.L, 1.0 M
solution, 0.42 mmol) at -78.degree. C. and the contents were
stirred for 1 h. The reaction was quenched by the addition of water
(1 mL). The organics were extracted with CH.sub.2Cl.sub.2 (10 mL),
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) afforded 31 mg of the title compound as white
solid. LC-MS (Method A): RT=4.16 min, (M+H).sup.+ 496.
[0390] The following compounds were similarly prepared:
[(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydr-
o-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol
##STR00103##
[0392] LC-MS (Method A): RT=3.57 min, (M+H).sup.+ 458.
[(R)-1-(4-Fluoro-phenyl)-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,-
6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol
##STR00104##
[0394] LC-MS (Method A): RT=3.68 min, (M+H).sup.+ 454.
[0395]
[(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,-
2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol:
##STR00105##
[0396] LC-MS (Method B): RT=10.89 min, (M+H).sup.+ 440.
Example 36
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxymethyl--
4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
(51A: R.sup.5=4-F-Ph; R.sup.1A=Me;
L.sup.2-R.sup.2=SO.sub.2(4-t-Butylphenyl)
##STR00106##
[0398] To compound 49A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (100 mg, 0.20 mmol) in
THF (1 mL) was added sodium hydride (24 mg, 0.60 mmol) and
iodomethane (37 .mu.L, 0.60 mmol) and the mixture was stirred at
75.degree. C. for 18 h. The cooled contents were partitioned
between EtOAc (10 mL) and water (10 mL) and washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 38
mg of the title compound as white solid. LC-MS (Method A): RT=4.51
min, (M+H).sup.+ 510.
[0399] The following compounds were similarly prepared:
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-eth-
oxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00107##
[0401] LC-MS (Method A) RT=4.68 min, (M+H).sup.+ 534.
(R)-6-(Benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-hydroxy-ethoxymethyl)-4,-
4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00108##
[0403] LC-MS (Method A) (M+H).sup.+ 484.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-4a-ethoxymethyl-1-(4-fluoro-phenyl)-4-
,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00109##
[0405] LC-MS (Method A): RT=4.57 min, (M+H).sup.+ 524.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(3-methoxy-pro-
poxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalen-
e
##STR00110##
[0407] LC-MS (Method A): RT=4.69 min, (M+H).sup.+ 568.
3-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethoxy]-propionitrile
##STR00111##
[0409] LC-MS (Method A): RT=4.38 min, (M+H).sup.+ 549.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-morpholin-4-
-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naph-
thalene
##STR00112##
[0411] LC-MS (Method A): RT=2.90 min, (M+H).sup.+ 609.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-piperidin-1-
-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naph-
thalene
##STR00113##
[0413] LC-MS (Method A): RT=2.94 min, (M+H).sup.+ 607.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-pyrrolidin--
1-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]nap-
hthalene
##STR00114##
[0415] LC-MS (Method A): RT=2.92 min, (M+H).sup.+ 593.
(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxym-
ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00115##
[0417] LC-MS (Method B): RT=12.26 min, (M+H).sup.+ 516.
(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a-
,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00116##
[0419] LC-MS (Method B): RT=12.47 min, (M+H).sup.+ 472.
(R)-1-(4-Fluoro-phenyl)-4a-methoxymethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7-
,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00117##
[0421] LC-MS (Method B):: RT=12.81 min, (M+H).sup.+ 468.
(R)-1-(4-Fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-6-(toluene-4-sulfonyl)-
-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00118##
[0423] LC-MS (Method B):: RT=12.67 min, (M+H).sup.+ 512.
(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a-
,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00119##
[0425] LC-MS (Method A): RT=3.88 min, (M+H).sup.+ 498.
(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a,5,6,7,8-he-
xahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00120##
[0427] LC-MS (Method A): RT=3.93 min, (M+H).sup.+ 454.
(R)-1-(4-Fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-1,4,4a,5,7,8-hexahydro-
-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonic acid
dimethylamide
##STR00121##
[0429] LC-MS (Method A): RT=3.58 min, (M+H).sup.+ 465.
(R)-1-(4-Fluoro-phenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-tria-
za-cyclopenta[b]naphthalene-6-sulfonic acid dimethylamide
##STR00122##
[0431] LC-MS (Method A): RT=3.62 min, (M+H).sup.+ 421.
(R)-6-(Butane-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)--
4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00123##
[0433] LC-MS (Method A): RT=3.05 min, (M+H).sup.+ 478.
(R)-(4-tert-butyl-benzenesulfonyl)-4a-(2-methoxy-ethoxymethyl)-1-methyl-4,-
4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00124##
[0435] LC-MS (Method A): RT=3.87 min, (M+H).sup.+ 474.
(R)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-4a-(2-methoxy-ethoxymethyl)-4-
,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00125##
[0437] LC-MS (Method A): RT=4.36 min, (M+H).sup.+ 516.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-(2-methoxy-ethoxymethy-
l)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00126##
[0439] LC-MS (Method A): RT=4.03 min, (M+H).sup.+ 502.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-methoxymethyl-4,4a,5,6-
,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00127##
[0441] LC-MS (Method A): RT=4.07 min, (M+H).sup.+ 458.
(R)-1-Butyl-4a-methoxymethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-
-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00128##
[0443] LC-MS (Method A): RT=3.78 min, (M+H).sup.+ 430.
(R)-1-Butyl-4a-(2-methoxy-ethoxymethyl)-6-(toluene-4-sulfonyl)-4,4a,5,6,7,-
8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00129##
[0445] LC-MS (Method A): RT=3.74 min, (M+H).sup.+ 474.
Example 37
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde (52A:
R.sup.3=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-Butylphenyl)
##STR00130##
[0447] Oxalyl chloride (0.23 mL, 2.57 mmol) in CH.sub.2Cl.sub.2 (10
mL) was cooled to -78.degree. C. and DMSO (0.4 mL, 5.62 mmol) in
CH.sub.2Cl.sub.2 (4 mL) was added. After 5 min, compound 49A
(R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (0.58 g,
1.17 mmol) was added and the contents were stirred for 20 min.
Triethylamine (0.81 mL, 5.85 mmol) was added and the contents were
warmed to ambient temperature. The organics were partitioned
between EtOAc (10 mL) and water (10 mL), washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 42
mg of the title compound as white solid. LC-MS (Method A): RT=4.13
min, (M+H).sup.+ 494.
Example 38
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
(53A: R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl),
R.sup.1C=R.sup.1D=Methyl)
##STR00131##
[0449] To a solution of compound 52A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (50 mg, 0.10 mmol) in
dichloroethane (1 mL) was added dimethylamine (0.1 mL, 0.20 mmol)
and sodium triacetoxyborohydride (30 mg, 0.14 mmol). The contents
were stirred for 18 h at ambient temperature, NaHCO.sub.3 (2 mL)
was added, and the organics were extracted with CH.sub.2Cl.sub.2
(10 mL), washed with brine and dried (MgSO.sub.4). Purification by
flash chromatography (Amino-SPE: CH.sub.2Cl.sub.2 100% to 5% EtOAc
in CH.sub.2Cl.sub.2) afforded 61 mg of the title compound as an off
white solid. LC-MS (Method A): RT=2.79 min, (M+H).sup.+ 523.
[0450] The following compounds were similarly prepared:
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-yl-
methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00132##
[0452] LC-MS (Method A): RT=3.73 min, (M+H).sup.+ 565.
(S)-6-(4-Trifluoromethyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-
-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalen-
e
##STR00133##
[0454] LC-MS (Method A): (M+H).sup.+ 577.
(S)-6-(1-Cyclopropylmethylsulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylm-
ethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00134##
[0456] LC-MS (M+H).sup.+ 485.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-y-
lmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00135##
[0458] LC-MS (Method A): RT=2.91 min, (M+H).sup.+ 549.
([(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hex-
ahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-ethyl-amine
##STR00136##
[0460] LC-MS (Method A): RT=2.82 min, (M+H).sup.+ 523.
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-diethyl-amine
##STR00137##
[0462] LC-MS (Method A): RT=2.92 min, (M+H).sup.+ 551.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-piperidin-1-yl-
methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00138##
[0464] LC-MS (Method A): RT=2.99 min, (M+H).sup.+ 563.
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-(2-methoxy-ethyl)--
amine
##STR00139##
[0466] LC-MS (Method A): RT=2.74 min, (M+H).sup.+ 553.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(4-methyl-pipe-
razin-1-ylmethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naph-
thalene
##STR00140##
[0468] LC-MS (Method A): RT=2.83 min, (M+H).sup.+ 578.
N'-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-h-
exahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N-dimethyl-et-
hane-1,2-diamine
##STR00141##
[0470] LC-MS (Method A): RT=2.63 min, (M+H).sup.+ 566.
N-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N,N-trimethyl--
ethane-1,2-diamine
##STR00142##
[0472] LC-MS (Method A): RT=2.96 min, (M+H).sup.+ 580.
N'-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-h-
exahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N-dimethyl-pr-
opane-1,3-diamine
##STR00143##
[0474] LC-MS (Method A): RT=2.20 min, (M+H).sup.+ 580.
N-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N',N'-trimethy-
l-propane-1,3-diamine
##STR00144##
[0476] LC-MS (Method A): RT=2.29 min, (M+H).sup.+ 594.
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-(2-methoxy-ethyl)--
methyl-amine
##STR00145##
[0478] LC-MS (Method A): RT=2.91 min, (M+H).sup.+ 567.
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-isopropyl-amine
##STR00146##
[0480] LC-MS (Method A): RT=2.88 min, (M+H).sup.+ 537.
(S)-4a-Azetidin-1-ylmethyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-ph-
enyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00147##
[0482] LC-MS (Method A): RT=2.85 min, (M+H).sup.+ 535.
Allyl-[(S)-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,-
8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amine
##STR00148##
[0484] LC-MS (Method A): RT=2.71 min, (M+H).sup.+ 535.
2-{[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7-8-h-
exahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amino}-ethanol
##STR00149##
[0486] LC-MS (Method A): RT=2.74 min, (M+H).sup.+ 539.
[(S)-1-(4-Fluoro-phenyl)-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,-
6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
##STR00150##
[0488] LC-MS (Method A): RT=2.50 min, (M+H).sup.+ 481.
(S)-1-(4-Fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-6-(toluene-4-sulfonyl)-4,-
4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00151##
[0490] LC-MS (Method A): RT=2.55 min, (M+H).sup.+ 507.
[(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydr-
o-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
##STR00152##
[0492] LC-MS (Method A): RT=2.45 min, (M+H).sup.+ 485.
(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-ylmet-
hyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00153##
[0494] LC-MS (Method A): RT=2.51 min, (M+H).sup.+ 511.
(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00154##
[0496] LC-MS (Method A): RT=2.49 min, (M+H).sup.+ 492.
(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-tria-
za-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
##STR00155##
[0498] LC-MS (Method A): RT=2.41 min, (M+H).sup.+ 467.
(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6-
,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00156##
[0500] LC-MS (Method B): RT=9.11 min, (M+H).sup.+ 509.
2-{[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-h-
exahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-methyl-amino}-e-
thanol
##STR00157##
[0502] LC-MS (Method B): RT=8.90 min, (M+H).sup.+ 553.
(S)-6-(Butane-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a-
,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00158##
[0504] LC-MS (Method A): RT=2.74 min, (M+H).sup.+ 489.
4-[(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-1,4,4a,5,7,8-hexahydro--
1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonyl]-benzonitrile
##STR00159##
[0506] LC-MS (Method A): RT=2.97 min, (M+H).sup.+ 534.
[(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-tri-
aza-cyclopenta[b]naphthalen-4a-ylmethyl]-diethyl-amine
##STR00160##
[0508] LC-MS (Method A): RT=2.50 min, (M+H).sup.+ 495.
Diethyl-[(S)-1-(4-fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-1,4,5,6,7,8-
-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amine
##STR00161##
[0510] LC-MS (Method A): RT=2.56 min, (M+H).sup.+ 525.
(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-piperidin-1-ylmethyl-4,4a,5,6-
,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00162##
[0512] LC-MS (Method A): RT=2.52 min, (M+H).sup.+ 507.
(S)-1-(4-Fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-4a-piperidin-1-ylmet-
hyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00163##
[0514] LC-MS (Method A): RT=2.57 min, (M+H).sup.+ 537.
(S)-1-Butyl-4a-piperidin-1-ylmethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-he-
xahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00164##
[0516] LC-MS (Method A): RT=2.54 min, (M+H).sup.+ 483.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-pyrrolidin-1-ylmethyl-1-(2,2,2-tri-
fluoro-ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthal-
ene
##STR00165##
[0518] LC-MS (Method A): RT=2.74 min, (M+H).sup.+ 537.
[(S)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6--
triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
##STR00166##
[0520] LC-MS (Method A): RT=2.76 min, (M+H).sup.+ 485.
(S)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-4a-piperidin-1-ylmethyl-4,4a,-
5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00167##
[0522] LC-MS (Method A): RT=2.85 min, (M+H).sup.+ 525.
[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-1,4,5,6,7,8-hexahydro-1,-
2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine
##STR00168##
[0524] LC-MS (Method A): RT=2.47 min, (M+H).sup.+ 471.
(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-piperidin-1-ylmethyl-4-
,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00169##
[0526] LC-MS (Method A): RT=2.58 min, (M+H).sup.+ 511.
(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-6-(toluene-2-sulfonyl)-4,4-
a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00170##
[0528] LC-MS (Method B): RT=9.18 min, (M+H).sup.+ 523.
(S)-6-(2-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmeth-
yl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00171##
[0530] LC-MS (Method B): RT=8.67 min, (M+H).sup.+ 527.
(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-6-(pyridine-2-sulfonyl)-4,-
4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00172##
[0532] LC-MS (Method B): RT=7.27 min, (M+H).sup.+ 510.
Example 39
(4aR,8aS)-1-(4-Fluoro-phenyl)-1,4,7,8,8a,9-hexahydro-1,2,6-triaza-cyclopen-
ta[b]naphthalene-4a,6-dicarboxylic acid 6-tert-butyl ester
4a-methyl ester (49B: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=CO.sub.2-t-Butyl)
##STR00173##
[0534] A solution of compound 49A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=CO.sub.2-t-butyl) (400 mg, 0.94 mmol) in methanol
(10 mL) was treated with platinum oxide (32 mg, 0.14 mmol) and
stirred under a hydrogen atmosphere for 2 h. The solution was
filtered and the filtrate was evaporated to dryness to afford 412
mg of the title compound as a colorless oil which was used in
subsequent examples without further purification. LC-MS (Method A):
RT=3.74 min, (M+H).sup.+ 430.
Example 40
(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-
,8a,9-octahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic
acid methyl ester (49B: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-Butylphenyl)
##STR00174##
[0536] To compound 49B (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=CO.sub.2-t-butyl) (404 mg, 0.94 mmol) was added a
20% solution of TFA in CH.sub.2Cl.sub.2 (4 mL) and the contents
were stirred at ambient temperature for 1 h. The solvents were then
removed. The residue was dissolved in CH.sub.2Cl.sub.2 (4 mL) and
diisopropylethyl amine (485 .mu.L, 2.79 mmol) and
4-tert-butylphenylsulfonyl chloride (540 mg, 2.32 mmol) were added
and the contents were stirred for 3 h. Water (10 mL) was added and
the organics were extracted with EtOAc (15 mL), washed with brine
and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 40% EtOAc in CH.sub.2Cl.sub.2) to
afforded 352 mg of the title compound as a yellow foam. LC-MS
(Method A): RT=4.36 min, (M+H).sup.+ 526.
Example 41
[(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,-
8,8a,9-octahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol
(50B: R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00175##
[0538] To compound 49B (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (500 mg, 0.95 mmol) in
CH.sub.2Cl.sub.2(10 mL) was added DIBAL-H (3.8 mL, 1.0 M solution,
3.80 mmol) at -78.degree. C. and the contents were stirred for 1 h.
The reaction was quenched by the addition of water (10 mL). The
organics were extracted with CH.sub.2Cl.sub.2 (50 mL) and washed
with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) afforded 286 mg of the title compound as white
solid. LC-MS (Method A): RT=4.14 min, (M+H).sup.+ 496.
Example 42
(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxym-
ethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
(51B: R.sup.1A=Me; R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00176##
[0540] To compound SOB (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (40 mg, 0.08 mmol) in THF
(1 mL) was added a sodium hydride (10 mg, 0.24 mmol) and
iodomethane (15 .mu.L, 0.24 mmol) and the contents were stirred at
70.degree. C. for 18 h. The cooled contents were partitioned
between EtOAc (10 mL) and water (10 mL) and washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 21
mg of the title compound as white solid. LC-MS (Method B): RT=14.12
min, (M+H).sup.+ 512.
[0541] The following compounds were similarly prepared:
(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-metho-
xy-ethoxymethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]-
naphthalene
##STR00177##
[0543] LC-MS (Method B): RT=14.04 min, (M+H).sup.+ 556.
(4aR,8aS)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl-
)-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00178##
[0545] LC-MS (Method B): RT=11.92 min, (M+H).sup.+ 500.
(4aR,8aS)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methoxymethyl
4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00179##
[0547] LC-MS (Method B): RT=12.06 min, (M+H).sup.+ 456.
Example 43
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid (54A:
R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00180##
[0549] A solution of compound 49A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (545 mg, 1.04 mmol) in
methanol (10 mL) was treated with 1M LiOH (3.1 mL, 3.12 mmol) and
the contents were stirred at ambient temperature for 18 h. The
solvents were removed and the residue was dissolved in
CH.sub.2Cl.sub.2, washed with 1 M citric acid and dried
(MgSO.sub.4). Removal of solvent gave 504 mg of the title compound
as a yellow solid, which was used in subsequent examples without
further purification. LC-MS (Method A): RT=4.06 min, (M+H).sup.+
510.
Example 44
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid
benzylamide (55A: R.sup.1C=R.sup.1D=Benzyl; R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00181##
[0551] To a solution of compound 54A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (50 mg, 0.09 mmol) in DMF
(1 mL) was added benzylamide (16 mL, 0.15 mmol),
diisopropylethylamine (51 mL, 0.29 mmol) and HATU (45 mg, 0.19
mmol) and the contents were stirred at ambient temperature for 18
h. Water (5 mL) was added and the organics were extracted with
EtOAc (5 mL), washed with brine and dried (MgSO.sub.4).
Purification by flash chromatography (CH.sub.2Cl.sub.2 100% to 5%
EtOAc in CH.sub.2Cl.sub.2) afforded 89 mg of the title compound as
a white solid. LC-MS (Method A): RT=4.33 min, (M+H).sup.+ 599.
[0552] The following compounds were similarly prepared:
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-morpholin-4-yl-methanone
##STR00182##
[0554] LC-MS (Method A): RT=3.86 min, (M+H).sup.+ 579.
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-piperidin-1-yl-methanone
##STR00183##
[0556] LC-MS (Method A): RT=4.33 min, (M+H).sup.+ 577.
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-pyrrolidin-1-yl-methanon-
e
##STR00184##
[0558] LC-MS (Method A): RT=4.14 min, (M+H).sup.+ 563.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid
ethylamide
##STR00185##
[0560] LC-MS (Method A): RT=4.08 min, (M+H).sup.+ 537.
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexah-
ydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid
dimethylamide
##STR00186##
[0562] LC-MS (Method A): RT=4.03 min, (M+H).sup.+ 537.
Example 45
1-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethanol (56A:
R'=Me; R.sup.5=4-F-Phenyl;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00187##
[0564] A 3M solution of methylmagnesium bromide (294 .mu.L, 0.88
mmol) was added to a solution of compound 52A (R.sup.5=4-F-phenyl;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (44 mg, 0.09 mmol) in THF
(3 mL) and the contents were stirred at ambient temperature for 4
h. A saturated solution of NH.sub.4Cl was added and the contents
were partitioned between diethyl ether (10 mL) and water (5 mL).
The organics were extracted with EtOAc (5 mL), washed with brine
and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 10
mg of the title compound as a white solid. LC-MS (Method A):
RT=4.25 min, (M+H).sup.+ 510.
[0565] The following compounds were similarly prepared:
1-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-propan-1-ol
##STR00188##
[0567] LC-MS (Method A): RT=4.29 min, (M+H).sup.+ 524.
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-phenyl-methanol
##STR00189##
[0569] LC-MS (Method A): RT=4.52 min, (M+H).sup.+ 572.
Example 46
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-phenyl-methanone
(57A: R.sup.1=Ph; R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00190##
[0571] Oxalyl chloride (15 .mu.L, 0.17 mmol) in CH.sub.2Cl.sub.2 (1
mL) was cooled to -78.degree. C. and DMSO (26 .mu.L, 0.37 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL) was added. After 5 min, compound 56A
(R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (44 mg,
0.08 mmol) was added and the contents were stirred for 20 min.
Triethylamine (54 .mu.L, 0.38 mmol) was added and the contents were
warmed to ambient temperature. The organics were partitioned
between EtOAc (10 mL) and water (10 mL) and washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 15% EtOAc in CH.sub.2Cl.sub.2) afforded
18 mg of the title compound as colorless oil. LC-MS (Method A):
RT=4.56 min, (M+H).sup.+ 570.
Example 47
(R)-1-Butyl-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cycl-
openta[b]naphthalene-4a-carboxylic acid methyl ester (44A:
R.sup.5=n-Butyl; L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-Methylphenyl)
##STR00191##
[0573] To compound 43A (L.sup.1-R.sup.1=CO.sub.2Me;
L.sup.2-R.sup.2=SO.sub.2(4-methylphenyl)) (145 mg, 0.37 mmol) in
ethanol (1 mL) was added N-butyl hydrazinecarboxylic acid
tert-butyl ester (70 mg, 0.37 mmol) (prepared as in J. Org. Chem.
2002, 67, 8962-8969) in ethanol (4 mL) and the contents were
stirred at 80.degree. C. for 2 h. The solvents were then removed.
The residue was dissolved in dichloroethane (4 mL) and TFA (1 mL)
was added and the contents were stirred at 60.degree. C. for 1 h.
Saturated aqueous NaHCO.sub.3 (5 mL) was added and the organics
were extracted with CH.sub.2Cl.sub.2 (3.times.5 mL), washed with
brine and dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 30% EtOAc in CH.sub.2Cl.sub.2) afforded
135 mg of the title compound as a white solid. LC-MS (Method B):
RT=16.71 min, (M+H).sup.+ 444.
[0574] The following compound was similarly prepared:
(R)-6-(4-Methyl-benzenesulfonyl)-1-(cyclopentyl)-4a-(2-methoxy-ethoxymethy-
l)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00192##
[0576] LC-MS (Method A) (M+H).sup.+ 486.
Example 48
(R)-6-(4-tert-Butyl-benzenesulfonyl)-4a-[1,3]dithian-2-ylidenemethyl-1-(4--
fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphtha-
lene (58A: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00193##
[0578] 2-Trimethylsilyl-1,3-dithiane (189 mL, 0.99 mmol) in THF (2
mL) was cooled to 0.degree. C. and n-BuLi (0.62 mL, 0.99 mmol) was
added. After 10 min, the temperature was lowered to -78.degree. C.
and a solution of compound 54A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (232 mg, 0.47 mmol) was
added. After 30 min brine (5 mL) was added and the organics were
extracted with CH.sub.2Cl.sub.2 (5 mL) and dried (MgSO.sub.4).
Purification by flash chromatography (CH.sub.2Cl.sub.2 100% to 10%
EtOAc in CH.sub.2Cl.sub.2) afforded 168 mg of the title compound as
a white solid. LC-MS (Method A): RT=4.27 min, (M+H).sup.+ 596.
Example 49
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-acetic acid
methyl ester (59A: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00194##
[0580] To compound 58A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (165 mg, 0.28 mmol) in
methanol (12 mL) was added perchloric acid (86 .mu.L, 1.42 mmol)
and mercury.sup.II chloride (301 mg, 1.11 mmol) and the contents
were heated at reflux for 2.5 h. The cooled solution was filtered
and the filtrate was concentrated. Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 30% EtOAc in
CH.sub.2Cl.sub.2) afforded 168 mg of the title compound as a white
solid. LC-MS (Method A): RT=4.38 min, (M+H).sup.+ 538.
Example 50
2-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-he-
xahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethanol (60A:
R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00195##
[0582] To compound 59A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (128 mg, 0.24 mmol) in
CH.sub.2Cl.sub.2 (2.5 mL) was added DIBAL-H (950 .mu.L, 1.0 M
solution, 0.95 mmol) at -78.degree. C. and the contents were
stirred for 1 h. The reaction was quenched by the addition of water
(5 mL). The organics were extracted with CH.sub.2Cl.sub.2 (20 mL),
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 30% EtOAc in
CH.sub.2Cl.sub.2) afforded 104 mg of the title compound as a white
solid. LC-MS (Method A): RT=3.90 min, (M+H).sup.+ 510.
Example 51
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-eth-
yl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
(61A: R.sup.1A=Me; R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00196##
[0584] To compound 60A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (32 mg, 0.06 mmol) in THF
(1 mL) was added a sodium hydride (7.5 mg, 0.19 mmol) and
iodomethane (12 .mu.L, 0.19 mmol) and the contents were stirred at
75.degree. C. for 18 h. The cooled contents were partitioned
between EtOAc (10 mL) and water (10 mL), washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 15% EtOAc in CH.sub.2Cl.sub.2) afforded
12 mg of the title compound as colorless glass. LC-MS (Method A):
RT=4.43 min, (M+H).sup.+ 524.
Example 52
[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexa-
hydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-acetaldehyde
(62A: R.sup.3=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00197##
[0586] Oxalyl chloride (29 .mu.L, 0.22 mmol) in CH.sub.2Cl.sub.2 (2
mL) was cooled to -78.degree. C. and DMSO (38 .mu.L, 0.48 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added. After 5 min, compound 60A
(R.sup.5=4-F-Ph; L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (50 mg,
0.10 mmol) was added and the contents were stirred for 20 min.
Triethylamine (51 .mu.L, 0.50 mmol) was added and the contents were
warmed to ambient temperature. The organics were partitioned
between EtOAc (10 mL) and water (10 mL), washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 35
mg of the title compound as white solid. LC-MS (Method A): RT=3.87
min, (M+H).sup.+ 508.
Example 53
{2-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-h-
exahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethyl}-dimethylamine
(63A: R.sup.1C=R.sup.1D=Me: R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00198##
[0588] To a solution of compound 62A (R.sup.5=4-F-Ph;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl) (35 mg, 0.07 mmol) in
dichloroethane (1 mL) was added dimethylamine (0.10 mL, 0.21 mmol)
and sodium triacetoxyborohydride (22 mg, 0.11 mmol). The contents
were stirred for 18 h at ambient temperature, NaHCO.sub.3 (2 mL)
was added, and the organics were extracted with CH.sub.2Cl.sub.2
(10 mL), washed with brine and dried (MgSO.sub.4). Purification by
flash chromatography (Amino-SPE: CH.sub.2Cl.sub.2 100% to 5% EtOAc
in CH.sub.2Cl.sub.2) afforded 61 mg of the title compound as an off
white solid. LC-MS (Method A): RT=2.68 min, (M+H).sup.+ 537.
[0589] The following compound was similarly prepared:
(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-pyrrolidin--
1-yl-ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalen-
e
##STR00199##
[0591] LC-MS (Method A): RT=2.93 min, (M+H).sup.+ 563.
Example 54
(4aS,8aS)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-1,4,4a,5,7,8,8a,9-oc-
tahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylic acid
tert-butyl ester (44B: L.sup.1=CH.sub.2; R.sup.1=Morpholine;
L.sup.2=CO.sub.2-t-Butyl)
##STR00200##
[0593] A mixture of compound 44A (L.sup.1=CH.sub.2;
R.sup.1=morpholine; L.sup.2=CO.sub.2-t-butyl) (125 mg, 0.27 mmol)
and platinum oxide (9 mg, 0.04 mmol) in methanol (3 mL) was stirred
for 2.5 h at ambient temperature under an atmosphere of hydrogen.
The solution was filtered and the filtrate was evaporated to
dryness. The residue was purified by preparative HPLC to yield the
title compound as a white solid, 22 mg, LC-MS: RT=2.48 min,
(M+H).sup.+ 471, together with the cis-regioisomer, 35 mg, LC-MS
(Method A): RT=2.61 min, (M+H).sup.+ 471.
Example 55
(4aS,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholi-
n-4-ylmethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triazacyclopenta[b]napht-
halene (44B: L.sup.1=CH.sub.2; R.sup.1=Morpholine;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00201##
[0595] To compound 44B (L.sup.1=CH.sub.2; R'=morpholine;
L.sup.2=CO.sub.2-t-butyl) (22 mg, 0.05 mmol) was added a 20%
solution of TFA in CH.sub.2Cl.sub.2 (1 mL) and the contents were
stirred at ambient temperature for 1 h. The solvents were then
removed. The residue was dissolved in CH.sub.2Cl.sub.2 (1 mL) and
diisopropylethyl amine (41 .mu.L, 0.23 mmol) and
4-tert-butylphenylsulfonyl chloride (22 mg, 0.09 mmol) were added
and the contents were stirred for 18 h. Water (5 mL) was added and
the organics extracted with EtOAc (5 mL), washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 40% EtOAc in CH.sub.2Cl.sub.2) afforded
36 mg of the title compound as a white solid. LC-MS (Method B):
RT=9.84 min, (M+H).sup.+ 567.
Example 56
4a-Benzyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2-diaza-6-azonia-
-cyclopenta[b]naphthalene hydrochloride (65A: R.sup.5=4-F-Phenyl;
L.sup.1-R.sup.1=Benzyl)
##STR00202##
[0597] Compound 64A (R.sup.5=4-F-phenyl; L.sup.1-R.sup.1=benzyl)
(41 mg, 0.10 mmol) and ACE-Cl (20 .mu.L, 0.18 mmol) were heated in
dichloroethane (0.25 mL) at reflux for 18 h. The contents were
cooled and the solvent was removed. The residue was dissolved in
methanol (1 mL) and the contents were heated for 3 h at reflux. The
solvent was removed to afford 21 mg of the title compound as a
colorless glass which was used in subsequent examples without
further purification. LC-MS (Method A): RT=2.32 min, (M+H).sup.+
360.
[0598] The following compounds were similarly prepared:
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2-dia-
za-6-azonia-cyclopenta[b]naphthalene
##STR00203##
[0600] LC-MS (Method A): RT=2.37 min. (M+H).sup.+ 378.
Example 57
6-(4-tert-Butyl-benzenesulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)--
4,4a,5,6,7,8-hexahydro-1H-1-2,6-triaza-cyclopenta[b]naphthalene
(44A: R.sup.5=4-F-Phenyl; L.sup.1=CH.sub.2; R'=4-F-Phenyl;
L.sup.2-R.sup.2=SO.sub.2(4-t-butylphenyl)
##STR00204##
[0602] Compound 65A (R.sup.5=4-F-phenyl;
L.sup.1-R.sup.1=4-F-benzyl) (100 mg, 0.24 mmol) was dissolved in
CH.sub.2Cl.sub.2 (5 mL) and diisopropylethylamine (134 .mu.L, 0.97
mmol) and 4-tert-butylphenylsulfonyl chloride (56 mg, 0.24 mmol)
were added and the contents were stirred for 18 h. Water (10 mL)
was added and the organics were extracted with EtOAc (15 mL),
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 5% EtOAc in
CH.sub.2Cl.sub.2) afforded 89 mg of the title compound as a cream
solid. LC-MS (Method A): RT=4.82 min, (M+H).sup.+ 574.
[0603] The following compounds were similarly prepared:
6-Benzenesulfonyl-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-he-
xahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00205##
[0605] LC-MS (Method A): RT=4.31 min, (M+H).sup.+ 518.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(toluene-4-sulfonyl)-4,4a,5,6,7-
,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00206##
[0607] LC-MS (Method A): RT=4.47 min, (M+H).sup.+ 532.
6-(4-Fluoro-benzenesulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a-
,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00207##
[0609] LC-MS (Method A): RT=4.34 min, (M+H).sup.+ 536.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-methanesulfonyl-4,4a,5,6,7,8-he-
xahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00208##
[0611] LC-MS (Method A): RT=3.78 min, (M+H).sup.+ 456.
6-(Butane-1-sulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,-
8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00209##
[0613] LC-MS (Method A): RT=4.26 min, (M+H).sup.+ 498.
4a-Benzyl-1-(4-fluoro-phenyl)-6-(propane-2-sulfonyl)-4,4a,5,6,7,8-hexahydr-
o-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00210##
[0615] LC-MS (Method A): RT=4.01 min, (M+H).sup.+ 466.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(1-methyl-1H-imidazole-4-sulfon-
yl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00211##
[0617] LC-MS (Method A): RT=3.59 min, (M+H).sup.+ 522.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-methyl-3,4-dihydro-2H-benzo[-
1,4]oxazine-7-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[-
b]naphthalene
##STR00212##
[0619] LC-MS (Method A): RT=4.38 min, (M+H).sup.+ 589.
6-(6-tert-Butyl-pyridine-3-sulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phen-
yl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00213##
[0621] LC-MS (Method A): RT=4.64 min, (M+H).sup.+ 575.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-morpholin-4-yl-benzenesulfon-
yl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00214##
[0623] LC-MS (Method A): RT=4.21 min, (M+H).sup.+ 603.
Example 58
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-4-ylmethyl-4,4a,5,6,7,8-
-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene (44A:
R.sup.5=4-F-Phenyl; L.sup.1-R.sup.1=4-F-benzyl;
L.sup.2-R.sup.2=4-Pyridinylmethyl)
##STR00215##
[0625] To a solution of compound 65A (R.sup.5=4-F-Phenyl;
=4-F-benzyl) (50 mg, 0.12 mmol) in CH.sub.2Cl.sub.2 (1 mL) was
added 4-pyridinecarboxaldehyde (12 .mu.L, 0.12 mmol) and sodium
triacetoxyborohydride (39 mg, 0.18 mmol). The contents were stirred
for 18 h at ambient temperature, NaHCO.sub.3 (2 mL) was added, and
the organics were extracted with CH.sub.2Cl.sub.2 (10 mL) and
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 25% EtOAc in
CH.sub.2Cl.sub.2) afforded 29 mg of the title compound as an
off-white solid. LC-MS (Method A): RT=2.71 min, (M+H).sup.+
469.
[0626] The following compounds were similarly prepared:
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-3-ylmethyl-4,4a,5,6,7,8-
-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00216##
[0628] LC-MS (Method A): RT=2.54 min, (M+H).sup.+ 469.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-2-ylmethyl-4,4a,5,6,7,8-
-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00217##
[0630] LC-MS (Method A): RT=2.55 min, (M+H).sup.+ 469.
6-(6-tert-Butyl-pyridin-3-ylmethyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-pheny-
l)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00218##
[0632] LC-MS (Method A): RT=3.07 min, (M+H).sup.+ 525.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-propyl-4,4a,5,6,7,8-hexahydro-1-
H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00219##
[0634] LC-MS (Method A): RT=2.44 min, (M+H).sup.+ 420.
4a-Benzyl-1-(4-fluoro-phenyl)-6-(1H-imidazol-4-ylmethyl)-4,4a,5,6,7,8-hexa-
hydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00220##
[0636] LC-MS (Method A): RT=2.18 min, (M+H).sup.+ 440.
4a-Benzyl-1-(4-fluoro-phenyl)-6-pyridin-4-ylmethyl-4,4a,5,6,7,8-hexahydro--
1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00221##
[0638] LC-MS (Method A): RT=2.65 min, (M+H).sup.+ 451.
Example 59
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-phenyl-4,4a5,6,7,8-hexahydro-1H-
-1,2,6-triaza-cyclopenta[b]naphthalene (44A: R.sup.5=4-F-Phenyl;
L.sup.1-R.sup.1=4-F-benzyl; L.sup.2-R.sup.2=Phenyl)
##STR00222##
[0640] To a solution of compound 65A (R.sup.5=4-F-phenyl;
L.sup.1-R.sup.1=4-F-benzyl) (70 mg, 0.17 mmol) in CH.sub.2Cl.sub.2
(2.5 mL) was added copper.sup.II acetate (61 mg, 0.34 mmol) and
phenyl boronic acid (41 mg, 0.34 mmol) and the contents were
stirred at ambient temperature for 48 h. Water (2 mL) was added and
the organics were extracted with CH.sub.2Cl.sub.2 (10 mL) and
washed with brine and dried (MgSO.sub.4). Purification by flash
chromatography (CH.sub.2Cl.sub.2 100% to 25% EtOAc in
CH.sub.2Cl.sub.2) afforded 15 mg of the title compound as an
off-white solid. LC-MS (Method A): RT=4.84 min, (M+H).sup.+
454.
Example 60
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-tria-
za-cyclopenta[b]naphthalene-6-carboxylic acid phenylamide (44A:
R.sup.5=4-F-Phenyl; L.sup.1-R.sup.1=4-F-benzyl;
L.sup.2-R.sup.2=CONHPhenyl)
##STR00223##
[0642] Compound 65A (R.sup.5=4-F-phenyl;
L.sup.1-R.sup.1=4-F-benzyl) (50 mg, 0.12 mmol) was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and triethylamine (18 .mu.L, 0.13 mmol) and
phenyl isocyanate (14 .mu.L, 0.13 mmol) were added and the contents
stirred for 18 h. Water (5 mL) was added and the organics were
extracted with EtOAc (5 mL) and washed with brine and dried
(MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 10
mg of the title compound as a cream solid. LC-MS (Method A):
RT=3.96 min, (M+H).sup.+ 497.
Example 61
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydro
triaza-cyclopenta[b]naphthalene-6-sulfonic acid phenylamide (44A:
R.sup.5=4-F-Phenyl; L.sup.1-R.sup.1=4-F-Phenyl;
L.sup.2-R.sup.2=SO.sub.2NHPhenyl)
##STR00224##
[0644] Compound 65A (R.sup.5=4-F-Phenyl;
L.sup.1-R.sup.1=4-F-benzyl) (25 mg, 0.06 mmol) was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and triethylamine (101 .mu.L, 0.73 mmol)
and phenyl sulfamoyl chloride (65 mg, 0.34 mmol) were added and the
contents were stirred for 18 h. Water (5 mL) was added and the
organics were extracted with EtOAc (5 mL) and washed with brine and
dried (MgSO.sub.4). Purification by flash chromatography
(CH.sub.2Cl.sub.2 100% to 5% EtOAc in CH.sub.2Cl.sub.2) afforded 15
mg of the title compound as a cream solid. LC-MS (Method A):
RT=4.14 min, (M+H).sup.+ 533.
[0645] The following compounds were similarly prepared:
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(morpholine-4-sulfonyl)-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00225##
[0647] LC-MS (Method A): RT=3.90 min, (M+H).sup.+ 527.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-methyl-piperazine-1-sulfonyl-
)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene
##STR00226##
[0649] LC-MS (Method A): RT=2.63 min, (M+H).sup.+ 540.
4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(piperidine-1-sulfonyl)-4,4a,5,-
6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene:F
##STR00227##
[0651] LC-MS (Method A): RT=4.36 min, (M+H).sup.+ 525.
Example 62
2-[4a-Benzyl-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclo-
penta[b]naphthalen-6-yl]-N,N-dimethyl-acetamide (44A: (44A:
R.sup.5=4-F-Phenyl; L.sup.1-R.sup.1=Benzyl;
L.sup.2-R.sup.2=CH.sub.2CONMe.sub.2)
##STR00228##
[0653] Compound 65A (R.sup.5=4-F-phenyl; L.sup.1-R.sup.1=benzyl)
(42 mg, 0.11 mmol) was dissolved in CH.sub.2Cl.sub.2 (2 mL) and
sodium hydride (5 mg, 0.13 mmol) and 2-chloro-N,N-dimethylacetamide
(13 .mu.L, 0.13 mmol) were added and the contents were stirred for
18 h. Water (5 mL) was added and the organics were extracted with
EtOAc (5 mL) and washed with brine and dried (MgSO.sub.4).
Purification by flash chromatography (CH.sub.2Cl.sub.2 100% to 10%
EtOAc in CH.sub.2Cl.sub.2) afforded 9 mg of the title compound as a
yellow oil LC-MS (Method A): RT=2.34 min, (M+H).sup.+ 445.
Example 63
Glucocorticoid Receptor Binding Assay
[0654] The following is a description of an assay for determining
the inhibition of dexamethasone binding of the Human Recombinant
Glucocorticoid Receptor:
[0655] Binding protocol: Compounds were tested in a binding
displacement assay using human recombinant glucocorticoid receptor
with .sup.3H-dexamethasone as the ligand. The source of the
receptor was recombinant baculovirus-infected insect cells. This GR
was a full-length steroid hormone receptor likely to be associated
with heat-shock and other endogenous proteins.
[0656] The assay was carried out in v-bottomed 96-well
polypropylene plates in a final volume of 200 .mu.l containing 0.5
nM GR solution, 2.5 nM 3H-dexamethasone (Amersham TRK 645) in
presence of test compounds, test compound vehicle (for total
binding) or excess dexamethasone (20 .mu.M, to determine
non-specific binding) in an appropriate volume of assay buffer.
[0657] For the Primary Screen, test compounds were tested at 1
.mu.M in duplicate. These compounds were diluted from 10 mM stock
in 100% DMSO. After dilution to 100 .mu.M, 5 .mu.l were added to
245 .mu.l assay buffer to obtained 2 .mu.M compound and 2%
DMSO.
[0658] For the IC.sub.50 determinations, test compounds were tested
at 6 concentrations in duplicate (concentration range depends on %
inhibition binding that was obtained in the Primary Screen,). Test
compounds were diluted from 10 mM stock in 100% DMSO. The tested
solutions were prepared at 2.times. final assay concentration in 2%
DMSO/assay buffer.
[0659] All reagents and the assay plate were kept on ice during the
addition of reagents. The reagents were added to wells of a
v-bottomed polypropylene plate in the following order: 50 .mu.l of
10 nM 3H-dexamethasone solution, 100 .mu.l of TB/NSB/compound
solution and 50 .mu.l of 2 nM GR solution. After the additions, the
incubation mixture was mixed and incubated for 2.5 hrs at 4.degree.
C.
[0660] After 2.5 hrs incubation, unbound counts were removed with
dextran coated charcoal (DCC) as follows: 25 .mu.l of DCC solution
(10% DCC in assay buffer) was added to all wells and mixed (total
volume 225 .mu.l). The plate was centrifuged at 4000 rpm for 10
minutes at 4.degree. C. 75 .mu.l of the supernatants (i.e. 1/3 of
total volume) was carefully pipetted into an optiplate. 200 .mu.l
of scintillation cocktail were added (Microscint-40, Packard
Bioscience. B.V.). The plate was vigorously shaken for approx. 10
minutes and counted on Topcount.
[0661] For the IC.sub.50 determinations, the results were
calculated as % inhibition [.sup.3H]-dexamethasone bound and fitted
to sigmoidal curves (fixed to 100 and 0) to obtain IC.sub.50 values
(concentration of compound that displaces 50% of the bound counts).
The IC.sub.50 values were converted to K.sub.i (the inhibition
constant) using the Cheng-Prusoff equation. Test results are
presented in Table I for selected compounds of the Invention.
Compounds with a K.sub.i value of <10 nM are designated with
***; compounds with a K.sub.i value of 10-100 nM are designated
with **; compounds with a K.sub.i of >100 nM are designated with
*. A--indicates that the compound was not tested.
[0662] Reagents: Assay buffer: 10 mM potassium phosphate buffer pH
7.6 containing 5 mM DTT, 10 mM sodium molybdate, 100 .mu.M EDTA and
0.1% BSA.
TABLE-US-00001 TABLE I GR Binding GR Functional ##STR00229## *** **
##STR00230## *** * ##STR00231## *** * ##STR00232## *** *
##STR00233## *** ** ##STR00234## *** *** ##STR00235## *** **
##STR00236## *** * ##STR00237## *** * ##STR00238## *** **
##STR00239## *** * ##STR00240## *** * ##STR00241## *** *
##STR00242## *** ** ##STR00243## *** *** ##STR00244## *** **
##STR00245## *** * ##STR00246## *** * ##STR00247## ** *
##STR00248## *** * ##STR00249## ** -- ##STR00250## ** *
##STR00251## * * ##STR00252## *** ** ##STR00253## ** * ##STR00254##
** * ##STR00255## *** ** ##STR00256## *** * ##STR00257## *** **
##STR00258## *** ** ##STR00259## ** * ##STR00260## *** ***
##STR00261## *** ** ##STR00262## *** *** ##STR00263## *** ***
##STR00264## *** *** ##STR00265## *** ** ##STR00266## *** **
##STR00267## ** * ##STR00268## *** *** ##STR00269## *** **
##STR00270## *** *** ##STR00271## *** *** ##STR00272## *** ***
##STR00273## *** ** ##STR00274## *** ** ##STR00275## *** **
##STR00276## *** ** ##STR00277## *** ** ##STR00278## *** ***
##STR00279## *** ** ##STR00280## *** *** ##STR00281## *** ***
##STR00282## ** ** ##STR00283## ** -- ##STR00284## ** *
##STR00285## ** * ##STR00286## *** ** ##STR00287## ** *
##STR00288## *** ** ##STR00289## *** ** ##STR00290## *** **
##STR00291## *** * ##STR00292## *** ** ##STR00293## *** *
##STR00294## ** * ##STR00295## *** ** ##STR00296## *** **
##STR00297## ** * ##STR00298## *** *** ##STR00299## *** **
##STR00300## *** ** ##STR00301## *** ** ##STR00302## ** *
##STR00303## ** * ##STR00304## * * ##STR00305## *** * ##STR00306##
** * ##STR00307## * * ##STR00308## ** * ##STR00309## ** *
##STR00310## *** ** ##STR00311## ** * ##STR00312## ** *
##STR00313## ** -- ##STR00314## *** ** ##STR00315## ** *
##STR00316## * * ##STR00317## ** * ##STR00318## *** * ##STR00319##
*** * ##STR00320## ** -- ##STR00321## *** ** ##STR00322## ** *
##STR00323## * * ##STR00324## ** * ##STR00325## *** * ##STR00326##
*** * ##STR00327## ** -- ##STR00328## *** *** ##STR00329## *** ***
##STR00330## *** ** ##STR00331## *** *** ##STR00332## *** ***
##STR00333## *** *** ##STR00334## ** * ##STR00335## * *
##STR00336## ** * ##STR00337## *** ** ##STR00338## ** *
##STR00339## *** ** ##STR00340## *** ** ##STR00341## ** *
##STR00342## ** * ##STR00343## * * ##STR00344## ** * ##STR00345##
*** ** ##STR00346## ** * ##STR00347## *** ** ##STR00348## *** **
##STR00349## ** * ##STR00350## ** * ##STR00351## *** **
##STR00352## *** ** ##STR00353## *** *** ##STR00354## ** *
##STR00355## *** * ##STR00356## *** ** ##STR00357## *** **
##STR00358## *** ** ##STR00359## *** -- ##STR00360## * *
##STR00361## *** * ##STR00362## *** *** ##STR00363## *** **
##STR00364## ** * ##STR00365## ** * ##STR00366## ** * ##STR00367##
* * ##STR00368## *** ** ##STR00369## *** ** ##STR00370## *** ***
##STR00371## ** ** ##STR00372## ** ** ##STR00373## *** **
##STR00374## *** ** ##STR00375## *** *** ##STR00376## *** *
##STR00377## *** ** ##STR00378## ** * ##STR00379## ** *
##STR00380## *** * ##STR00381## *** * ##STR00382## ** *
##STR00383## ** * ##STR00384## * * ##STR00385## *** **
Example 64
Selectivity Binding assays
[0663] Selectivity binding assays were performed against human
estrogen (ER.alpha.), progesterone (PR), androgen (AR) and
mineralocorticoid (MR) receptors. The selectivity assays were
carried out in the same assay buffer and volumes as the GR binding
assay and DCC was used to separate free from bound label.
[0664] Mineralocorticoid binding assay: MR was obtained from Sf9
cells infected with recombinant baculovirus containing MR, and the
MR was isolated according to the method of Binart et al (Binart,
N.; Lombes, M.; Rafestin-Oblin, M. E.; Baulieu, E. E.
Characterisation of human mineralocorticoid receptor expressed in
the baculovirus system. PNAS US, 1991, 88, 10681-10685). Compounds
were tested against an appropriate dilution of the MR (determined
for each batch of receptor) with 2.4 nM of [.sup.3H] aldosterone
(Perkin Elmer NET419) and incubated for 60 mins at room
temperature.
[0665] Estrogen binding assay: Compounds were tested for
displacement of 0.56 nM [.sup.3H]-estradiol (Perkin Elmer NET517)
binding to 0.5 nM ER.alpha. (obtained from PanVera 26467A)
following an incubation period of 90 mins at room temperature.
[0666] Progesterone binding assay: Compounds were tested for
displacement of 3 nM [.sup.3H]-progesterone (Perkin Elmer NET381)
binding to 1 nM PR (obtained from PanVera 24900). This assay was
incubated for 120 mins at 4.degree. C.
[0667] Androgen binding assay: Compounds were tested, in
triplicate, for displacement of 6 nM [.sup.3H]-dihydrotestosterone
(Perkin Elmer NET453) binding to 3 nM PR (obtained from PanVera
24938). This assay was incubated overnight at 4.degree. C.
[0668] Compounds in Table I inhibited <50% binding at the MR,
ER, PR, and AR receptors under the above protocols when tested at
10 .mu.M.
Example 65
GR Functional Assay Using SW1353/MMTV-5 Cells
[0669] SW1353/MMTV-5 is an adherent human chondrosarcoma cell line
that contains endogenous glucocorticoid receptors. It was
transfected with a plasmid (pMAMneo-Luc) encoding firefly
luciferase located behind a glucocorticoid-responsive element (GRE)
derived from a viral promoter (long terminal repeat of mouse
mammary tumor virus). A stable cell line SW1353/MMTV-5 was selected
with geneticin, which was required to maintain this plasmid. This
cell line was thus sensitive to glucocorticoids (dexamethasone)
leading to expression of luciferase (EC.sub.50.sup.dex 10 nM). This
dexamethasone-induced response was gradually lost over time, and a
new culture from an earlier passage was started (from a cryo-stored
aliquot) every three months.
[0670] In order to test for a GR-antagonist, SW1353/MMTV-5 cells
were incubated with several dilutions of the compounds in the
presence of 5xEC.sub.50.sup.dex (50 nM), and the inhibition of
induced luciferase expression was measured using a luminescence in
a Topcounter (LucLite kit from Perkin Elmer). For each assay, a
dose-response curve for dexamethasone was prepared in order to
determine the EC.sub.50.sup.dex required for calculating the
K.sub.i from the IC.sub.50's of each tested compound. Test results
are presented in Table I for selected compounds of the Invention.
Compounds with a K.sub.i value of <10 nM are designated with
***; compounds with a K.sub.i value of 10-100 nM are designated
with **; compounds with a K.sub.i of >100 nM are designated with
*. A--indicates that the compound was not tested.
[0671] SW1353/MMTV-5 cells were distributed in 96-well plates and
incubated in medium (without geneticin) for 24 hrs (in the absence
of CO.sub.2). Dilutions of the compounds in medium+50 nM
dexamethasone were added and the plates further incubated for
another 24 hrs after which the luciferase expression is
measured.
Example 66
Cytotoxicity Assay Using SW1353/Luc-4 Cells
[0672] In order to exclude the possibility that compounds inhibit
the dexamethasone-induced luciferase response (GR-antagonist) due
to their cytotoxicity or due to their direct inhibition of
luciferase, a SW1353 cell line was developed that constitutively
expressed firefly luciferase, by transfection with plasmid
pcDNA3.1-Luc and selection with geneticin. The cell line
SW1353/Luc-4 was isolated that constitutively expressed
luciferase.
[0673] SW1353/Luc-4 cells were distributed in 96-well plates and
incubated (no CO.sub.2) for 24 hrs, after which compound dilutions
(without dexamethasone) were added. After a further 24 hrs
incubation, luciferase expression was measured using the "LucLite"
assay. The compounds listed in Table I did not demonstrate
cytotoxicity in this assay when tested at a concentration of 1-3
micromolar.
Example 67
MR and PR Functional Assays Using T47D/MMTV-5 Cells
[0674] T47D/MMTV-5 is an adherent human breast carcinoma cell line
containing endogenous mineralocorticoid- (MR) and progesterone (PR)
receptors. As for the SW1353 cell line, T47D cells was transfected
with the same pMAMneo-Luc plasmid, and stable lines selected with
geneticin. A cell line T47D/MMTV-5 was isolated which responded to
aldosterone (EC.sub.50.sup.ald 100 nM), and progesterone
(EC.sub.50.sup.prog 10 nM), leading to expression of
luciferase.
[0675] As for the GR assay to test for MR- or PR-antagonists, the
T47D/MMTV-5 cells were incubated with several dilutions of the
compounds in the presence of the 5xEC.sub.50 of the agonist
aldosterol (EC.sub.50.sup.ald 100 nM) or progesterone
(EC.sub.50.sup.prog 10 nM), respectively. For each assay, a dose
response curve was prepared for both aldosterone and
progesterone.
[0676] T47D/MMTV-5 cells were distributed in 96-well plates (100P
in RPMI1640 medium+10% Charcoal stripped FCS. The cells were
incubated for 24 hrs in the CO.sub.2-oven. A volume of 100 .mu.l of
the compound dilutions in medium+agonist (500 nM aldost; 50 nM
progest) were added, and the plates further incubated for another
24 hrs after which the luciferase expression was measured.
[0677] Compounds of the Invention did not display MR or PR
functional activity in these assays. For example, the compound of
Example 29 inhibited only 8% of the PR agonist response and 10% of
the MR functional response when tested at a concentration of 3
micromolar.
* * * * *