U.S. patent application number 14/617448 was filed with the patent office on 2015-06-04 for bromodomain inhibitors.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Andrew Bogdan, Lisa A. Hasvold, Dachun Liu, John Pratt, Le Wang.
Application Number | 20150150884 14/617448 |
Document ID | / |
Family ID | 50543314 |
Filed Date | 2015-06-04 |
United States Patent
Application |
20150150884 |
Kind Code |
A1 |
Liu; Dachun ; et
al. |
June 4, 2015 |
BROMODOMAIN INHIBITORS
Abstract
The present invention provides for compounds of formula (I)
##STR00001## wherein R.sup.1, R.sup.2, R.sup.6, Y.sup.1, Y.sup.2,
A.sup.1, A.sup.2, A.sup.3, and A.sup.4 have any of the values
defined in the specification, and pharmaceutically acceptable salts
thereof, that are useful as agents in the treatment of diseases and
conditions, including inflammatory diseases, cancer, and AIDS. Also
provided are pharmaceutical compositions comprising one or more
compounds of formula (I).
Inventors: |
Liu; Dachun; (Vernon Hills,
IL) ; Pratt; John; (Kenosha, WI) ; Wang;
Le; (Vernon Hills, IL) ; Hasvold; Lisa A.;
(Grayslake, IL) ; Bogdan; Andrew; (Evanston,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
50543314 |
Appl. No.: |
14/617448 |
Filed: |
February 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14203651 |
Mar 11, 2014 |
8980879 |
|
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14617448 |
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61776547 |
Mar 11, 2013 |
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Current U.S.
Class: |
514/214.02 |
Current CPC
Class: |
A61P 1/18 20180101; C07D
471/22 20130101; A61P 21/00 20180101; A61P 43/00 20180101; A61P
37/02 20180101; A61K 31/55 20130101; A61P 19/06 20180101; A61P
19/08 20180101; A61P 9/10 20180101; A61P 35/00 20180101; A61P 9/00
20180101; A61P 1/04 20180101; A61P 37/06 20180101; A61P 5/06
20180101; A61P 3/10 20180101; A61P 25/00 20180101; A61P 11/06
20180101; C07D 471/12 20130101; Y02A 50/30 20180101; A61P 13/12
20180101; A61P 5/10 20180101; A61P 17/06 20180101; A61P 29/00
20180101; A61P 19/02 20180101; A61P 1/16 20180101; Y02A 50/463
20180101; A61P 35/02 20180101; A61P 1/00 20180101; C07D 471/16
20130101; A61P 17/00 20180101 |
International
Class: |
A61K 31/55 20060101
A61K031/55 |
Claims
1-32. (canceled)
33. A method for treating cancer in a subject comprising
administering a therapeutically effective amount of a compound of
formula (I) ##STR00009## wherein R.sup.1 is CD.sub.3,
C.sub.1-C.sub.3 alkyl, or C.sub.1-3 haloalkyl; R.sup.2 is H or
C.sub.1-3 alkyl; Y.sup.1 is N or CR.sup.3; R.sup.3 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.3a,
--C(O)OR.sup.3a, --C(O)NR.sup.3bR.sup.3c,
--C(O)N(R.sup.3b)NR.sup.3bR.sup.3c, --S(O)R.sup.3d,
--S(O).sub.2R.sup.3a, --S(O).sub.2NR.sup.3bR.sup.3c, or G.sup.1;
wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 alkynyl are each independently unsubstituted or
substituted with 1 or 2 substituents independently selected from
the group consisting of G.sup.1, --C(O)R.sup.3a, --C(O)OR.sup.3a,
--C(O)NR.sup.3bR.sup.3c, --S(O)R.sup.3d, --S(O).sub.2R.sup.3a,
--S(O).sub.2NR.sup.3bR.sup.3c, --OR.sup.3a, --OC(O)R.sup.3d,
--NR.sup.3bR.sup.3c, N(R.sup.3b)C(O)R.sup.3d,
N(R.sup.3b)SO.sub.2R.sup.3d, N(R.sup.3b)C(O)OR.sup.3d,
N(R.sup.3b)C(O)NR.sup.3bR.sup.3c,
N(R.sup.3b)SO.sub.2NR.sup.3bR.sup.3c, and
N(R.sup.3b)C(NR.sup.3bR.sup.3c).dbd.NR.sup.3bR.sup.3c; Y.sup.2 is
C(O), S(O).sub.2, or CR.sup.4R.sup.5; R.sup.4 is H, deuterium,
C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6 haloalkyl; and
R.sup.5 is H, deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --S(O)R.sup.5d, --S(O).sub.2R.sup.5a,
--S(O).sub.2NR.sup.5bR.sup.5c, or G.sup.1; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.1, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --C(O)N(R.sup.5b)NR.sup.5bR.sup.5c,
--S(O)R.sup.5d, --S(O).sub.2R.sup.5a,
--S(O).sub.2NR.sup.5bR.sup.5c, --OR.sup.5a, --OC(O)R.sup.5d,
--NR.sup.5bR.sup.5c, N(R.sup.5b)C(O)R.sup.5d,
N(R.sup.5b)SO.sub.2R.sup.5d, N(R.sup.5b)C(O)OR.sup.5d,
N(R.sup.5b)C(O)NR.sup.5bR.sup.5c,
N(R.sup.5b)SO.sub.2NR.sup.5bR.sup.5c, and
N(R.sup.5b)C(NR.sup.5bR.sup.5c).dbd.NR.sup.5bR.sup.5c; R.sup.3a,
R.sup.3b, R.sup.3c, R.sup.5a, R.sup.5b, and R.sup.5c, at each
occurrence, are each independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.1, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1;
R.sup.3d and R.sup.5d, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.1, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1; G.sup.1, at each occurrence, is independently
aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and
each G.sup.1 is optionally substituted with 1, 2, 3, 4, or 5
R.sup.1g groups; R.sup.6 is H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --S(O).sub.2R.sup.6a,
--S(O).sub.2NR.sup.6bR.sup.6c, or G.sup.2; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.2, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --C(O)N(R.sup.6b)NR.sup.6bR.sup.6c,
--S(O)R.sup.6d, --S(O).sub.2R.sup.6a,
--S(O).sub.2NR.sup.6bR.sup.6c, --OR.sup.6a, --OC(O)R.sup.6d,
--NR.sup.6bR.sup.6c, N(R.sup.6b)C(O)R.sup.6d,
N(R.sup.6b)SO.sub.2R.sup.6d, N(R.sup.6b)C(O)OR.sup.6d,
N(R.sup.6b)C(O)NR.sup.6bR.sup.6c,
N(R.sup.6b)SO.sub.2NR.sup.6bR.sup.6c, and
N(R.sup.6b)C(NR.sup.6bR.sup.6c).dbd.NR.sup.6bR.sup.6c; R.sup.6a,
R.sup.6b, and R.sup.6c, at each occurrence, are each independently
H, alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
haloalkyl, G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; R.sup.6d, at each
occurrence, is independently alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, haloalkyl, G.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; G.sup.2, at each
occurrence, is independently aryl, heteroaryl, heterocycle,
cycloalkyl, or cycloalkenyl; and each G.sup.2 is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.2g groups; A.sup.1 is
C(R.sup.7) or N; A.sup.2 is C(R.sup.8) or N; A.sup.3 is C(R.sup.9)
or N; and A.sup.4 is C(R.sup.10) or N; wherein zero, one, or two of
A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N; R.sup.7, R.sup.8, and
R.sup.9, are each independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2, --OR.sup.y1,
--OC(O)R.sup.y2, --OC(O)NR.sup.y3R.sup.y4, --SR.sup.y1,
--S(O).sub.2R.sup.y1, --S(O).sub.2NR.sup.y3R.sup.y4,
--C(O)R.sup.y1, --C(O)OR.sup.y1, --C(O)NR.sup.y3R.sup.y4,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, --N(R.sup.y3)C(O)O(R.sup.y2),
--N(R.sup.y3)C(O)NR.sup.y3R.sup.y4,
--N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-CN, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.y1, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.y2,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.y1,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-CN, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3; R.sup.y1, R.sup.y3, and R.sup.y4, at each
occurrence, are each independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.3, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; R.sup.y2, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl,
G.sup.3, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; G.sup.3, at each
occurrence, is independently aryl, heteroaryl, cycloalkyl,
cycloalkenyl, or heterocycle; and each G.sup.3 group is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.4g groups; R.sup.10 is H,
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or --CN;
R.sup.1g, R.sup.2g, and R.sup.4g, at each occurrence, is
independently selected from the group consisting of oxo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2,
G.sup.2a, --OR.sup.a, --OC(O)R.sup.b, --OC(O)NR.sup.cR.sup.d,
--SR.sup.a, --S(O).sub.2R.sup.a, --S(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cR.sup.d, --N(R.sup.e)C(O)R.sup.b,
--N(R.sup.e)S(O).sub.2R.sup.b, --N(R.sup.e)C(O)O(R.sup.b),
--N(R.sup.e)C(O)NR.sup.cR.sup.d,
--N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-CN, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d, or
--(C.sub.1-C.sub.6 alkylenyl)-CN; R.sup.a, R.sup.c, R.sup.d, and
R.sup.e, at each occurrence, are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.2a, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a; R.sup.b, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.2a, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a; G.sup.2a, at each occurrence, are each
independently aryl, heteroaryl, heterocycle, cycloalkyl, or
cycloalkenyl; and each G.sup.2a group is optionally substituted
with 1, 2, 3, 4, or 5 R.sup.3g groups; R.sup.3g, at each
occurrence, is independently oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2, --OR.sup.z1,
--OC(O)R.sup.z2, --OC(O)NR.sup.z3R.sup.z4, --SR.sup.z1,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z3R.sup.z4,
--C(O)R.sup.z1, --C(O)OR.sup.z1, --C(O)NR.sup.z3R.sup.z4,
--NR.sup.z3R.sup.z4, --N(R.sup.z3)C(O)R.sup.z2,
--N(R.sup.z3)S(O).sub.2R.sup.z2, --N(R.sup.z3)C(O)O(R.sup.z2),
--N(R.sup.z3)C(O)NR.sup.z3R.sup.z4,
--N(R.sup.z3)S(O).sub.2NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.z1, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.z2,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.z3R.sup.z4,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.z1,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.z3R.sup.z4,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)R.sup.z2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)S(O).sub.2R.sup.z2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)O(R.sup.z2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)S(O).sub.2NR.sup.z3R.sup.z4, or
--(C.sub.1-C.sub.6 alkylenyl)-CN; R.sup.z1, R.sup.z3, and R.sup.z4,
at each occurrence, are each independently H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.1-C.sub.6 haloalkyl; and R.sup.z2, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.1-C.sub.6 haloalkyl or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof.
34. The method of claim 33 wherein the cancer is selected from the
group consisting of: acoustic neuroma, acute leukemia, acute
lymphocytic leukemia, acute myelocytic leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer, bronchogenic carcinoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell
lymphoma, dysproliferative changes (dysplasias and metaplasias),
embryonal carcinoma, endometrial cancer, endotheliosarcoma,
ependymoma, epithelial carcinoma, erythroleukemia, esophageal
cancer, estrogen-receptor positive breast cancer, essential
thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma,
germ cell testicular cancer, glioma, glioblastoma, gliosarcoma,
heavy chain disease, hemangioblastoma, hepatoma, hepatocellular
cancer, hormone insensitive prostate cancer, leiomyosarcoma,
leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma,
lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and
non-Hodgkin's), malignancies and hyperproliferative disorders of
the bladder, breast, colon, lung, ovaries, pancreas, prostate,
skin, and uterus, lymphoid malignancies of T-cell or B-cell origin,
leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor.
35. A method for treating a disease or condition in a subject
comprising administering a therapeutically effective amount of a
compound of formula (I) according to claim 33 or a pharmaceutically
acceptable salt thereof, to a subject in need thereof, wherein said
disease or condition is selected from the group consisting of
Addison's disease, acute gout, ankylosing spondylitis, asthma,
atherosclerosis, Behcet's disease, bullous skin diseases, cardiac
myopathy, cardiac hypertrophy, chronic obstructive pulmonary
disease (COPD), Crohn's disease, dermatitis, eczema, giant cell
arteritis, glomerulonephritis, heart failure, hepatitis,
hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus
nephritis, multiple sclerosis, myocarditis, myositis, nephritis,
organ transplant rejection, osteoarthritis, pancreatitis,
pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary
cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,
scleritis, sclerosing cholangitis, sepsis systemic lupus
erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type
I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and
Wegener's granulomatosis.
36. A method for treating a chronic kidney disease or condition in
a subject comprising administering a therapeutically effective
amount of a compound of formula (I) according to claim 33 or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof, wherein said disease or condition is selected from the
group consisting of: diabetic nephropathy, hypertensive
nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus
nephritis, IgA nephropathy, focal segmental glomerulosclerosis,
membranous glomerulonephritis, minimal change disease, polycystic
kidney disease, and tubular interstitial nephritis.
37. A method for treating an acute kidney disease or condition in a
subject comprising administering a therapeutically effective amount
of a compound of formula (I) according to claim 33 or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof, wherein said acute kidney disease or condition is selected
from the group consisting of: ischemia-reperfusion induced kidney
disease, cardiac and major surgery induced kidney disease,
percutaneous coronary intervention induced kidney disease,
radio-contrast agent induced kidney disease, sepsis induced kidney
disease, pneumonia induced kidney disease, and drug toxicity
induced and pharmaceutically acceptable salts thereof.
38. A method for treating an acquired immunodeficiency syndrome
(AIDS) in a subject comprising administering a therapeutically
effective amount of a compound of formula (I) according to claim 33
or a pharmaceutically acceptable salt thereof, to a subject in need
thereof.
39. A method for treating a disease or condition in a subject
comprising administering a therapeutically effective amount of a
compound of formula (I) according to claim 33 or a pharmaceutically
acceptable salt thereof, to a subject in need thereof, wherein said
disease or condition is selected from the group consisting of:
obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,
metabolic syndrome, hepatic steatosis, type II diabetes, insulin
resistance, diabetic retinopathy, and diabetic neuropathy.
40. A method of contraception in a male subject comprising
administering a therapeutically effective amount of a compound of
formula (I) according to claim 33 or a pharmaceutically acceptable
salt thereof, to a subject in need thereof.
Description
BACKGROUND
[0001] Bromodomains refer to conserved protein structural folds
which bind to N-acetylated lysine residues that are found in some
proteins. The BET family of bromodomain containing proteins is
comprised of four members (BRD2, BRD3, BRD4 and BRDt). Each member
of the BET family employs two bromodomains to recognize
N-acetylated lysine residues found primarily, but not exclusively,
on the amino-terminal tails of histone proteins. These interactions
modulate gene expression by recruiting transcription factors to
specific genome locations within chromatin. For example,
histone-bound BRD4 recruits the transcription factor P-TEFb to
promoters, resulting in the expression of a subset of genes
involved in cell cycle progression (Yang et al., Mol. Cell. Biol.
28: 967-976 (2008)). BRD2 and BRD3 also function as transcriptional
regulators of growth promoting genes (LeRoy et al., Mol. Cell. 30:
51-60 (2008)). BET family members were recently established as
being important for the maintenance of several cancer types (Zuber
et al., Nature 478: 524-528 (2011); Mertz et al; Proc. Nat'l. Acad.
Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14,
(2011); Dawson et al., Nature 478: 529-533 (2011)). BET family
members have also been implicated in mediating acute inflammatory
responses through the canonical NF-KB pathway (Huang et al., Mol.
Cell. Biol. 29: 1375-1387 (2009)) resulting in the upregulation of
genes associated with the production of cytokines (Nicodeme et al.,
Nature 468: 1119-1123, (2010)). Suppression of cytokine induction
by BET bromodomain inhibitors has been shown to be an effective
approach to treat inflammation-mediated kidney disease in an animal
model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2
function has been linked to predisposition for dyslipidemia or
improper regulation of adipogenesis, elevated inflammatory profiles
and increased susceptibility to autoimmune diseases (Denis,
Discovery Medicine 10: 489-499 (2010)). The human immunodeficiency
virus utilizes BRD4 to initiate transcription of viral RNA from
stably integrated viral DNA (Jang et al., Mol. Cell, 19: 523-534
(2005)). BET bromodomain inhibitors have also been shown to
reactivate HIV transcription in models of latent T cell infection
and latent monocyte infection (Banerjee, et al, J. Leukocyte Biol.
doi:10.1189/jlb.0312165). BRDt has an important role in
spermatogenesis that is blocked by BET bromodomain inhibitors
(Matzuk, et al., Cell 150: 673-684 (2012)). Thus, compounds that
inhibit the binding of BET family bromodomains to their cognate
acetylated lysine proteins are being pursued for the treatment of
cancer, inflammatory diseases, kidney diseases, diseases involving
metabolism or fat accumulation, and some viral infections, as well
as for providing a method for male contraception. Accordingly,
there is an ongoing medical need to develop new drugs to treat
these indications.
SUMMARY
[0002] In one aspect the present invention provides for compounds
of formula (I) or a salt thereof,
##STR00002## [0003] wherein [0004] R.sup.1 is CD.sub.3,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl; [0005] R.sup.2
is H or C.sub.1-C.sub.3 alkyl; [0006] Y.sup.1 is N or CR.sup.3;
[0007] R.sup.3 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --C(O)R.sup.3a, --C(O)OR.sup.3a,
--C(O)NR.sup.3bR.sup.3c, --C(O)N(R.sup.3b)NR.sup.3bR.sup.3c,
--S(O)R.sup.3d, --S(O).sub.2R.sup.3a, --S(O).sub.2NR.sup.3bR.sup.3c
or G.sup.1; wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl are each independently
unsubstituted or substituted with 1 or 2 substituents independently
selected from the group consisting of G.sup.1, --C(O)R.sup.3a,
--C(O)OR.sup.3a, --C(O)NR.sup.3bR.sup.3c, --S(O)R.sup.3d,
--S(O).sub.2R.sup.3a, --S(O).sub.2NR.sup.3bR.sup.3c, --OR.sup.3a,
--OC(O)R.sup.3d, --NR.sup.3bR.sup.3c, N(R.sup.3b)C(O)R.sup.3d,
N(R.sup.3b)SO.sub.2R.sup.3d, N(R.sup.3b)C(O)OR.sup.3d,
N(R.sup.3b)C(O)NR.sup.3bR.sup.3c,
N(R.sup.3b)SO.sub.2NR.sup.3bR.sup.3c, and
N(R.sup.3b)C(NR.sup.3bR.sup.3c).dbd.NR.sup.3bR.sup.3c; [0008]
Y.sup.2 is C(O), S(O).sub.2, or CR.sup.4R.sup.5; [0009] R.sup.4 is
H, deuterium, C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6
haloalkyl; and [0010] R.sup.5 is H, deuterium, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --S(O)R.sup.5d, --S(O).sub.2R.sup.5a,
--S(O).sub.2NR.sup.5bR.sup.5c, or G.sup.1; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.1, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --C(O)N(R.sup.5b)NR.sup.5bR.sup.5c,
--S(O)R.sup.5d, --S(O).sub.2R.sup.5a,
--S(O).sub.2NR.sup.5bR.sup.5c, --OR.sup.5a, --OC(O)R.sup.5d,
--NR.sup.5bR.sup.5c, N(R.sup.5b)C(O)R.sup.5d,
N(R.sup.5b)SO.sub.2R.sup.5d, N(R.sup.5b)C(O)OR.sup.5d,
N(R.sup.5b)C(O)NR.sup.5bR.sup.5c,
N(R.sup.5b)SO.sub.2NR.sup.5bR.sup.5c, and
N(R.sup.5b)C(NR.sup.5bR.sup.5c).dbd.NR.sup.5bR.sup.5c; [0011]
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.5a, R.sup.5b, and R.sup.5c, at
each occurrence, are each independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.1, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1;
[0012] R.sup.3d and R.sup.5d, at each occurrence, are each
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.1, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1; [0013] G.sup.1, at each
occurrence, is independently aryl, heteroaryl, heterocycle,
cycloalkyl, or cycloalkenyl; and each G.sup.1 is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.1g groups; [0014] R.sup.6
is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl,
--C(O)R.sup.6a, --C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c,
--S(O).sub.2R.sup.6a, --S(O).sub.2NR.sup.6bR.sup.6c, or G.sup.2;
wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 alkynyl are each independently unsubstituted or
substituted with 1 or 2 substituents independently selected from
the group consisting of G.sup.2, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --C(O)N(R.sup.6b)NR.sup.6bR.sup.6c,
--S(O)R.sup.6d, --S(O).sub.2R.sup.6a,
--S(O).sub.2NR.sup.6bR.sup.6c, --OR.sup.6a, --OC(O)R.sup.6d,
--NR.sup.6bR.sup.6c, N(R.sup.6b)C(O)R.sup.6d,
N(R.sup.6b)SO.sub.2R.sup.6d, N(R.sup.6b)C(O)OR.sup.6d,
N(R.sup.6b)C(O)NR.sup.6bR.sup.6c,
N(R.sup.6b)SO.sub.2NR.sup.6bR.sup.6c, and
N(R.sup.6b)C(NR.sup.6bR.sup.6c).dbd.NR.sup.6bR.sup.6c; [0015]
R.sup.6a, R.sup.6b, and R.sup.6c, at each occurrence, are each
independently H, alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, haloalkyl, G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; [0016] R.sup.6d, at
each occurrence, is independently alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, haloalkyl, G.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; [0017] G.sup.2, at
each occurrence, is independently aryl, heteroaryl, heterocycle,
cycloalkyl, or cycloalkenyl; and each G.sup.2 is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.2g groups; [0018] A.sup.1
is C(R.sup.7) or N; A.sup.2 is C(R.sup.8) or N; A.sup.3 is
C(R.sup.9) or N; and A.sup.4 is C(R.sup.10) or N; wherein zero,
one, or two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N; [0019]
R.sup.7, R.sup.8, and R.sup.9, are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2,
--OR.sup.y1, --OC(O)R.sup.y2, --OC(O)NR.sup.y3R.sup.y4,
--SR.sup.y1, --S(O).sub.2R.sup.y1, --S(O).sub.2NR.sup.y3R.sup.y4,
--C(O)R.sup.y1, --C(O)OR.sup.y1, --C(O)NR.sup.y3R.sup.y4,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, --N(R.sup.y3)C(O)O(R.sup.y2),
--N(R.sup.y3)C(O)NR.sup.y3R.sup.y4,
--N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-CN, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.y1, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.y2,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.y1,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-CN, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3; [0020] R.sup.y1, R.sup.y3, and R.sup.y4, at
each occurrence, are each independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.3, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; [0021] R.sup.y2, at
each occurrence, is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.3, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d; [0022] G.sup.3, at
each occurrence, is independently aryl, heteroaryl, cycloalkyl,
cycloalkenyl, or heterocycle; and each G.sup.3 group is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.4g groups;
[0023] R.sup.10 is H, C.sub.1-C.sub.3 alkyl, halogen,
C.sub.1-C.sub.3 haloalkyl, or --CN; [0024] R.sup.1g, R.sup.2g, and
R.sup.4g, at each occurrence, is independently selected from the
group consisting of oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, G.sup.2a, --OR.sup.a, --OC(O)R.sup.b,
--OC(O)NR.sup.cR.sup.d, --SR.sup.a, --S(O).sub.2R.sup.a,
--S(O).sub.2NR.sup.cR.sup.d, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.cR.sup.d, --NR.sup.cR.sup.d, --N(R.sup.e)C(O)R.sup.b,
--N(R.sup.e)S(O).sub.2R.sup.b, --N(R.sup.e)C(O)O(R.sup.b),
--N(R.sup.e)C(O)NR.sup.cR.sup.d,
--N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-CN, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.a, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.cR.sup.d,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2R.sup.b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)NR.sup.cR.sup.d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)S(O).sub.2NR.sup.cR.sup.d, or
--(C.sub.1-C.sub.6 alkylenyl)-CN; [0025] R.sup.a, R.sup.c, R.sup.d,
and R.sup.e, at each occurrence, are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.2a, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a; [0026] R.sup.b, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, G.sup.2a, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.2a; [0027] G.sup.2a, at each
occurrence, are each independently aryl, heteroaryl, heterocycle,
cycloalkyl, or cycloalkenyl; and each G.sup.2a group is optionally
substituted with 1, 2, 3, 4, or 5 R.sup.3g groups; [0028] R.sup.3g,
at each occurrence, is independently oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2, --OR.sup.z1,
--OC(O)R.sup.z2, --OC(O)NR.sup.z3R.sup.z4, --SR.sup.z1,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z3R.sup.z4,
--C(O)R.sup.z1, --C(O)OR.sup.z1, --C(O)NR.sup.z3R.sup.z4,
--NR.sup.z3R.sup.z4, --N(R.sup.z3)C(O)R.sup.z2,
--N(R.sup.z3)S(O).sub.2R.sup.z2, --N(R.sup.z3)C(O)O(R.sup.z2),
--N(R.sup.z3)C(O)NR.sup.z3R.sup.z4,
--N(R.sup.z3)S(O).sub.2NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.z1, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.z2,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.z3R.sup.z4,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.z1,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.z3R.sup.z4,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)R.sup.z2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)S(O).sub.2R.sup.z2, (C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)O(R.sup.z2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)C(O)NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.z3)S(O).sub.2NR.sup.z3R.sup.z4, or
--(C.sub.1-C.sub.6 alkylenyl)-CN; [0029] R.sup.z1, R.sup.z3, and
R.sup.z4, at each occurrence, are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, or C.sub.1-C.sub.6 haloalkyl; and [0030] R.sup.z2, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or C.sub.1-C.sub.6 haloalkyl.
[0031] In another aspect, the present invention provides for
methods for treating or preventing disorders that are ameliorated
by inhibition of BET. Such methods comprise of administering to the
subject a therapeutically effective amount of a compound of formula
(I), alone, or in combination with a pharmaceutically acceptable
carrier.
[0032] Some of the methods are directed to treating or preventing
an inflammatory disease or cancer or AIDS.
[0033] In another aspect, the present invention relates to methods
of treating cancer in a subject comprising administering a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the cancer is selected from the
group consisting of: acoustic neuroma, acute leukemia, acute
lymphocytic leukemia, acute myelocytic leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer, bronchogenic carcinoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell
lymphoma, dysproliferative changes (dysplasias and metaplasias),
embryonal carcinoma, endometrial cancer, endotheliosarcoma,
ependymoma, epithelial carcinoma, erythroleukemia, esophageal
cancer, estrogen-receptor positive breast cancer, essential
thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma,
germ cell testicular cancer, glioma, glioblastoma, gliosarcoma,
heavy chain disease, hemangioblastoma, hepatoma, hepatocellular
cancer, hormone insensitive prostate cancer, leiomyosarcoma,
leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma,
lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and
non-Hodgkin's), malignancies and hyperproliferative disorders of
the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin
and uterus, lymphoid malignancies of T-cell or B-cell origin,
leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor. In certain embodiments, the
methods further comprise administering a therapeutically effective
amount of at least one additional therapeutic agent. In certain
embodiments, the additional therapeutic agent is selected from the
group consisting of cytarabine, bortezomib, and 5-azacitidine.
[0034] In another aspect, the present invention relates to methods
of treating a disease or condition in a subject comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof, to a
subject in need thereof, wherein said disease or condition is
selected from the group consisting of: Addison's disease, acute
gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's
disease, bullous skin diseases, cardiac myopathy, cardiac
hypertrophy, chronic obstructive pulmonary disease (COPD), Crohn's
disease, dermatitis, eczema, giant cell arteritis,
glomerulonephritis, heart failure, hepatitis, hypophysitis,
inflammatory bowel disease, Kawasaki disease, lupus nephritis,
multiple sclerosis, myocarditis, myositis, nephritis, organ
transplant rejection, osteoarthritis, pancreatitis, pericarditis,
Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis,
psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis,
sclerosing cholangitis, sepsis, systemic lupus erythematosus,
Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,
ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's
granulomatosis. In certain embodiments, the methods further
comprise administering a therapeutically effective amount of at
least one additional therapeutic agent.
[0035] In another aspect, the present invention relates to methods
of treating a chronic kidney disease or condition in a subject
comprising administering a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a subject in need thereof, wherein said disease or
condition is selected from the group consisting of: diabetic
nephropathy, hypertensive nephropathy, HIV-associated nephropathy,
glomerulonephritis, lupus nephritis, IgA nephropathy, focal
segmental glomerulosclerosis, membranous glomerulonephritis,
minimal change disease, polycystic kidney disease and tubular
interstitial nephritis. In certain embodiments, the methods further
comprise administering a therapeutically effective amount of at
least one additional therapeutic agent.
[0036] In another aspect, the present invention relates to methods
of treating an acute kidney injury or disease or condition in a
subject comprising administering a therapeutically effective amount
of a compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a subject in need thereof, wherein said acute kidney
injury or disease or condition is selected from the group
consisting of: ischemia-reperfusion induced kidney disease, cardiac
and major surgery induced kidney disease, percutaneous coronary
intervention induced kidney disease, radio-contrast agent induced
kidney disease, sepsis induced kidney disease, pneumonia induced
kidney disease, and drug toxicity induced and pharmaceutically
acceptable salts thereof. In certain embodiments, the methods
further comprise administering a therapeutically effective amount
of at least one additional therapeutic agent.
[0037] In another aspect, the present invention relates to methods
of treating AIDS in a subject comprising administering a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the methods further comprise
administering a therapeutically effective amount of at least one
additional therapeutic agent.
[0038] In another aspect, the present invention relates to methods
of treating obesity, dyslipidemia, hypercholesterolemia,
Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II
diabetes, insulin resistance, diabetic retinopathy or diabetic
neuropathy in a subject comprising administering a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof, to a subject in need thereof. In certain
embodiments, the methods further comprise administering a
therapeutically effective amount of at least one additional
therapeutic agent.
[0039] In another aspect, the present invention provides for
contraception in a male subject comprising administering a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the methods further comprise
administering a therapeutically effective amount of at least one
additional therapeutic agent.
[0040] A further aspect of the invention provides the use of a
compound of formula (I), alone or in combination with a second
active pharmaceutical agent, in the manufacture of a medicament for
treating or preventing conditions and disorders disclosed herein,
with or without a pharmaceutically acceptable carrier.
[0041] Pharmaceutical compositions comprising a compound of formula
(I), or a pharmaceutically acceptable salt, alone or in combination
with a second active pharmaceutical agent, are also provided. In
certain embodiments, pharmaceutical compositions comprise a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
DETAILED DESCRIPTION
[0042] Disclosed herein are compounds of formula (I)
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.6, Y.sup.1, Y.sup.2, A.sup.1,
A.sup.2, A.sup.3, and A.sup.4 are defined above in the Summary of
the Invention and below in the Detailed Description. Further,
compositions comprising such compounds and methods for treating
conditions and disorders using such compounds and compositions are
also disclosed.
[0043] Compounds disclosed herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds, which can be isolated from a reaction mixture.
a). DEFINITIONS
[0044] It is noted that, as used in this specification and the
intended claims, the singular form "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a single
compound as well as one or more of the same or different compounds,
reference to "optionally a pharmaceutically acceptable carrier"
refers to a single optional pharmaceutically acceptable carrier as
well as one or more pharmaceutically acceptable carriers, and the
like.
[0045] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0046] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond, optionally
substituted with 1, 2, or 3 halogen atoms. The term
"C.sub.2-C.sub.6 alkenyl" means an alkenyl group containing 2-6
carbon atoms. Non-limiting examples of alkenyl include
buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl,
and 3-decenyl.
[0047] The term "alkenylene" means a divalent group derived from a
straight or branched chain hydrocarbon of 2 to 4 carbon atoms and
contains at least one carbon-carbon double bond. Representative
examples of alkenylene include, but are not limited to,
--CH.dbd.CH-- and --CH.sub.2CH.dbd.CH--.
[0048] The term "alkyl" as used herein, means a saturated, straight
or branched hydrocarbon chain radical. In some instances, the
number of carbon atoms in an alkyl moiety is indicated by the
prefix "C.sub.x-C.sub.y", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for
example, "C.sub.1-C.sub.6 alkyl" means an alkyl substituent
containing from 1 to 6 carbon atoms and "C.sub.1-C.sub.3 alkyl"
means an alkyl substituent containing from 1 to 3 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,
1-methylpropyl, 2-methylpropyl, 1-ethylpropyl,
1,2,2-trimethylpropyl, 2-ethylhexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0049] The term "alkylene" or "alkylenyl" means a divalent radical
derived from a straight or branched, saturated hydrocarbon chain,
for example, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkylenyl), or of 1 to 4 carbon atoms, or of 2 to
3 carbon atoms (C.sub.2-C.sub.3 alkylenyl). Examples of alkylene
and alkylenyl include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0050] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond,
optionally substituted with 1, 2, or 3 halogen atoms. The term
"C.sub.2-C.sub.6 alkynyl" means an alkynyl group of 2 to 6 carbon
atoms. Representative examples of alkynyl include, but are not
limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,
2-pentynyl, and 1-butynyl.
[0051] The term "aryl" as used herein, means phenyl or a bicyclic
aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a
monocyclic cycloalkyl, or a phenyl fused to a monocyclic
cycloalkenyl. Non-limiting examples of the aryl groups include
dihydroindenyl (indanyl), indenyl, naphthyl, dihydronaphthalenyl,
and tetrahydronaphthalenyl. The aryls are attached to the parent
molecular moiety through any carbon atom contained within the
bicyclic ring systems and can be unsubstituted or substituted.
[0052] The term "cycloalkyl" as used herein, refers to a radical
that is a monocyclic cyclic alkyl, a bicyclic cycloalkyl, or a
spiro cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring
system containing three to eight carbon atoms, zero heteroatoms and
zero double bonds. Examples of monocyclic ring systems include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl
fused to a monocyclic cycloalkyl ring. The monocyclic and the
bicyclic cycloalkyl groups may contain one or two alkylene bridges,
each consisting of one, two, three, or four carbon atoms in length,
and each bridge links two non-adjacent carbon atoms of the ring
system. Non-limiting examples of bicyclic ring systems include
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and
bicyclo[4.2.1]nonane, tricyclo[3.3.1.0.sup.3,7]nonane
(octahydro-2,5-methanopentalene or noradamantane), and
tricyclo[3.3.1.1.sup.3,7]decane (adamantane). A spiro cycloalkyl is
a monocyclic cycloalkyl wherein two substituents on the same carbon
atom of the monocyclic cycloalkyl ring together with said carbon
atom form a second monocyclic cycloalkyl ring. The monocyclic, the
bicyclic, and the spiro cycloalkyl groups can be unsubstituted or
substituted, and are attached to the parent molecular moiety
through any substitutable atom contained within the ring
system.
[0053] The term "cycloalkenyl" as used herein, refers to a
monocyclic or a bicyclic hydrocarbon ring radical. The monocyclic
cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms
and zero heteroatoms. The four-membered ring systems have one
double bond, the five- or six-membered ring systems have one or two
double bonds, and the seven- or eight-membered ring systems have
one, two, or three double bonds. Representative examples of
monocyclic cycloalkenyl groups include, but are not limited to,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and
cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic
cycloalkenyl fused to a monocyclic cycloalkyl group, or a
monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
The monocyclic or bicyclic cycloalkenyl ring may contain one or two
alkylene bridges, each consisting of one, two, or three carbon
atoms, and each linking two non-adjacent carbon atoms of the ring
system. Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic
and bicyclic cycloalkenyls can be attached to the parent molecular
moiety through any substitutable atom contained within the ring
systems, and can be unsubstituted or substituted.
[0054] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0055] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. The term "C.sub.1-C.sub.6
haloalkyl" means a C.sub.1-C.sub.6 alkyl group, as defined herein,
in which one, two, three, four, five, six, or seven hydrogen atoms
are replaced by halogen. The term "C.sub.1-C.sub.3 haloalkyl" means
a C.sub.1-C.sub.3 alkyl group, as defined herein, in which one,
two, three, four, five, or six hydrogen atoms are replaced by
halogen. Representative examples of haloalkyl include, but are not
limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,
pentafluoroethyl, 4-chlorobutyl, 2-chloro-3-fluoropentyl,
trifluorobutyl, trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and
2,2,3,3,4,4,4-heptafluorobutyl.
[0056] The term "heterocycle" or "heterocyclic" as used herein,
means a radical of a monocyclic heterocycle, a bicyclic
heterocycle, and a spiro heterocycle. A monocyclic heterocycle is a
three-, four-, five-, six-, seven-, or eight-membered carbocyclic
ring also containing at least one heteroatom independently selected
from the group consisting of O, N, and S. A three- or four-membered
ring contains zero or one double bond, and one heteroatom selected
from the group consisting of O, N, and S. When two O atoms or one O
atom and one S atom are present in a heterocyclic ring, then the
two O atoms or one O atom and one S atom are not bonded directly to
each other. A five-membered ring contains zero or one double bond
and one, two, or three heteroatoms selected from the group
consisting of O, N, and S. Examples of five-membered heterocyclic
rings include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3
N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Examples
of 5-membered heterocyclic groups include tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl,
oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl,
2-pyrrolinyl, and 3-pyrrolinyl. A six-membered ring contains zero,
one, or two double bonds and one, two, or three heteroatoms
selected from the group consisting of O, N, and S. Examples of
six-membered heterocyclic rings include those containing in the
ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and
1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 Q and 1 N; and 1 O
and 2 N. Examples of 6-membered heterocyclic groups include
tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl,
1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,
piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,
1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,
1,1-dioxo-hexahydro-1-thiopyranyl,
1,1-dioxo-1.lamda..sup.6-thiomorpholinyl, thiomorpholinyl,
thioxanyl, and trithianyl. Seven- and eight-membered rings contains
zero, one, two, or three double bonds and one, two, or three
heteroatoms selected from the group consisting of O, N, and S.
Representative examples of monocyclic heterocycles include, but are
not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,
oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl,
tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
thiopyranyl, and trithianyl. The bicyclic heterocycle is a
monocyclic heterocycle fused to a phenyl group, or a monocyclic
heterocycle fused to a monocyclic cycloalkyl, or a monocyclic
heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic
heterocycle fused to a monocyclic heterocycle. Representative
examples of bicyclic heterocycles include, but are not limited to,
benzo[d][1,3]dioxolyl, benzopyranyl, benzothiopyranyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydro-1H-indolyl, isoindolinyl,
3,4-dihydroisoquinolin-2(1H)-yl,
2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,
hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic
heterocycle and the bicyclic heterocycle may contain one or two
alkylene bridges or an alkenylene bridge, or mixture thereof, each
consisting of no more than four carbon atoms and each linking two
non adjacent atoms of the ring system. Examples of such bridged
heterocycle include, but are not limited to,
azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),
8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,
hexahydro-2H-2,5-methanocyclopenta[b]furan,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane
(1-azatricyclo[3.3.1.1.sup.3,7]decane), and oxa-adamantane
(2-oxatricyclo[3.3.1.1.sup.3,7]decane). A spiro heterocycle is a
monocyclic heterocycle wherein two substituents on the same carbon
atom of the monocyclic heterocycle ring together with said carbon
atom form a second ring system selected from a monocyclic
cycloalkyl, a bicyclic cycloalkyl, a monocyclic heterocycle, or a
bicyclic heterocycle. Examples of spiro heterocycle include, but
not limited to, 6-azaspiro[2.5]oct-6-yl, 1'H,
4H-spiro[1,3-benzodioxine-2,4'-piperidin]-1'-yl, 1'H,
3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl, and
1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic,
and the spiro heterocycles can be unsubstituted or substituted. The
monocyclic, the bicyclic and the spiro heterocycles are connected
to the parent molecular moiety through any carbon atom or any
nitrogen atom contained within the ring systems. The nitrogen and
sulfur heteroatoms in the heterocycle rings may optionally be
oxidized (e.g. 1,1-dioxidotetrahydrothienyl,
1,2-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and the
nitrogen atoms may optionally be quarternized.
[0057] The term "heteroaryl" as used herein, means a monocyclic
heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is
a five- or six-membered monocyclic ring. The five-membered ring
contains two double bonds. The five membered ring may contain one
heteroatom selected from O or S; or one, two, three, or four
nitrogen atoms and optionally one oxygen or one sulfur atom. The
six-membered ring contains three double bonds and one, two, three
or four nitrogen atoms. Representative examples of monocyclic
heteroaryl include, but are not limited to, furanyl, imidazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,
tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and
triazinyl. The bicyclic heteroaryl consists of a monocyclic
heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a
monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a
monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a
monocyclic heteroaryl, or a monocyclic heteroaryl fused to a
monocyclic heterocycle. Representative examples of bicyclic
heteroaryl groups include, but are not limited to, benzofuranyl,
benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,
phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,
6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl,
2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,
thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic
heteroaryl groups can be substituted or unsubstituted and are
connected to the parent molecular moiety through any substitutable
carbon atom or any substitutable nitrogen atom contained within the
ring systems. The nitrogen atom in the heteroaryl rings may
optionally be oxidized and may optionally be quarternized.
[0058] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0059] The term "oxo" as used herein, means a .dbd.O group.
[0060] If a moiety is described as "substituted", a non-hydrogen
radical is in the place of hydrogen radical of any substitutable
atom of the moiety. Thus, for example, a substituted heterocycle
moiety is a heterocycle moiety in which at least one non-hydrogen
radical is in the place of a hydrogen radical on the heterocycle.
It should be recognized that if there are more than one
substitution on a moiety, each non-hydrogen radical may be
identical or different (unless otherwise stated).
[0061] If a moiety is described as being "optionally substituted,"
the moiety may be either (1) not substituted or (2) substituted. If
a moiety is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either (1) not substituted; or (2) substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum
number of substitutable positions on the moiety, whichever is less.
Thus, for example, if a moiety is described as a heteroaryl
optionally substituted with up to 3 non-hydrogen radicals, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen radicals
as the heteroaryl has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) would be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to 2 non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to 2
non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
[0062] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0063] The terms "prevent", "preventing", and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0064] The phrase "therapeutically effective amount" means an
amount of a compound, or a pharmaceutically acceptable salt
thereof, sufficient to prevent the development of or to alleviate
to some extent one or more of the symptoms of the condition or
disorder being treated when administered alone or in conjunction
with another pharmaceutical agent or treatment in a particular
subject or subject population. For example in a human or other
mammal, a therapeutically effective amount can be determined
experimentally in a laboratory or clinical setting, or may be the
amount required by the guidelines of the United States Food and
Drug Administration, or equivalent foreign agency, for the
particular disease and subject being treated.
[0065] The term "subject" is defined herein to refer to animals
such as mammals, including, but not limited to, primates (e.g.,
humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,
mice and the like. In preferred embodiments, the subject is a
human.
b. COMPOUNDS
[0066] Compounds of the invention have the general formula (I) as
described above.
[0067] Particular values of variable groups in compounds of formula
(I) are as follows. Such values may be used where appropriate with
any of the other values, definitions, claims or embodiments defined
hereinbefore or hereinafter.
[0068] In certain embodiments, R.sup.1 is CD.sub.3, C.sub.1-C.sub.3
alkyl, or C.sub.1-C.sub.3 haloalkyl.
[0069] In certain embodiments, R.sup.1 is C.sub.1-C.sub.3 alkyl. In
some such embodiments, R.sup.1 is methyl.
[0070] In certain embodiments, R.sup.2 is H or C.sub.1-C.sub.3
alkyl.
[0071] In certain embodiments, R.sup.2 is H or methyl.
[0072] In certain embodiments, R.sup.2 is H.
[0073] In certain embodiments, R.sup.2 is C.sub.1-C.sub.3 alkyl. In
some such embodiments, R.sup.2 is methyl.
[0074] In certain embodiments, Y.sup.1 is N or CR.sup.3.
[0075] In certain embodiments, Y.sup.1 is N.
[0076] In certain embodiments, Y.sup.1 is CR.sup.3.
[0077] In certain embodiments, R.sup.3 is H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.3a, --C(O)OR.sup.3a,
--C(O)NR.sup.3bR.sup.3c, --C(O)N(R.sup.3b)NR.sup.3bR.sup.3c,
--S(O)R.sup.3d, --S(O).sub.2R.sup.3a, --S(O).sub.2NR.sup.3bR.sup.3c
or G.sup.1; wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl are each independently
unsubstituted or substituted with 1 or 2 substituents independently
selected from the group consisting of G.sup.1, --C(O)R.sup.3a,
--C(O)OR.sup.3a, --C(O)NR.sup.3bR.sup.3c, --S(O)R.sup.3d,
--S(O).sub.2R.sup.3a, --S(O).sub.2NR.sup.3bR.sup.3c, --OR.sup.3a,
--OC(O)R.sup.3d, NR.sup.3bR.sup.3c, N(R.sup.3b)C(O)R.sup.3d,
N(R.sup.3b)SO.sub.2R.sup.3d, N(R.sup.3b)C(O)OR.sup.3d,
N(R.sup.3b)C(O)NR.sup.3bR.sup.3c,
N(R.sup.3b)SO.sub.2NR.sup.3bR.sup.3c, and
N(R.sup.3b)C(NR.sup.3bR.sup.3c).dbd.NR.sup.3bR.sup.3c.
[0078] In certain embodiments, R.sup.3 is H, --C(O)R.sup.3a,
--C(O)OR.sup.3a, --C(O)NR.sup.3bR.sup.3c, or C.sub.1-C.sub.6 alkyl,
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with a
substituent selected from the group consisting of G.sup.1,
--NR.sup.3bR.sup.3c, N(R.sup.3b)C(O)R.sup.3d,
N(R.sup.3b)SO.sub.2R.sup.3d, N(R.sup.3b)C(O)OR.sup.3d,
N(R.sup.3b)C(O)NR.sup.3bR.sup.3c, and
N(R.sup.3b)SO.sub.2NR.sup.3bR.sup.3c. In some such embodiments, the
G.sup.1 group is optionally substituted heterocycle.
[0079] In certain embodiments, R.sup.3 is H, --C(O)R.sup.3a, or
--C(O)NR.sup.3bR.sup.3c. In some such embodiments, R.sup.3a is
G.sup.1. In some such embodiments, R.sup.3a is G.sup.1 wherein
G.sup.1 is optionally substituted heterocycle.
[0080] In certain embodiments, R.sup.3 is H or
--C(O)NR.sup.3bR.sup.3c. In some such embodiments, R.sup.3b and
R.sup.3c are each independently H or C.sub.1-C.sub.6 alkyl.
[0081] In certain embodiments, R.sup.3 is H.
[0082] In certain embodiments, R.sup.3 is --C(O)NR.sup.3bR.sup.3c.
In some such embodiments, R.sup.3b and R.sup.3c are each
independently H or C.sub.1-C.sub.3 alkyl.
[0083] In certain embodiments, Y.sup.2 is C(O), S(O).sub.2, or
CR.sup.4R.sup.5.
[0084] In certain embodiments, Y.sup.2 is C(O).
[0085] In certain embodiments, Y.sup.2 is S(O).sub.2.
[0086] In certain embodiments, Y.sup.2 is CR.sup.4R.sup.5.
[0087] In certain embodiments, R.sup.4 is H, deuterium,
C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6 haloalkyl.
[0088] In certain embodiments, R.sup.4 is H or deuterium.
[0089] In certain embodiments, R.sup.4 is H.
[0090] In certain embodiments, R.sup.5 is H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.5a,
--C(O)OR.sup.5a, --C(O)NR.sup.5bR.sup.5c, --S(O)R.sup.5d,
--S(O).sub.2R.sup.5a, --S(O).sub.2NR.sup.5bR.sup.5c, or G.sup.1;
wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 alkynyl are each independently unsubstituted or
substituted with 1 or 2 substituents independently selected from
the group consisting of G.sup.1, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --C(O)N(R.sup.5b)NR.sup.5bR.sup.5c,
--S(O)R.sup.5d, --S(O).sub.2R.sup.5a,
--S(O).sub.2NR.sup.5bR.sup.5c, --OR.sup.5a, --OC(O)R.sup.5d,
--NR.sup.5bR.sup.5c, N(R.sup.5b)C(O)R.sup.5d,
N(R.sup.5b)SO.sub.2R.sup.5d, N(R.sup.5b)C(O)OR.sup.5d,
N(R.sup.5b)C(O)NR.sup.5bR.sup.5c,
N(R.sup.5b)SO.sub.2NR.sup.5bR.sup.5c, and
N(R.sup.5b)C(NR.sup.5bR.sup.5c).dbd.NR.sup.5bR.sup.5c.
[0091] In certain embodiments, R.sup.5 is H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.5a,
--C(O)OR.sup.5a, or G.sup.1; wherein the C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are each
independently unsubstituted or substituted with 1 or 2 substituents
independently selected from the group consisting of G.sup.1,
--C(O)R.sup.5a, --C(O)OR.sup.5a, --C(O)NR.sup.5bR.sup.5c,
--C(O)N(R.sup.5b)NR.sup.5bR.sup.5c, --OR.sup.5a, --OC(O)R.sup.5d,
--NR.sup.5bR.sup.5c, N(R.sup.5b)C(O)R.sup.5d,
N(R.sup.5b)SO.sub.2R.sup.5d, N(R.sup.5b)C(O)OR.sup.5d,
N(R.sup.5b)C(O)NR.sup.5bR.sup.5c, and
N(R.sup.5b)SO.sub.2NR.sup.5bR.sup.5c.
[0092] In certain embodiments, R.sup.5 is H, --C(O)OR.sup.5a,
G.sup.1, or C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with a substituent selected from the group consisting
of G.sup.1, --C(O)OR.sup.5a, and --OR.sup.5a.
[0093] In certain embodiments, R.sup.5 is H, deuterium, or
C.sub.1-C.sub.6 alkyl optionally substituted with a substituent
selected from the group consisting of --C(O)OR.sup.5a and
OR.sup.5a. In some such embodiments, R.sup.5a is C.sub.1-C.sub.6
alkyl.
[0094] In certain embodiments, R.sup.5 is H or C.sub.1-C.sub.6
alkyl optionally substituted with a substituent selected from the
group consisting of --C(O)OR.sup.5a and OR.sup.5a. In some such
embodiments, R.sup.5a is C.sub.1-C.sub.6 alkyl.
[0095] In certain embodiments, R.sup.6 is H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --S(O).sub.2R.sup.6a,
--S(O).sub.2NR.sup.6bR.sup.6c, or G.sup.2; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.2, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --C(O)N(R.sup.6b)NR.sup.6bR.sup.6c,
--S(O)R.sup.6d, --S(O).sub.2R.sup.6a,
--S(O).sub.2NR.sup.6bR.sup.6c, --OR.sup.6a, --OC(O)R.sup.6d,
--NR.sup.6bR.sup.6c, N(R.sup.6b)C(O)R.sup.6d,
N(R.sup.6b)SO.sub.2R.sup.6d, N(R.sup.6b)C(O)OR.sup.6d,
N(R.sup.6b)C(O)NR.sup.6bR.sup.6c,
N(R.sup.6b)SO.sub.2NR.sup.6bR.sup.6c, and
N(R.sup.6b)C(NR.sup.6bR.sup.6c).dbd.NR.sup.6bR.sup.6c.
[0096] In certain embodiments, R.sup.6 is H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, --C(O)R.sup.6a, --C(O)OR.sup.6a,
--C(O)NR.sup.6bR.sup.6c, --S(O).sub.2R.sup.6a, or G.sup.2; wherein
the C.sub.1-C.sub.6 alkyl and the C.sub.2-C.sub.6 alkenyl are each
independently unsubstituted or substituted with 1 or 2 substituents
independently selected from the group consisting of G.sup.2,
--C(O)OR.sup.6a, --NR.sup.6bR.sup.6c, N(R.sup.6b)C(O)R.sup.6d,
N(R.sup.6b)SO.sub.2R.sup.6d, N(R.sup.6b)C(O)OR.sup.6d,
N(R.sup.6b)C(O)NR.sup.6bR.sup.6c, and
N(R.sup.6b)SO.sub.2NR.sup.6bR.sup.6c.
[0097] In certain embodiments, R.sup.6 is H, C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.6a, or G.sup.2; wherein the C.sub.1-C.sub.6 alkyl is
unsubstituted or substituted with a G.sup.2 group.
[0098] In certain embodiments, R.sup.6 is --C(O)R.sup.6a, G.sup.2,
or C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with
a G.sup.2 group. In some such embodiments, R.sup.6a is G.sup.2. In
some such embodiments, R.sup.6a is G.sup.2 wherein G.sup.2 is
optionally substituted cycloalkyl. In some such embodiments,
R.sup.6a is G.sup.2 wherein G.sup.2 is optionally substituted
cyclopropyl. In some such embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted phenyl.
[0099] In certain embodiments, R.sup.6 is G.sup.2 or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with a
G.sup.2 group. In some such embodiments, R.sup.6 is optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocycle, or C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with an optionally substituted
cycloalkyl. In some such embodiments, R.sup.6 is optionally
substituted aryl or C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with an optionally substituted cycloalkyl. In some such
embodiments, R.sup.6 is optionally substituted phenyl, optionally
substituted pyridinyl, optionally substituted piperidinyl, or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with an
optionally substituted cyclopropyl. In some such embodiments,
R.sup.6 is optionally substituted phenyl or C.sub.1-C.sub.6 alkyl
which is unsubstituted or substituted with an optionally
substituted cyclopropyl. In some such embodiments, said optional
substituents are independently selected from the group consisting
of halogen, --C(O)(C.sub.1-C.sub.6 alkyl), --C(O)O(C.sub.1-C.sub.6
alkyl), --O(C.sub.1-C.sub.3 alkyl), --O(C.sub.1-C.sub.3 haloalkyl),
C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3 haloalkyl. In some such
embodiments, said optional substituents are independently selected
from the group consisting of halogen, --O(C.sub.1-C.sub.3 alkyl),
--O(C.sub.1-C.sub.3 haloalkyl), C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl. In some such embodiments, said optional
substituents are halogen. In some such embodiments, said halogen is
F or Cl.
[0100] In certain embodiments, A.sup.1 is C(R.sup.7) or N; A.sup.2
is C(R.sup.8) or N; A.sup.3 is C(R.sup.9) or N; and A.sup.4 is
C(R.sup.10) or N; wherein zero, one, or two of A.sup.1, A.sup.2,
A.sup.3, and A.sup.4 are N.
[0101] In certain embodiments, A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0102] In certain embodiments, one of A.sup.1, A.sup.2, A.sup.3,
and A.sup.4 is N. In some such embodiments, A.sup.1 is N; A.sup.2
is C(R.sup.8); A.sup.3 is C(R.sup.9); and A.sup.4 is
C(R.sup.10).
[0103] In certain embodiments, two of A.sup.1, A.sup.2, A.sup.3,
and A.sup.4 are N. In some such embodiments, A.sup.1 is N; A.sup.2
is C(R.sup.8); A.sup.3 is N; and A.sup.4 is C(R.sup.10).
[0104] In certain embodiments, A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
A.sup.1 is N; A.sup.2 is C(R.sup.8); A.sup.3 is C(R.sup.9); and
A.sup.4 is C(R.sup.10); or A.sup.1 is N; A.sup.2 is C(R.sup.8);
A.sup.3 is N; and A.sup.4 is C(R.sup.10).
[0105] In certain embodiments, R.sup.7, R.sup.8, and R.sup.9, are
each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, --OR.sup.y1, --OC(O)R.sup.y2,
--OC(O)NR.sup.y3R.sup.y4, --SR.sup.y1, --S(O).sub.2R.sup.y1,
--S(O).sub.2NR.sup.y3R.sup.y4, --C(O)R.sup.y1, --C(O)OR.sup.y1,
--C(O)NR.sup.y3R.sup.y4, --NR.sup.y3R.sup.y4,
--N(R.sup.y3)C(O)R.sup.y2, --N(R.sup.y3)S(O).sub.2R.sup.y2,
--N(R.sup.y3)C(O)O(R.sup.y2), --N(R.sup.y3)C(O)NR.sup.y3R.sup.y4,
--N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, G.sup.3,
--(C.sub.1-C.sub.6 alkylenyl)-CN, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.y1, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.y2,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.y1,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-CN, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3.
[0106] In certain embodiments, R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl. In
some such embodiments, the cyclopropyl is optionally substituted
with 1, 2, 3, 4, or 5 R.sup.4g groups, wherein R.sup.4g is
C.sub.1-C.sub.3 alkyl, halogen, or C.sub.1-C.sub.3 haloalkyl.
[0107] In certain embodiments, R.sup.7 is H or halogen. In some
such embodiments, the halogen is F or Cl. In some such embodiments,
the halogen is F.
[0108] In certain embodiments, R.sup.7 is H.
[0109] In certain embodiments, R.sup.8 is H, C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 haloalkyl, --CN, optionally substituted
heterocycle, --C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle.
[0110] In certain embodiments, R.sup.8 is H.
[0111] In certain embodiments, R.sup.9 is H, C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 haloalkyl, --CN, --S(O).sub.2R.sup.y1,
--S(O).sub.2NR.sup.y3R.sup.y4, --C(O)NR.sup.y3R.sup.y4,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, --N(R.sup.y3)C(O)O(R.sup.y2),
--N(R.sup.y3)C(O)NR.sup.y3R.sup.y4,
--N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4.
[0112] In certain embodiments, R.sup.9 is H, halogen,
--S(O).sub.2R.sup.y1, --C(O)NR.sup.y3R.sup.y4, --NR.sup.y3R.sup.y4,
--N(R.sup.y3)C(O)R.sup.y2, --N(R.sup.y3)S(O).sub.2R.sup.y2,
--N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1.
[0113] In certain embodiments, R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1. In some such embodiments, R.sup.y1
is C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.y3 is H.
In certain embodiments wherein R.sup.9 is --NR.sup.y3R.sup.y4 and
R.sup.y3 is H, an example of R.sup.y4 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3. In certain embodiments wherein R.sup.9 is
--N(R.sup.y3)C(O)R.sup.y2 and R.sup.y3 is H, examples of R.sup.y2
are C.sub.1-C.sub.6 alkyl and --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3. In certain embodiments wherein R.sup.9 is
--N(R.sup.y3)S(O).sub.2R.sup.y2 and R.sup.y3 is H, examples of
R.sup.y2 are C.sub.1-C.sub.6 alkyl and optionally substituted
phenyl.
[0114] In certain embodiments, R.sup.10 is H, C.sub.1-C.sub.3
alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or --CN.
[0115] In certain embodiments, R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen.
[0116] In certain embodiments, R.sup.10 is H.
[0117] Various embodiments of substituents R.sup.1, R.sup.2,
R.sup.6, Y.sup.1, Y.sup.2, A.sup.1, A.sup.2, A.sup.3, and A.sup.4
have been discussed above. These substituents embodiments can be
combined to form various embodiments of compounds of formula (I).
All embodiments of compounds of formula (I), formed by combining
the substituent embodiments discussed above are within the scope of
Applicant's invention, and some illustrative embodiments of the
compounds of formula (I) are provided below.
[0118] In certain embodiments,
[0119] Y.sup.1 is CR.sup.3; and
[0120] Y.sup.2 is CR.sup.4R.sup.5.
[0121] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0122] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0123] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0124] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0125] In certain embodiments, [0126] Y.sup.1 is CR.sup.3; [0127]
Y.sup.2 is CR.sup.4R.sup.5; and [0128] R.sup.3 is H,
--C(O)R.sup.3a, --C(O)OR.sup.3a, --C(O)NR.sup.3bR.sup.3c, or
C.sub.1-C.sub.6 alkyl, wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with a substituent selected from the group
consisting of G.sup.1, --NR.sup.3bR.sup.3c,
N(R.sup.3b)C(O)R.sup.3d, N(R.sup.3b)SO.sub.2R.sup.3d,
N(R.sup.3b)C(O)OR.sup.3d, N(R.sup.3b)C(O)NR.sup.3bR.sup.3c, and
N(R.sup.3b)SO.sub.2NR.sup.3bR.sup.3c.
[0129] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0130] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0131] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0132] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0133] In certain embodiments, [0134] Y.sup.1 is CR.sup.3; [0135]
Y.sup.2 is CR.sup.4R.sup.5; [0136] R.sup.4 is H or deuterium; and
[0137] R.sup.5 is H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, --C(O)R.sup.5a, --C(O)OR.sup.5a, or G.sup.1; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.1, --C(O)R.sup.5a, --C(O)OR.sup.5a,
--C(O)NR.sup.5bR.sup.5c, --C(O)N(R.sup.5b)NR.sup.5bR.sup.5c,
--OR.sup.5a, --OC(O)R.sup.5d, --NR.sup.5bR.sup.5c,
N(R.sup.5b)C(O)R.sup.5d, N(R.sup.5b)SO.sub.2R.sup.5d,
N(R.sup.5b)C(O)OR.sup.5d, N(R.sup.5b)C(O)NR.sup.5bR.sup.5c, and
N(R.sup.5b)SO.sub.2NR.sup.5bR.sup.5c.
[0138] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0139] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0140] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0141] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0142] In certain embodiments, [0143] Y.sup.1 is CR.sup.3; [0144]
Y.sup.2 is CR.sup.4R.sup.5; and [0145] R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, --C(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, S(O).sub.2R.sup.6a, or
G.sup.2; wherein the C.sub.1-C.sub.6 alkyl and the C.sub.2-C.sub.6
alkenyl are each independently unsubstituted or substituted with 1
or 2 substituents independently selected from the group consisting
of G.sup.2, --C(O)OR.sup.6a, --NR.sup.6bR.sup.6c,
N(R.sup.6b)C(O)R.sup.6d, N(R.sup.6b)SO.sub.2R.sup.6d,
N(R.sup.6b)C(O)OR.sup.6d, N(R.sup.6b)C(O)NR.sup.6bR.sup.6c, and
N(R.sup.6b)SO.sub.2NR.sup.6bR.sup.6c.
[0146] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0147] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0148] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0149] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0150] In certain embodiments, [0151] Y.sup.1 is CR.sup.3; [0152]
Y.sup.2 is CR.sup.4R.sup.5; and [0153] R.sup.9 is H,
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN,
--S(O).sub.2R.sup.y1, --S(O).sub.2NR.sup.y3R.sup.y4,
--C(O)NR.sup.y3R.sup.y4, --NR.sup.y3R.sup.y4,
--N(R.sup.y3)C(O)R.sup.y2, --N(R.sup.y3)S(O).sub.2R.sup.y2,
--N(R.sup.y3)C(O)O(R.sup.y2), --N(R.sup.y3)C(O)NR.sup.y3R.sup.y4,
--N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4.
[0154] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0155] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0156] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0157] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0158] In certain embodiments, [0159] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0160] R.sup.2 is H; [0161] Y.sup.1 is CR.sup.3; and [0162]
Y.sup.2 is CR.sup.4R.sup.5.
[0163] In some further embodiments, R.sup.1 is methyl.
[0164] In certain embodiments, [0165] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0166] R.sup.2 is H; [0167] Y.sup.1 is CR.sup.3; [0168]
Y.sup.2 is CR.sup.4R.sup.5; [0169] R.sup.4 is H; and [0170] R.sup.5
is H, --C(O)OR.sup.5a, G.sup.1, or C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a substituent selected from the
group consisting of G.sup.1, --C(O)OR.sup.5a, and --OR.sup.5a.
[0171] In some further embodiments, R.sup.1 is methyl.
[0172] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0173] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0174] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0175] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0176] In certain embodiments, [0177] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0178] R.sup.2 is H; [0179] Y.sup.1 is CR.sup.3; [0180]
Y.sup.2 is CR.sup.4R.sup.5; and [0181] R.sup.3 is H.
[0182] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0183] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0184] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0185] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0186] In some further embodiments, R.sup.1 is methyl.
[0187] In certain embodiments, [0188] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0189] R.sup.2 is H; [0190] Y.sup.1 is CR.sup.3; [0191]
Y.sup.2 is CR.sup.4R.sup.5; and [0192] R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, --C(O)R.sup.6a, or G.sup.2; wherein the
C.sub.1-C.sub.6 alkyl is unsubstituted or substituted with a
G.sup.2 group.
[0193] In some further embodiments, R.sup.1 is methyl.
[0194] In some further embodiments, R.sup.6a is G.sup.2.
[0195] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cycloalkyl.
[0196] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cyclopropyl.
[0197] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0198] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0199] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0200] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0201] In certain embodiments, [0202] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0203] R.sup.2 is H; [0204] Y.sup.1 is CR.sup.3; [0205]
Y.sup.2 is CR.sup.4R.sup.5; and [0206] R.sup.9 is H, halogen,
--S(O).sub.2R.sup.y1, --C(O)NR.sup.y3R.sup.y4, --NR.sup.y3R.sup.y4,
--N(R.sup.y3)C(O)R.sup.y2, --N(R.sup.y3)S(O).sub.2R.sup.y2,
--N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1.
[0207] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10);
or A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and
A.sup.4 is C(R.sup.10); or A.sup.1 is N, A.sup.2 is C(R.sup.8),
A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0208] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0209] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0210] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0211] In some further embodiments, R.sup.1 is methyl.
[0212] In certain embodiments, [0213] R.sup.1 is C.sub.1-C.sub.3
alkyl; [0214] R.sup.2 is H; [0215] Y.sup.1 is CR.sup.3; [0216]
Y.sup.2 is CR.sup.4R.sup.5; and [0217] A.sup.1 is C(R.sup.7),
A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10); or [0218] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3
is C(R.sup.9), and A.sup.4 is C(R.sup.10); or [0219] A.sup.1 is N,
A.sup.2 is C(R.sup.8), A.sup.3 is N, and A.sup.4 is
C(R.sup.10).
[0220] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0221] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0222] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0223] In yet some further embodiments, R.sup.1 is methyl. [0224]
In certain embodiments, [0225] R.sup.1 is methyl; [0226] R.sup.2 is
H; [0227] Y.sup.1 is CR.sup.3; [0228] Y.sup.2 is CR.sup.4R.sup.5;
[0229] A.sup.1 is C(R.sup.7), A.sup.2 is C(R.sup.8), A.sup.3 is
C(R.sup.9), and A.sup.4 is C(R.sup.10); or [0230] A.sup.1 is N,
A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10); or [0231] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3
is N, and A.sup.4 is C(R.sup.10); [0232] R.sup.4 is H or deuterium;
[0233] R.sup.7 is H, halogen, C.sub.1-C.sub.3 alkyl, or optionally
substituted cyclopropyl; [0234] R.sup.8 is H, C.sub.1-C.sub.6
alkyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, optionally
substituted heterocycle, --C(O)NR.sup.y3R.sup.y4,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle; and [0235] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen.
[0236] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0237] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0238] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0239] In certain embodiments, [0240] R.sup.1 is methyl; [0241]
R.sup.2 is H; [0242] Y.sup.1 is CR.sup.3; [0243] Y.sup.2 is
CR.sup.4R.sup.5; [0244] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0245] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0246] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0247]
R.sup.4 is H or deuterium; [0248] R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0249] R.sup.8 is H, C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, optionally substituted
heterocycle, --C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle; [0250] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0251] R.sup.3 is H or
--C(O)NR.sup.3bR.sup.3c.
[0252] In some further embodiments, R.sup.3b and R.sup.3c are each
independently H or C.sub.1-C.sub.6 alkyl.
[0253] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0254] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0255] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0256] In certain embodiments, [0257] R.sup.1 is methyl; [0258]
R.sup.2 is H; [0259] Y.sup.1 is CR.sup.3; [0260] Y.sup.2 is
CR.sup.4R.sup.5; [0261] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0262] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0263] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0264]
R.sup.4 is H or deuterium; [0265] R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0266] R.sup.8 is H, C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, optionally substituted
heterocycle, --C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle; [0267] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0268] R.sup.5 is H, deuterium, or
C.sub.1-C.sub.6 alkyl optionally substituted with a substituent
selected from the group consisting of --C(O)OR.sup.5a and
OR.sup.5a.
[0269] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0270] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0271] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0272] In yet some further embodiments, R.sup.5a is C.sub.1-C.sub.6
alkyl.
[0273] In certain embodiments, [0274] R.sup.1 is methyl; [0275]
R.sup.2 is H; [0276] Y.sup.1 is CR.sup.3; [0277] Y.sup.2 is
CR.sup.4R.sup.5; [0278] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0279] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0280] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0281]
R.sup.4 is H or deuterium; [0282] R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0283] R.sup.8 is H, C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, optionally substituted
heterocycle, --C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle; [0284] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0285] R.sup.6 is --C(O)R.sup.6a, G.sup.2,
or C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with
a G.sup.2 group.
[0286] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0287] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0288] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0289] In some further embodiments, R.sup.6a is G.sup.2.
[0290] In some further embodiments, R.sup.6a is G.sup.2, and
G.sup.2 is optionally substituted cycloalkyl.
[0291] In some further embodiments, R.sup.6a is G.sup.2, and
G.sup.2 is optionally substituted cyclopropyl.
[0292] In certain embodiments, [0293] R.sup.1 is methyl; [0294]
R.sup.2 is H; [0295] Y.sup.1 is CR.sup.3; [0296] Y.sup.2 is
CR.sup.4R.sup.5; [0297] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0298] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0299] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0300]
R.sup.4 is H or deuterium; [0301] R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0302] R.sup.8 is H, C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, optionally substituted
heterocycle, --C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.y3R.sup.y4, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3 wherein G.sup.3 is optionally
substituted heterocycle; [0303] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0304] R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1.
[0305] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10);
[0306] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0307] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0308] In some further embodiments, R.sup.y3 is H.
[0309] In some further embodiments, R.sup.y1 is C.sub.1-C.sub.6
alkyl.
[0310] In some further embodiments, R.sup.y2 is C.sub.1-C.sub.6
alkyl.
[0311] In certain embodiments, [0312] R.sup.1 is methyl; [0313]
R.sup.2 is H; [0314] Y.sup.1 is CR.sup.3; [0315] Y.sup.2 is
CR.sup.4R.sup.5; [0316] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0317] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0318] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0319]
R.sup.4 is H; [0320] R.sup.7 is H or halogen; [0321] R.sup.8 is H;
and [0322] R.sup.10 is H.
[0323] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0324] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0325] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0326] In certain embodiments, [0327] R.sup.1 is methyl; [0328]
R.sup.2 is H; [0329] Y.sup.1 is CR.sup.3; [0330] Y.sup.2 is
CR.sup.4R.sup.5; [0331] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0332] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0333] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); and [0334]
R.sup.4 is H; [0335] R.sup.7 is H or halogen; [0336] R.sup.8 is H;
[0337] R.sup.10 is H; and [0338] R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1.
[0339] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0340] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0341] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0342] In some further embodiments, R.sup.y1 is C.sub.1-C.sub.6
alkyl and R.sup.y3 is H.
[0343] In some further embodiments, R.sup.y1 and R.sup.y2 are
C.sub.1-C.sub.6 alkyl, and R.sup.y3 is H.
[0344] In certain embodiments, [0345] R.sup.1 is methyl; [0346]
R.sup.2 is H; [0347] Y.sup.1 is CR.sup.3; [0348] Y.sup.2 is
CR.sup.4R.sup.5; [0349] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0350] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0351] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0352]
R.sup.4 is H; [0353] R.sup.7 is H or halogen; [0354] R.sup.8 is H;
[0355] R.sup.10 is H; [0356] R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1; and [0357] R.sup.6 is
--C(O)R.sup.6a, G.sup.2, or C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a G.sup.2 group.
[0358] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0359] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0360] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0361] In some further embodiments, R.sup.y1 is C.sub.1-C.sub.6
alkyl, and R.sup.y3 is H.
[0362] In some further embodiments, R.sup.6a is G.sup.2.
[0363] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cycloalkyl.
[0364] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cyclopropyl.
[0365] In certain embodiments, [0366] R.sup.1 is methyl; [0367]
R.sup.2 is H; [0368] Y.sup.1 is CR.sup.3; [0369] Y.sup.2 is
CR.sup.4R.sup.5; [0370] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0371] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0372] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0373]
R.sup.4 is H; [0374] R.sup.7 is H or halogen; [0375] R.sup.8 is H;
[0376] R.sup.10 is H; [0377] R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1; [0378] R.sup.6 is --C(O)R.sup.6a,
G.sup.2, or C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with a G.sup.2 group; and [0379] R.sup.5 is H or
C.sub.1-C.sub.6 alkyl optionally substituted with a substituent
selected from the group consisting of --C(O)OR.sup.5a and
OR.sup.5a.
[0380] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0381] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0382] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0383] In some further embodiments, R.sup.y1 is C.sub.1-C.sub.6
alkyl, and R.sup.y3 is H.
[0384] In some further embodiments, R.sup.6a is G.sup.2.
[0385] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cycloalkyl.
[0386] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cyclopropyl.
[0387] In certain embodiments, [0388] R.sup.1 is methyl; [0389]
R.sup.2 is H; [0390] Y.sup.1 is CR.sup.3; [0391] Y.sup.2 is
CR.sup.4R.sup.5; [0392] A.sup.1 is C(R.sup.7), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0393] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0394] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0395]
R.sup.4 is H; [0396] R.sup.7 is H or halogen; [0397] R.sup.8 is H;
[0398] R.sup.10 is H; [0399] R.sup.9 is halogen,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)C(O)R.sup.y2,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.y1; [0400] R.sup.6 is --C(O)R.sup.6a,
G.sup.2, or C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with a G.sup.2 group; [0401] R.sup.5 is H or
C.sub.1-C.sub.6 alkyl optionally substituted with a substituent
selected from the group consisting of --C(O)OR.sup.5a and
OR.sup.5a; and [0402] R.sup.3 is H.
[0403] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0404] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0405] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0406] In some further embodiments, R.sup.y1 is C.sub.1-C.sub.6
alkyl, and R.sup.y3 is H.
[0407] In some further embodiments, R.sup.6a is G.sup.2.
[0408] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cyclopropyl.
[0409] In certain embodiments, [0410] R.sup.1 is methyl; [0411]
R.sup.2 is H; [0412] Y.sup.1 is CR.sup.3; [0413] Y.sup.2 is
CR.sup.4R.sup.5; [0414] A.sup.1 is C(R.sup.2), A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10); or
[0415] A.sup.1 is N, A.sup.2 is C(R.sup.8), A.sup.3 is C(R.sup.9),
and A.sup.4 is C(R.sup.10); or [0416] A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10); [0417]
R.sup.4 is H; [0418] R.sup.7 is H; [0419] R.sup.8 is H; [0420]
R.sup.10 is H; [0421] R.sup.9 is halogen, --NR.sup.y3R.sup.y4,
--N(R.sup.y3)C(O)R.sup.y2, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.y1; [0422] R.sup.6 is
--C(O)R.sup.6a, G.sup.2, or C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a G.sup.2 group; [0423] R.sup.5
is H or C.sub.1-C.sub.6 alkyl optionally substituted with a
substituent selected from the group consisting of --C(O)OR.sup.5a
and OR.sup.5a; [0424] R.sup.3 is H; [0425] R.sup.5a is
C.sub.1-C.sub.6 alkyl; [0426] R.sup.y1 is C.sub.1-C.sub.6 alkyl;
and [0427] R.sup.y3 is H.
[0428] In some further embodiments, A.sup.1 is C(R.sup.7), A.sup.2
is C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is
C(R.sup.10).
[0429] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is C(R.sup.9), and A.sup.4 is C(R.sup.10).
[0430] In some further embodiments, A.sup.1 is N, A.sup.2 is
C(R.sup.8), A.sup.3 is N, and A.sup.4 is C(R.sup.10).
[0431] In some further embodiments, R.sup.6a is G.sup.2 wherein
G.sup.2 is optionally substituted cyclopropyl.
[0432] In some further embodiments, R.sup.y2 is C.sub.1-C.sub.6
alkyl.
[0433] Compounds of formula (I) may contain one or more
asymmetrically substituted atoms. Compounds of formula (I) may also
exist as individual stereoisomers (including enantiomers and
diastereomers) and mixtures thereof. Individual stereoisomers of
compounds of formula (I) may be prepared synthetically from
commercially available starting materials that contain asymmetric
or chiral centers or by preparation of racemic mixtures followed by
resolution of the individual stereoisomer using methods that are
known to those of ordinary skill in the art. Examples of resolution
are, for example, (i) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography, followed by
liberation of the optically pure product; or (ii) separation of the
mixture of enantiomers or diastereomers on chiral chromatographic
columns.
[0434] Compounds of formula (I) may also include the various
geometric isomers and mixtures thereof resulting from the
disposition of substituents around a carbon-carbon double bond, a
carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle
group. Substituents around a carbon-carbon double bond or a
carbon-nitrogen double bond are designated as being of Z or E
configuration and substituents around a cycloalkyl or heterocycle
are designated as being of cis or trans configuration.
[0435] Within the present invention it is to be understood that
compounds disclosed herein may exhibit the phenomenon of
tautomerism and all tautomeric isomers are included in the scope of
the invention.
[0436] Thus, the formula drawings within this specification can
represent only one of the possible tautomeric, geometric, or
stereoisomeric forms. It is to be understood that the invention
encompasses any tautomeric, geometric, or stereoisomeric form, and
mixtures thereof, and is not to be limited merely to any one
tautomeric, geometric, or stereoisomeric form utilized within the
formula drawings.
[0437] Compounds of the invention are named using ChemDraw Ultra
Version 12.
[0438] Exemplary compounds of formula (I) include, but are not
limited to: [0439]
11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-1-one; [0440]
5-(cyclopropylmethyl)-11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H-
-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0441]
5-(cyclopropylmethyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetra-
hydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0442]
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahyd-
ro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0443]
5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetr-
ahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0444]
5-(cyclopropanecarbonyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0445]
5-benzoyl-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahydro-1H-2,5-
,11-triazadibenzo[cd,h]azulen-1-one; [0446]
5-(4-fluorophenyl)-4-(2-methoxyethyl)-11-methyl-8-((methylsulfonyl)methyl-
)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0447] methyl
3-(5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-1-oxo-2-
,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-4-yl)propanoate;
[0448]
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-4-((tetrah-
ydro-2H-pyran-4-yl)methyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,-
h]azulen-1-one; [0449]
5-(cyclopropylmethyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triazadiben-
zo[cd,h]azulen-1-one; [0450]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0451]
8-chloro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-1-one; [0452]
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-1-one; [0453] ethyl
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-4-carboxylate; [0454]
8-fluoro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-1-one; [0455]
2-(2-chloro-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide;
[0456]
2-(1,5-dimethyl-1H-pyrazol-3-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-
-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acet-
amide; [0457]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)-2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)aceta-
mide; [0458]
2-(4-chloro-2-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide;
[0459]
2-(chroman-6-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide;
[0460]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide;
[0461]
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-1-one; [0462]
8-chloro-5-(4-fluorophenyl)-11-methyl-4-phenyl-2,4,5,11-tetrahydro-1H-2,5-
,11-triazadibenzo[cd,h]azulen-1-one; [0463]
11-methyl-8-((methylsulfonyl)methyl)-4-phenyl-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-1-one; [0464]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)benzenesulfonamide; [0465]
N-(4-(N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-8-yl)sulfamoyl)phenyl)acetamide; [0466]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide;
[0467]
2-(4-chloro-2-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0468]
2-(2-chloro-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0469]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)acetamide-
; [0470]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-8-yl)-2-(2-methylthiazol-5-yl)acetamide;
[0471]
2-(1,5-dimethyl-1H-pyrazol-3-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-
-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamid-
e; [0472]
N.sup.1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro--
1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)-N.sup.5-phenylglutaramide;
[0473]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)-5-methylpyrazine-2-carboxamide;
[0474]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide;
[0475]
8-(((1-ethyl-1H-pyrazol-3-yl)methyl)amino)-5-(4-fluorophenyl)-11-methyl-2-
,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0476]
5-(4-fluorophenyl)-11-methyl-8-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)--
2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0477]
8-((3-(1H-pyrazol-1-yl)propyl)amino)-5-(4-fluorophenyl)-11-methyl-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0478]
5-(4-fluorophenyl)-11-methyl-8-(((6-methylpyridin-2-yl)methyl)amino)-2,4,-
5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0479]
methyl
4-((5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-tria-
zadibenzo[cd,h]azulen-8-yl)amino)butanoate; [0480]
5-(4-fluorophenyl)-11-methyl-8-(((1-methyl-1H-imidazol-5-yl)methyl)amino)-
-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0481]
5-(4-fluorophenyl)-11-methyl-8-(((3-methylpyridin-2-yl)methyl)amino)-2,4,-
5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0482]
1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-3-(3-phenoxyphenyl)urea; [0483]
1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-3-(3-methoxyphenyl)urea; [0484]
2-(chroman-6-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydr-
o-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide; [0485]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-3-(4-methylpiperazin-1-yl)propanamide;
[0486]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-3-(piperidin-1-yl)propanamide; [0487]
2-(2-bromo-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0488]
2-(2,5-dichlorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tet-
rahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide; [0489]
2-(5-fluoro-2-(trifluoromethyl)phenyl)-N-(5-(4-fluorophenyl)-11-methyl-1--
oxo-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide-
; [0490]
2-(2,5-difluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,-
5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0491]
2-(2,5-dimethylphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tet-
rahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide; [0492]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-2-phenylacetamide; [0493]
2-(5-chloro-2-phenoxyphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,-
11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0494]
N-(5-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11--
tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0495]
N-(5-fluoro-2-methylbenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-t-
etrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0496]
N-(2-bromo-5-fluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide; [0497]
5-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-11-methyl-1-oxo-2,4,5,11-t-
etrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0498]
N-(2-chloro-5-fluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-t-
etrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0499]
N-(1-(2,4-dichlorophenyl)ethyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,-
11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0500]
N-((1-benzyl-1H-pyrazol-4-yl)methyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2-
,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide;
[0501]
N-benzyl-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-
-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide; [0502]
N-(2,5-difluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrah-
ydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide; [0503]
2-(5-fluoro-2-methoxyphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,-
11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0504]
2-(5-fluoro-2-nitrophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide;
[0505]
8-amino-5-(2,4-difluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11--
tetraazadibenzo[cd,h]azulen-1-one; [0506]
N-(5-(2,4-difluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-
-tetraazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0507]
8-amino-5-(4-chlorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-1-one; [0508]
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0509]
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)methanesulfonamide; and [0510]
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)acetamide.
[0511] In certain embodiments, a compound of formula (I) is
selected from the group consisting of: [0512]
5-(cyclopropylmethyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetra-
hydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0513]
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahyd-
ro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0514]
5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetr-
ahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0515]
5-(cyclopropanecarbonyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0516]
5-(4-fluorophenyl)-4-(2-methoxyethyl)-11-methyl-8-((methylsulfonyl)methyl-
)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0517] methyl
3-(5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-1-oxo-2-
,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-4-yl)propanoate;
[0518]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0519]
8-fluoro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-1-one; [0520]
2-(2-chloro-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide;
[0521]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6-
,11-tetraazadibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamid-
e; [0522]
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-1-one; [0523]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)benzenesulfonamide; [0524]
N-(4-(N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-8-yl)sulfamoyl)phenyl)acetamide; [0525]
5-(4-fluorophenyl)-11-methyl-8-(((6-methylpyridin-2-yl)methyl)amino)-2,4,-
5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0526]
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaz-
adibenzo[cd,h]azulen-8-yl)-3-(piperidin-1-yl)propanamide; [0527]
N-(5-(2,4-difluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-
-tetraazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0528]
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0529]
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tet-
raazadibenzo[cd,h]azulen-8-yl)acetamide; [0530]
5-(1-acetylpiperidin-4-yl)-8-amino-11-methyl-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-1-one; [0531]
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide; [0532]
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-8-yl)-2-(2-methylthiazol-5-yl)acetamide;
[0533]
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro--
1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)-2-(2-chloro-5-fluorophenyl)aceta-
mide; [0534]
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-8-yl)acetamide; [0535]
6-cyclopropyl-5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-
-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one;
[0536]
11-methyl-8-((methylsulfonyl)methyl)-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-
-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one; [0537] tert-butyl
4-(11-methyl-8-((methylsulfonyl)methyl)-1-oxo-1H-2,5,11-triazadibenzo[cd,-
h]azulen-5(2H,4H,11H)-yl)piperidine-1-carboxylate; [0538] methyl
11-methyl-8-((methylsulfonyl)methyl)-1-oxo-4,11-dihydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulene-5(2H)-carboxylate; and [0539]
N-(11-methyl-1-oxo-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-8-yl)ethanesulfonamide.
[0540] Compounds of formula I can be used in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like and are commensurate
with a reasonable benefit/risk ratio.
[0541] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[0542] Compounds of formula (I) may contain either a basic or an
acidic functionality, or both, and can be converted to a
pharmaceutically acceptable salt, when desired, by using a suitable
acid or base. The salts may be prepared in situ during the final
isolation and purification of the compounds of the invention.
[0543] Examples of acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as, but not limited to, methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain
halides such as, but not limited to, decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; arylalkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained. Examples of acids which
may be employed to form pharmaceutically acceptable acid addition
salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and such
organic acids as acetic acid, fumaric acid, maleic acid,
4-methylbenzenesulfonic acid, succinic acid and citric acid.
[0544] Basic addition salts may be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
examples of organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0545] The term "pharmaceutically acceptable prodrug" or "prodrug"
as used herein, represents those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use.
[0546] The present invention contemplates compounds of formula (I)
formed by synthetic means or formed by in vivo biotransformation of
a prodrug.
[0547] Compounds described herein can exist in unsolvated as well
as solvated forms, including hydrated forms, such as hemi-hydrates.
In general, the solvated forms, with pharmaceutically acceptable
solvents such as water and ethanol among others are equivalent to
the unsolvated forms for the purposes of the invention.
General Synthesis
[0548] The compounds described herein, including compounds of
general formula (I) and specific examples, may be prepared, for
example, through the reaction routes depicted in schemes 1-5. The
variables A.sup.1, A.sup.2, A.sup.3, A.sup.4, Y.sup.1, Y.sup.2,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.3b,
R.sup.3c, R.sup.6a, R.sup.6b, and R.sup.6c used in the following
schemes have the meanings as set forth in the summary and detailed
description sections unless otherwise noted.
[0549] Abbreviations used in the descriptions of the schemes and
the specific examples have the following meanings: DMF for
dimethylformamide, DMSO for dimethyl sulfoxide, TFA for
trifluoroacetic acid, and HPLC for high performance liquid
chromatography.
##STR00004##
[0550] Compounds of general formula (I) wherein Y.sup.2 is
CR.sup.4R.sup.5 may be prepared by treating compounds of the
general formula (1) with an aldehyde or ketone (2) under acidic
conditions, as illustrated in Scheme 1. Generally, this cyclization
reaction may be effected in the presence of an acid, such as acetic
acid or hydrochloric acid, in the absence or presence of a solvent
such as, but not limited to, methanol or ethanol, at a temperature
ranging from about 50.degree. C. to about 150.degree. C.
Alternatively, this cyclization reaction may be effected in the
presence of a reagent such as titanium tetrachloride in a solvent
such as, but not limited to, tetrahydrofuran or dichloromethane, at
a temperature ranging from about 0.degree. C. to about 50.degree.
C.
##STR00005##
[0551] Compounds of formula (1) wherein R.sup.2 is H may be
prepared by general synthetic methods as shown in Scheme 2.
Reaction of compounds of formula (4) wherein X is Br, Cl, I, or
triflate with a C.sub.1-C.sub.3 alkyl halide, in the presence of a
base such as, for example, carbonate of cesium, sodium, or
potassium and in a solvent such as, for example, dimethylformamide,
tetrahydrofuran, or dimethylsulfoxide, provides intermediates of
formula (5) wherein R.sup.1 is C.sub.1-C.sub.3 alkyl. The reaction
may be conducted at temperature such as, for example, about
25.degree. C. to about 60.degree. C.
[0552] Pinacol esters of formula (6), may be synthesized, for
example, by treatment of compounds of formula (5), wherein X is Br,
Cl, I, or triflate, with a reagent such as, but not limited to,
butyllithium followed by
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, in a solvent
such as, for example, tetrahydrofuran, at a temperature such as,
for example, about -78.degree. C. (6) may be prepared by reaction
of compounds of general formula (5), wherein X is Br, Cl, I, or
triflate, with a reagent such as, but not limited to,
bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
in the presence of a palladium catalyst and a base, and optionally
in the presence of a ligand, and in a suitable solvent at elevated
temperature (about 80.degree. C. to about 150.degree. C.). The
reaction may be facilitated by microwave irradiation. Examples of
the palladium catalyst include, but are not limited to,
tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0),
bis(triphenylphosphine)palladium(II) dichloride, and palladium(II)
acetate. Examples of suitable bases that may be employed include,
but not limited to, carbonates or phosphates of sodium, potassium,
and cesium, and cesium fluoride. Examples of suitable ligands
include, but are not limited to,
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and
1,1'-bis(diphenylphosphanyl) ferrocene. Non-limiting examples of
suitable solvent include methanol, ethanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran,
and water, or a mixture thereof. Preparation of compounds of
formula (8) may be achieved by reaction of boronic acids or a
derivative thereof (e.g., a pinacol ester) of formula (6) with
compounds of formula (7), wherein X is Cl, Br, I, or triflate,
under Suzuki coupling conditions (N. Miyama and A. Suzuki, Chem.
Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148).
For example, the coupling reaction may be conducted in the presence
of a palladium catalyst and a base, and optionally in the presence
of a ligand, and in a suitable solvent at elevated temperature
(about 80.degree. C. to about 150.degree. C.). The reaction may be
facilitated by microwave irradiation. Examples of the palladium
catalyst include, but are not limited to,
tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0),
bis(triphenylphosphine)palladium(II) dichloride, and
palladium(II)acetate. Examples of suitable bases that may be
employed include, but not limited to, carbonates or phosphates of
sodium, potassium, and cesium, and cesium fluoride. Examples of
suitable ligands include, but are not limited to,
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and
1,1'-bis(diphenylphosphanyl) ferrocene. Non-limiting examples of
suitable solvent include methanol, ethanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran,
toluene, and water, or a mixture thereof. Compounds of general
formula (8) may also be prepared from the reaction of boronic acids
or a derivative thereof (e.g., a pinacol ester) (9) with halides
(5) wherein X is Cl, Br, or I under Suzuki coupling conditions as
described above. Compounds of general formula (10) may be
synthesized by the treatment of compounds (8) with an acid such as,
for example, hydrochloric acid, acetic acid, or p-toluene sulfonic
acid in a solvent such as, for example, water, dioxane, or
dimethylformamide, at a temperature such as, for example, about
25.degree. C. to about 120.degree. C. Alternatively, compounds of
general formula (10) may be obtained from the reaction of compounds
(8) with trimethylsilyl iodide in a solvent such as, for example,
dichloromethane or chloroform, and at a temperature such as, for
example, about 25.degree. C. to about 75.degree. C.
##STR00006##
[0553] Compound of formula (8) may be prepared according to Scheme
3. Amines of formula (13) may be prepared from halides of formula
(5) or boronic acid or derivatives thereof (e.g. pinacol ester) (6)
using reaction conditions as described in Scheme 2. Reductive
amination of amines of formula (13) with a suitable aldehyde or
ketone in the presence of a reducing agent and an acid (e.g. acetic
acid) provides compounds of formula (8) wherein R.sup.6 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl, each of which is optionally substituted, or R.sup.6 is
C.sub.1-C.sub.6 haloalkyl. Examples of reducing agents that may be
employed include, but are not limited to, sodium
triacetoxyhydroborate, sodium borohydride, and sodium
cyanoborohydride. The reaction is generally conducted in a solvent
such as, for example, dichloromethane, methanol, or ethanol, at a
temperature of about 0.degree. C. to about 100.degree. C.
##STR00007##
[0554] Compounds of formula (14) may be prepared by acid hydrolysis
of compounds of formula (13), as described above in Scheme 2.
Compounds of formula (15) may be prepared by treating compounds of
formula (14) with an aldehyde or ketone (2) using conditions
described in Scheme 1. Compounds of formula (16) wherein R.sup.6 is
optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, or R.sup.6 is C.sub.1-C.sub.6
haloalkyl may be prepared by the reductive amination reaction of
compounds of formula (15) with a suitable aldehyde or ketone using
reaction conditions as described in Scheme 3. Compounds of formula
(16) wherein R.sup.6 is C(O)OR.sup.6a, C(O)R.sup.6a,
S(O).sub.2R.sup.6a, and C(O)NR.sup.6bR.sup.6c may be prepared by
the reaction of compounds of formula (15) with chloroformates, acid
chlorides, sulfonyl chlorides or isocyanates in the presence of a
base such as, but not limited to, diisopropylethylamine,
triethylamine, or cesium carbonate, in a solvent such as
dimethylformamide, dimethylacetamide, 1,2-dichloroethane, or
dichloromethane, at temperatures ranging from ambient temperature
to about 100.degree. C. for about 2 to about 72 hours.
##STR00008##
[0555] Compounds of formula (7) and formula (9) may be prepared
according to the synthesis outlined in Scheme 5. Reductive
amination of amines (17) wherein X is I, Br, or Cl with a suitable
aldehyde or ketone provides compounds (7) wherein R.sup.6 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, or C.sub.1-C.sub.6 haloalkyl. Compounds of formula (9) may
be prepared from compounds of formula (7) under Suzuki coupling
conditions as described in Scheme 2. Similarly, compound (20)
wherein X.sup.101 is I, Cl, or Br may be converted to (9).
[0556] Compound (19) may be prepared using Buchwald reaction
conditions. For example, halides (18) may be treated with a
suitable amine in the presence of a catalyst, a ligand, a base, and
in a solvent to provide compounds (19). Examples of catalysts that
may be employed include, but are not limited to,
tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0),
bis(triphenylphosphine)palladium(II) dichloride, and
palladium(II)acetate. Examples of suitable bases that may be
employed include, but not limited to, carbonates or phosphates of
sodium, potassium, and cesium, and cesium fluoride. Examples of
suitable ligands include, but are not limited to,
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and
1,1'-bis(diphenylphosphanyl) ferrocene. Non-limiting examples of
suitable solvent include toluene, tert-butanol, methanol, ethanol,
dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane,
tetrahydrofuran, and water, or a mixture thereof. Halogenation of
compounds of formula (19) by reaction with a reagent such as, but
not limited to, N-bromosuccinimide, N-chlorosuccinimide, or
N-iodosuccinimide, in a solvent such as, but not limited to, acetic
acid, at temperatures from about 0.degree. C. to about 50.degree.
C., provides compounds of formula (20).
[0557] It can be appreciated that the synthetic schemes and
specific examples as illustrated in the synthetic examples section
are illustrative and are not to be read as limiting the scope of
the invention as it is defined in the appended claims. All
alternatives, modifications, and equivalents of the synthetic
methods and specific examples are included within the scope of the
claims.
[0558] Optimum reaction conditions and reaction times for each
individual step can vary depending on the particular reactants
employed and substituents present in the reactants used. Unless
otherwise specified, solvents, temperatures and other reaction
conditions can be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Reactions can be worked up in the conventional manner,
e.g. by eliminating the solvent from the residue and further
purified according to methodologies generally known in the art such
as, but not limited to, crystallization, distillation, extraction,
trituration and chromatography. Unless otherwise described, the
starting materials and reagents are either commercially available
or can be prepared by one skilled in the art from commercially
available materials using methods described in the chemical
literature.
[0559] Routine experimentations, including appropriate manipulation
of the reaction conditions, reagents and sequence of the synthetic
route, protection of any chemical functionality that can not be
compatible with the reaction conditions, and deprotection at a
suitable point in the reaction sequence of the method are included
in the scope of the invention. Suitable protecting groups and the
methods for protecting and deprotecting different substituents
using such suitable protecting groups are well known to those
skilled in the art; examples of which can be found in T. Greene and
P. Wuts, Protecting Groups in Organic Synthesis (3.sup.rd ed.),
John Wiley & Sons, NY (1999), which is incorporated herein by
reference in its entirety. Synthesis of the compounds of the
invention can be accomplished by methods analogous to those
described in the synthetic schemes described hereinabove and in
specific examples.
[0560] Starting materials, if not commercially available, can be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[0561] When an optically active form of a compound is required, it
can be obtained by carrying out one of the procedures described
herein using an optically active starting material (prepared, for
example, by asymmetric induction of a suitable reaction step), or
by resolution of a mixture of the stereoisomers of the compound or
intermediates using a standard procedure (such as chromatographic
separation, recrystallization or enzymatic resolution).
[0562] Similarly, when a pure geometric isomer of a compound is
required, it can be prepared by carrying out one of the above
procedures using a pure geometric isomer as a starting material, or
by resolution of a mixture of the geometric isomers of the compound
or intermediates using a standard procedure such as chromatographic
separation.
Pharmaceutical Compositions
[0563] This invention also provides for pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof together
with a pharmaceutically acceptable carrier, diluent, or excipient
therefor. The phrase "pharmaceutical composition" refers to a
composition suitable for administration in medical or veterinary
use.
[0564] The pharmaceutical compositions that comprise a compound of
formula (I), alone or or in combination with a second active
pharmaceutical agent, may be administered to the subjects orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops),
bucally or as an oral or nasal spray. The term "parenterally" as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[0565] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0566] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions as well as sterile
powders for reconstitution into sterile injectable solutions or
dispersions just prior to use. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water,
ethanol, polyols (such as glycerol, propylene glycol, polyethylene
glycol and the like), vegetable oils (such as olive oil),
injectable organic esters (such as ethyl oleate) and suitable
mixtures thereof. Proper fluidity can be maintained, for example,
by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants.
[0567] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms can be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the
inclusion of agents, which delay absorption such as aluminum
monostearate and gelatin.
[0568] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally-administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0569] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0570] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0571] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In certain embodiments, solid
dosage forms may contain from 1% to 95% (w/w) of a compound of
formula I. In certain embodiments, the compound of formula I may be
present in the solid dosage form in a range of from 5% to 70%
(w/w). In such solid dosage forms, the active compound may be mixed
with at least one inert, pharmaceutically acceptable excipient or
carrier, such as sodium citrate or dicalcium phosphate and/or a)
fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol and silicic acid; b) binders such as
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,
sucrose and acacia; c) humectants such as glycerol; d)
disintegrating agents such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates and sodium
carbonate; e) solution retarding agents such as paraffin; f)
absorption accelerators such as quaternary ammonium compounds; g)
wetting agents such as cetyl alcohol and glycerol monostearate; h)
absorbents such as kaolin and bentonite clay and i) lubricants such
as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may also comprise
buffering agents.
[0572] The pharmaceutical composition may be a 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 ampules. 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. The quantity
of active component in a unit dose preparation may be varied or
adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to
95% (w/w) of a unit dose, according to the particular application
and the potency of the active component. The composition can, if
desired, also contain other compatible therapeutic agents.
[0573] The dose to be administered to a subject may be determined
by the efficacy of the particular compound employed and the
condition of the subject, as well as the body weight or surface
area of the subject to be treated. The size of the dose also will
be determined by the existence, nature, and extent of any adverse
side-effects that accompany the administration of a particular
compound in a particular subject. In determining the effective
amount of the compound to be administered in the treatment or
prophylaxis of the disorder being treated, the physician can
evaluate factors such as the circulating plasma levels of the
compound, compound toxicities, and/or the progression of the
disease, etc. In general, the dose equivalent of a compound is from
about 1 .mu.g/kg to 100 mg/kg for a typical subject.
[0574] For administration, compounds of the formula I can be
administered at a rate determined by factors that can include, but
are not limited to, the LD.sub.50 of the compound, the
pharmacokinetic profile of the compound, contraindicated drugs, and
the side-effects of the compound at various concentrations, as
applied to the mass and overall health of the subject.
Administration can be accomplished via single or divided doses.
[0575] The compounds utilized in the pharmaceutical method of the
invention can be administered at the initial dosage of about 0.001
mg/kg to about 100 mg/kg daily. In certain embodiments, the daily
dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages,
however, may be varied depending upon the requirements of the
subject, the severity of the condition being treated, and the
compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the practitioner.
Treatment may be initiated with smaller dosages, which are less
than the optimum dose of the compound. Thereafter, the dosage is
increased by small increments until the optimum effect under
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day, if
desired.
[0576] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[0577] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0578] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0579] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0580] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0581] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[0582] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0583] Compounds of formula I may also be administered in the form
of liposomes. Liposomes generally may be derived from phospholipids
or other lipid substances. Liposomes are formed by mono- or
multi-lamellar hydrated liquid crystals which are dispersed in an
aqueous medium. Any non-toxic, physiologically acceptable and
metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form may contain, in addition to a
compound of formula (I), stabilizers, preservatives, excipients and
the like. Examples of lipids include, but are not limited to,
natural and synthetic phospholipids and phosphatidyl cholines
(lecithins), used separately or together.
[0584] Methods to form liposomes have been described, see example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y. (1976), p. 33 et seq.
[0585] Dosage forms for topical administration of a compound
described herein include powders, sprays, ointments and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
Methods of Use
[0586] The compounds of formula I, or pharmaceutically acceptable
salts thereof, and pharmaceutical compositions comprising a
compound of formula I, or a pharmaceutically acceptable salt
thereof, can be administered to a subject suffering from a
bromodomain-mediated disorder or condition. The term
"administering" refers to the method of contacting a compound with
a subject. Thus, the compounds of formula I can be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, parentally, or
intraperitoneally. Also, the compounds described herein can be
administered by inhalation, for example, intranasally.
Additionally, the compounds of formula I can be administered
transdermally, topically, via implantation, transdermally,
topically, and via implantation. In certain embodiments, the
compounds of the formula I may be delivered orally. The compounds
can also be delivered rectally, bucally, intravaginally, ocularly,
andially, or by insufflation. Bromodomain-mediated disorders and
conditions can be treated prophylactically, acutely, and
chronically using compounds of formula I, depending on the nature
of the disorder or condition. Typically, the host or subject in
each of these methods is human, although other mammals can also
benefit from the administration of a compound of formula I.
[0587] A "bromodomain-mediated disorder or condition" is
characterized by the participation of one or more bromodomains
(e.g., BRD4) in the inception, manifestation of one or more
symptoms or disease markers, severity, or progression of a disorder
or condition. Accordingly, compounds of formula I may be used to
treat cancer, including, but not limited to acoustic neuroma, acute
leukemia, acute lymphocytic leukemia, acute myelocytic leukemia
(monocytic, myeloblastic, adenocarcinoma, angiosarcoma,
astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal cell carcinoma, bile duct carcinoma, bladder
cancer, brain cancer, breast cancer, bronchogenic carcinoma,
cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic
leukemia, chronic lymphocytic leukemia, chronic myelocytic
(granulocytic) leukemia, chronic myelogenous leukemia, colon
cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,
diffuse large B-cell lymphoma, dysproliferative changes (dysplasias
and metaplasias), embryonal carcinoma, endometrial cancer,
endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive
breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, follicular lymphoma, germ cell testicular cancer,
glioma, glioblastoma, gliosarcoma, heavy chain disease,
hemangioblastoma, hepatoma, hepatocellular cancer, hormone
insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma,
lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma,
lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's),
malignancies and hyperproliferative disorders of the bladder,
breast, colon, lung, ovaries, pancreas, prostate, skin and uterus,
lymphoid malignancies of T-cell or B-cell origin, leukemia,
lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor.
[0588] Further, compounds of formula I may be used to treat
inflammatory diseases, inflammatory conditions, and autoimmune
diseases, including, but not limited to: Addison's disease, acute
gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's
disease, bullous skin diseases, chronic obstructive pulmonary
disease (COPD), Crohn's disease, dermatitis, eczema, giant cell
arteritis, glomerulonephritis, hepatitis, hypophysitis,
inflammatory bowel disease, Kawasaki disease, lupus nephritis,
multiple sclerosis, myocarditis, myositis, nephritis, organ
transplant rejection, osteoarthritis, pancreatitis, pericarditis,
Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis,
psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis,
sclerosing cholangitis, sepsis, systemic lupus erythematosus,
Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,
ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's
granulomatosis.
[0589] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat AIDS.
[0590] The compounds of formula I can be co-administered to a
subject. The term "co-administered" means the administration of two
or more different pharmaceutical agents or treatments (e.g.,
radiation treatment) that are administered to a subject by
combination in the same pharmaceutical composition or separate
pharmaceutical compositions. Thus co-administration involves
administration at the same time of a single pharmaceutical
composition comprising two or more pharmaceutical agents or
administration of two or more different compositions to the same
subject at the same or different times.
[0591] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to treat a
cancer, where examples of the agents include, such as radiation,
alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL,
Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway,
Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager)
antibodies, antibody drug conjugates, biologic response modifiers,
cyclin-dependent kinase inhibitors, cell cycle inhibitors,
cyclooxygenase-2 inhibitors, DVDs (dual variable domain
antibodies), leukemia viral oncogene homolog (ErbB2) receptor
inhibitors, growth factor inhibitors, heat shock protein (HSP)-90
inhibitors, histone deacetylase (HDAC) inhibitors, hormonal
therapies, immunologicals, inhibitors of inhibitors of apoptosis
proteins (IAPs), intercalating antibiotics, kinase inhibitors,
kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin
inhibitors, microRNA's, mitogen-activated extracellular
signal-regulated kinase inhibitors, multivalent binding proteins,
non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine
diphosphate)-ribose polymerase (PARP) inhibitors, platinum
chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (bromodomain) inhibitors, proteosome
inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine
kinase inhibitors, etinoids/deltoids plant alkaloids, small
inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,
ubiquitin ligase inhibitors, and the like, and in combination with
one or more of these agents.
[0592] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B. In this regard, Bcl-2 has been
shown to attenuate the induction of apoptosis by both perforin and
granzyme B. These data suggest that inhibition of Bcl-2 could
enhance the cytotoxic effects elicited by T-cells when targeted to
cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of
Immunology 1997, 158 (12), 5783).
[0593] SiRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand.
[0594] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy chain
DVD polypeptides and two light chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD
polypeptide, a light chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy chain variable domain
and a light chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site. Multispecific DVDs
include DVD binding proteins that bind DLL4 and VEGF, or C-met and
EFGR or ErbB3 and EGFR.
[0595] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE.RTM. (laromustine, VNP
40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, TREANDA.RTM.
(bendamustine), treosulfan, rofosfamide and the like.
[0596] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0597] Antimetabolites include ALIMTA.RTM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine),
carmofur, LEUSTAT.RTM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or
in combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[0598] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0599] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[0600] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263), GX-070 (obatoclax), ABT-199, and the like.
[0601] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[0602] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
[0603] COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.RTM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[0604] EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFR
immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab),
HR3, IgA antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM.
(erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM.
(lapatinib) and the like.
[0605] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB
AR-209, mAB 2B-1 and the like.
[0606] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0607] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM. (human recombinant antibody to HSP-90), NCS-683664,
PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[0608] Inhibitors of inhibitors of apoptosis proteins include
HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[0609] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75 and the like
[0610] Activators of death receptor pathway include TRAIL,
antibodies or other agents that target TRAIL or death receptors
(e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01,
GDC0145, (lexatumumab), HGS-1029, LBY-135, PRO-1762 and
trastuzumab.
[0611] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[0612] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[0613] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0614] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30, Torin 1 and the
like.
[0615] Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam), ibuprofen cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO.RTM.
(oxaprozin) and the like.
[0616] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0617] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[0618] Polo-like kinase inhibitors include BI-2536 and the
like.
[0619] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[0620] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0621] VEGFR inhibitors include AVASTIN.RTM. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits
angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron,
(Emeryville, Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632,
IM-862, MACUGEN (pegaptamib), NEXAVAR.RTM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT.RTM.
(sunitinib, SU-11248), VEGF trap, ZACTIMA.TM. (vandetanib,
ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3 specific
antibodies, BSG2 specific antibodies, DLL4 specific antibodies and
C-met specific antibodies, and the like.
[0622] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[0623] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
[0624] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD20 antibodies
types I and II and the like.
[0625] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM. (trilostane), dexamethasone, DROGENIL.RTM.
(flutamide), EVISTA.RTM. (raloxifene), AFEMA.TM. (fadrozole),
FARESTON.RTM. (toremifene), FASLODEX.RTM. (fulvestrant),
FEMARA.RTM. (letrozole), formestane, glucocorticoids, HECTOROL.RTM.
(doxercalciferol), RENAGEL.RTM. (sevelamer carbonate),
lasofoxifene, leuprolide acetate, MEGACE.RTM. (megesterol),
MIFEPREX.RTM. (mifepristone), NILANDRON.TM. (nilutamide),
NOLVADEX.RTM. (tamoxifen citrate), PLENAXIS.TM. (abarelix),
prednisone, PROPECIA.RTM. (finasteride), rilostane, SUPREFACT.RTM.
(buserelin), TRELSTAR.RTM. (luteinizing hormone releasing hormone
(LHRH)), VANTAS.RTM. (Histrelin implant), VETORYL.RTM. (trilostane
or modrastane), ZOLADEX.RTM. (fosrelin, goserelin) and the
like.
[0626] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[0627] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[0628] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0629] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0630] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, ACTIMMUNE.RTM. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM., (IFN-.alpha.), BAM-002 (oxidized
glutathione), BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab),
CAMPATH.RTM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
decarbazine, denileukin, epratuzumab, GRANOCYTE.RTM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM. (filgrastim),
OncoVAC-CL, OVAREX.RTM. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.RTM. (sipuleucel-T), sargaramostim, sizofilan, teceleukin,
THERACYS.RTM. (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN.RTM.
(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific
Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),
PROLEUKIN.RTM. (aldesleukin), ZADAXIN.RTM. (thymalfasin),
ZENAPAX.RTM. (daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan)
and the like.
[0631] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofuran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0632] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.RTM.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM.
(gemcitabine), TOMUDEX.RTM. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[0633] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[0634] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine,
ZK-EPO (synthetic epothilone) and the like.
[0635] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[0636] Compounds of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy
and the like.
[0637] Additionally, compounds having Formula (I) may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papillomavirus
vaccine), CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A4P, DAB(389)EGF (catalytic and translocation domains
of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R.TM. (diphtheria toxins),
dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), enzastaurin, EPO906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM. (AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin),
ONCONASE.RTM. (a ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma
vaccine treatment), ONCOVAX.RTM. (IL-2 Vaccine), ORATHECIN.TM.
(rubitecan), OSIDEM.RTM. (antibody-based cell drug), OVAREX.RTM.
MAb (murine monoclonal antibody), paclitaxel, PANDIMEX.TM.
(aglycone saponins from ginseng comprising 20(S)protopanaxadiol
(aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
PANVAC.RTM.-VF (investigational cancer vaccine), pegaspargase, PEG
Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB.RTM.
(catumaxomab), REVLIMID.RTM. (lenalidomide), RSR13 (efaproxiral),
SOMATULINE.RTM. LA (lanreotide), SORIATANE.RTM. (acitretin),
staurosporine (Streptomyces staurospores), talabostat (PT100),
TARGRETIN.RTM. (bexarotene), TAXOPREXIN.RTM. (DHA-paclitaxel),
TELCYTA.RTM. (canfosfamide, TLK286), temilifene, TEMODAR.RTM.
(temozolomide), tesmilifene, thalidomide, THERATOPE.RTM. (STn-KLH),
thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.RTM. (trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane),
ZOMETA.RTM. (zolendronic acid), zorubicin and the like.
[0638] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents to
treat an inflammatory disease or condition, or autoimmune disease,
where examples of the agents include, such as methotrexate,
6-mercaptopurine, azathioprine sulphasalazine, mesalazine,
olsalazine chloroquinine/hydroxychloroquine, pencillamine,
aurothiomalate (intramuscular and oral), azathioprine, cochicine,
corticosteroids (oral, inhaled and local injection), beta-2
adrenoreceptor agonists (salbutamol, terbutaline, salmeteral),
xanthines (theophylline, aminophylline), cromoglycate, nedocromil,
ketotifen, ipratropium and oxitropium, cyclosporin, FK506,
rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example,
ibuprofen, corticosteroids such as prednisolone, phosphodiesterase
inhibitors, adensosine agonists, antithrombotic agents, complement
inhibitors, adrenergic agents, agents which interfere with
signalling by proinflammatory cytokines such as TNF.alpha. or IL-1
(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta.
converting enzyme inhibitors, T-cell signalling inhibitors such as
kinase inhibitors, metalloproteinase inhibitors, sulfasalazine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors and the derivatives p75TNFRIgG
(etanercept) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII,
sIL-6R), antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13
and TGF.beta.), celecoxib, folic acid, hydroxychloroquine sulfate,
rofecoxib, etanercept, infliximab, naproxen, valdecoxib,
sulfasalazine, methylprednisolone, meloxicam, methylprednisolone
acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,
propoxyphene napsylate/apap, folate, nabumetone, diclofenac,
piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl,
hydrocodone bitartrate/apap, diclofenac sodium/misoprostol,
fentanyl, anakinra, tramadol HCl, salsalate, sulindac,
cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium,
prednisolone, morphine sulfate, lidocaine hydrochloride,
indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,
sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl
misoprostol, naproxen sodium, omeprazole, cyclophosphamide,
rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12,
Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,
Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC
family inhibitors (such as Ruboxistaurin or AEB-071) and Mesopram.
In certain embodiments, combinations include methotrexate or
leflunomide and in moderate or severe rheumatoid arthritis cases,
cyclosporine and anti-TNF antibodies as noted above.
[0639] Non-limiting examples of therapeutic agents for inflammatory
bowel disease with which a compound of Formula (I) of the invention
may be co-administered include the following: budenoside; epidermal
growth factor; corticosteroids; cyclosporin, sulfasalazine;
aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;
lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;
antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;
anti-IL-1.beta. monoclonal antibodies; anti-IL-6 monoclonal
antibodies; growth factors; elastase inhibitors;
pyridinyl-imidazole compounds; antibodies to or antagonists of
other human cytokines or growth factors, for example, TNF, LT,
IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II,
GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3,
CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their
ligands; methotrexate; cyclosporine; FK506; rapamycin;
mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen;
corticosteroids such as prednisolone; phosphodiesterase inhibitors;
adenosine agonists; antithrombotic agents; complement inhibitors;
adrenergic agents; agents which interfere with signalling by
proinflammatory cytokines such as TNF.alpha. or IL-1 (e.g. NIK,
IKK, or MAP kinase inhibitors); IL-1.beta. converting enzyme
inhibitors; TNF.alpha. converting enzyme inhibitors; T-cell
signalling inhibitors such as kinase inhibitors; metalloproteinase
inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines;
angiotensin converting enzyme inhibitors; soluble cytokine
receptors and derivatives thereof (e.g. soluble p55 or p75 TNF
receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory
cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF.beta.). Preferred
examples of therapeutic agents for Crohn's disease with which a
compound of Formula (I) can be combined include the following: TNF
antagonists, for example, anti-TNF antibodies, D2E7 (adalimumab),
CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG
(etanercept) and p55TNFRIgG (LENERCEPT.TM.) inhibitors and PDE4
inhibitors. A compound of Formula (I) can be combined with
corticosteroids, for example, budenoside and dexamethasone;
sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which
interfere with synthesis or action of proinflammatory cytokines
such as IL-1, for example, IL-1.beta. converting enzyme inhibitors
and IL-1ra; T cell signaling inhibitors, for example, tyrosine
kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone;
azathioprine; mercaptopurine; infliximab; methylprednisolone sodium
succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;
methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;
hydrocodone bitartrate/apap; tetracycline hydrochloride;
fluocinonide; metronidazole; thimerosal/boric acid;
cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine
sulfate; meperidine hydrochloride; midazolam hydrochloride;
oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium
phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil;
propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide
disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin;
folic acid; levofloxacin; methylprednisolone; natalizumab and
interferon-gamma.
[0640] Non-limiting examples of therapeutic agents for multiple
sclerosis with which a compound of Formula (I) may be
co-administered include the following: corticosteroids;
prednisolone; methylprednisolone; azathioprine; cyclophosphamide;
cyclosporine; methotrexate; 4-aminopyridine; tizanidine;
interferon-.beta.1a (AVONEX.RTM.; Biogen); interferon-.beta.1b
(BETASERON.RTM.; Chiron/Berlex); interferon .alpha.-n3) (Interferon
Sciences/Fujimoto), interferon-.alpha. (Alfa Wassermann/J&J),
interferon .beta.1A-IF (Serono/Inhale Therapeutics), Peginterferon
.alpha. 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;
COPAXONE.RTM.; Teva Pharmaceutical Industries, Inc.); hyperbaric
oxygen; intravenous immunoglobulin; cladribine; antibodies to or
antagonists of other human cytokines or growth factors and their
receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8,
IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A
compound of Formula (I) can be combined with antibodies to cell
surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25,
CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A
compound of Formula (I) may also be combined with agents such as
methotrexate, cyclosporine, FK506, rapamycin, mycophenolate
mofetil, leflunomide, an S1P1 agonist, NSAIDs, for example,
ibuprofen, corticosteroids such as prednisolone, phosphodiesterase
inhibitors, adensosine agonists, antithrombotic agents, complement
inhibitors, adrenergic agents, agents which interfere with
signalling by proinflammatory cytokines such as TNF.alpha. or IL-1
(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta.
converting enzyme inhibitors, TACE inhibitors, T-cell signaling
inhibitors such as kinase inhibitors, metalloproteinase inhibitors,
sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin
converting enzyme inhibitors, soluble cytokine receptors and
derivatives thereof (e.g. soluble p55 or p75 TNF receptors,
sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (e.g.
IL-4, IL-10, IL-13 and TGF.beta.).
[0641] A compound of Formula (I) may also be co-administered with
agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone,
xaliproden hydrochloride, fampridine, glatiramer acetate,
natalizumab, sinnabidol, .alpha.-immunokine NNSO3, ABR-215062,
AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine,
CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD
(cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor),
MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone
allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide,
TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-14035,
VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma
antagonists and IL-4 agonists.
[0642] Non-limiting examples of therapeutic agents for ankylosing
spondylitis with which a compound of Formula (I) can be
co-administered include the following: ibuprofen, diclofenac,
misoprostol, naproxen, meloxicam, indomethacin, diclofenac,
celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine,
minocyclin, prednisone, and anti-TNF antibodies, D2E7
(HUMIRA.RTM.), CA2 (infliximab), CDP 571, TNFR-Ig constructs,
(p75TNFRIgG (ENBREL.RTM.) and p55TNFRIgG (LENERCEPT.RTM.).
[0643] Non-limiting examples of therapeutic agents for asthma with
which a compound of Formula (I) may be co-administered include the
following: albuterol, salmeterol/fluticasone, montelukast sodium,
fluticasone propionate, budesonide, prednisone, salmeterol
xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium,
prednisolone sodium phosphate, triamcinolone acetonide,
beclomethasone dipropionate, ipratropium bromide, azithromycin,
pirbuterol acetate, prednisolone, theophylline anhydrous,
methylprednisolone sodium succinate, clarithromycin, zafirlukast,
formoterol fumarate, influenza virus vaccine, amoxicillin
trihydrate, flunisolide, allergy injection, cromolyn sodium,
fexofenadine hydrochloride, flunisolide/menthol,
amoxicillin/clavulanate, levofloxacin, inhaler assist device,
guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,
doxycycline hyclate, guaifenesin/d-methorphan,
p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine
hydrochloride, mometasone furoate, salmeterol xinafoate,
benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine
HCl/pseudoephed, phenylephrine/cod/promethazine,
codeine/promethazine, cefprozil, dexamethasone,
guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone,
nedocromil sodium, terbutaline sulfate, epinephrine,
methylprednisolone, anti-IL-13 antibody, and metaproterenol
sulfate.
[0644] Non-limiting examples of therapeutic agents for COPD with
which a compound of Formula (I) may be co-administered include the
following: albuterol sulfate/ipratropium, ipratropium bromide,
salmeterol/fluticasone, albuterol, salmeterol xinafoate,
fluticasone propionate, prednisone, theophylline anhydrous,
methylprednisolone sodium succinate, montelukast sodium,
budesonide, formoterol fumarate, triamcinolone acetonide,
levofloxacin, guaifenesin, azithromycin, beclomethasone
dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium,
amoxicillin trihydrate, gatifloxacin, zafirlukast,
amoxicillin/clavulanate, flunisolide/menthol,
chlorpheniramine/hydrocodone, metaproterenol sulfate,
methylprednisolone, mometasone furoate,
p-ephedrine/cod/chlorphenir, pirbuterol acetate,
p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide,
(R,R)-formoterol, TgAAT, cilomilast and roflumilast.
[0645] Non-limiting examples of therapeutic agents for psoriasis
with which a compound of Formula (I) may be co-administered include
the following: calcipotriene, clobetasol propionate, triamcinolone
acetonide, halobetasol propionate, tazarotene, methotrexate,
fluocinonide, betamethasone diprop augmented, fluocinolone
acetonide, acitretin, tar shampoo, betamethasone valerate,
mometasone furoate, ketoconazole, pramoxine/fluocinolone,
hydrocortisone valerate, flurandrenolide, urea, betamethasone,
clobetasol propionate/emoll, fluticasone propionate, azithromycin,
hydrocortisone, moisturizing formula, folic acid, desonide,
pimecrolimus, coal tar, diflorasone diacetate, etanercept folate,
lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,
methylprednisolone acetate, prednisone, sunscreen, halcinonide,
salicylic acid, anthralin, clocortolone pivalate, coal extract,
coal tar/salicylic acid, coal tar/salicylic acid/sulfur,
desoximetasone, diazepam, emollient, fluocinonide/emollient,
mineral oil/castor oil/na lact, mineral oil/peanut oil,
petroleum/isopropyl myristate, psoralen, salicylic acid,
soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab,
cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus,
PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.
[0646] Non-limiting examples of therapeutic agents for psoriatic
arthritis with which a compound of Formula (I) may be
co-administered include the following: methotrexate, etanercept,
rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen,
leflunomide, methylprednisolone acetate, indomethacin,
hydroxychloroquine sulfate, prednisone, sulindac, betamethasone
diprop augmented, infliximab, methotrexate, folate, triamcinolone
acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac
sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone,
tolmetin sodium, calcipotriene, cyclosporine, diclofenac
sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium
thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate
sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7
(adalimumab), and efalizumab.
[0647] Preferred examples of therapeutic agents for SLE (Lupus)
with which a compound of Formula (I) may be co-administered include
the following: NSAIDS, for example, diclofenac, naproxen,
ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example,
celecoxib, rofecoxib, valdecoxib; anti-malarials, for example,
hydroxychloroquine; steroids, for example, prednisone,
prednisolone, budenoside, dexamethasone; cytotoxics, for example,
azathioprine, cyclophosphamide, mycophenolate mofetil,
methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for
example Cellcept.RTM.. A compound of Formula (I) may also be
combined with agents such as sulfasalazine, 5-aminosalicylic acid,
olsalazine, Imuran.RTM. and agents which interfere with synthesis,
production or action of proinflammatory cytokines such as IL-1, for
example, caspase inhibitors like IL-1.beta. converting enzyme
inhibitors and IL-1ra. A compound of Formula (I) may also be used
with T cell signaling inhibitors, for example, tyrosine kinase
inhibitors; or molecules that target T cell activation molecules,
for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1
family antibodies. A compound of Formula (I) can be combined with
IL-11 or anti-cytokine antibodies, for example, fonotolizumab
(anti-IFNg antibody), or anti-receptor receptor antibodies, for
example, anti-IL-6 receptor antibody and antibodies to B-cell
surface molecules. A compound of Formula (I) may also be used with
LJP 394 (abetimus), agents that deplete or inactivate B-cells, for
example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS
antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7
(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs,
(p75TNFRIgG (etanercept) and p55TNFRIgG (LENERCEPT.TM.).
[0648] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents used
in the prevention or treatment of AIDS, where examples of the
agents include, HIV reverse transcriptase inhibitors, HIV protease
inhibitors, immunomodulators, and other retroviral drugs. Examples
of reverse transcriptase inhibitors include, but are not limited
to, abacavir, adefovir, didanosine, dipivoxil delavirdine,
efavirenz, lamivudine, nevirapine, stavudine zalcitabine, and
zidovudine. Examples of protease inhibitors include, but are not
limited to, amprenavir, indinavir, lopinavir, nelfinavir,
ritonavir, and saquinavir.
[0649] A compound of Formula (I) may also be co-administered with
insulin for the treatment of type I diabetes.
[0650] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents used
in the prevention or treatment of AIDS, where examples of the
agents include, HIV reverse transcriptase inhibitors, HIV protease
inhibitors, immunomodulators, and other retroviral drugs. Examples
of reverse transcriptase inhibitors include, but are not limited
to, abacavir, adefovir, didanosine, dipivoxil delavirdine,
efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine,
stavudine, tenofovir, zalcitabine, and zidovudine. Examples of
protease inhibitors include, but are not limited to, amprenavir,
atazanavir, darunavir, indinavir, fosamprenavir, lopinavir,
nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of
other retroviral drugs include, but are not limited to,
elvitegravir, enfuvirtide, maraviroc and raltegravir.
[0651] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents used
in the treatment of obesity, where examples of the agents include
orlistat.
[0652] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents used
in the treatment of type II diabetes, where examples of the agents
include, alpha glucosidase inhibitors, insulin, metformin,
sulfonylureas (e.g., carbutamide, acetohexamide, chlorpropamide,
glibenclamide, glibornuride, gliclazide, glimepiride, glipizide,
gliquidone, glisoxepide, glyclopyramide, tolbutamide, and
tolazamide), nonsulfonylureas (e.g., nateglinide, and repaglinide),
and thiazolidinediones (e.g., pioglitazone).
[0653] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to prevent
or treat type II diabetes, hepatic steatosis, insulin resistance,
metabolic syndrome and related disorders, where examples of the
agents include, but are not limited to, insulin and insulins that
have been modified to improve the duration of action in the body;
agents that stimulate insulin secretion such as acetohexamide,
chlorpropamide, glyburide, glimepiride, glipizide, glicazide,
glycopyramide, gliquidone, rapaglinide, nataglinide, tolazamide and
tolbutamide; agents that are glucagon-like peptide agonists such as
exanatide, liraglutide and taspoglutide; agents that inhibit
dipeptidyl-peptidase IV such as vildagliptin, sitagliptin,
saxagliptin, linagliptin, allogliptin and septagliptin; agents that
bind to the peroxisome proliferator-activated receptor gamma such
as rosiglitazone and pioglitazone; agents that decrease insulin
resistance such as metformin; agents that reduce glucose absorbance
in the small intestine such as acarbose, miglitol and
voglibose.
[0654] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to prevent
or treat acute kidney disorders and chronic kidney diseases, where
examples of the agents include, but are not limited to, dopamine,
diuretics such as furosemide, bumetanide, thiazide and the like,
mannitol, calcium gluconate, sodium bicarbonate, albuterol,
paricalcitol, doxercalciferol, and cinacalcet.
[0655] The following Examples may be used for illustrative purposes
and should not be deemed to narrow the scope of the invention.
EXAMPLES
Example 1
11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[c-
d,h]azulen-1-one
Example 1a
3-iodo-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine
[0656] 3-Iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.75 g, 2.74
mmol) in dimethylformamide (10 mL) was treated with 60% sodium
hydride in mineral oil (0.219 g, 5.47 mmol) at ambient temperature
for 20 minutes. To this solution was added methyl iodide (0.505 g,
3.56 mmol). The reaction mixture was stirred for 3 hours at ambient
temperature. The reaction mixture was partitioned between water and
ethyl acetate. The aqueous layer was extracted three times with
ethyl acetate. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 10% ethyl acetate in hexanes) to
afford the title compound (0.75 g, 95%).
Example 1b
7-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrr-
olo[2,3-c]pyridine
[0657] Example 1a (3.89 g, 13.5 mmol) was flow purged with nitrogen
for 30 minutes, then treated with tetrahydrofuran (135 mL). The
reaction mixture was cooled to -78.degree. C. Butyllithium (5.40
mL, 13.5 mmol, 2.5 M butyllithium in hexanes) was added dropwise.
The reaction mixture was stirred at -78.degree. C. for 30 minutes.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.75 mL,
13.50 mmol) was added dropwise. The reaction mixture was stirred at
-78.degree. C. for 2.5 hours. The reaction mixture was poured onto
water and extracted twice with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 0-30% ethyl acetate
in heptanes) to afford the title compound (2.75 g, 70%).
Example 1c
2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(methylsulfonyl)ani-
line
[0658] Example 1b (1.00 g, 3.47 mmol),
2-bromo-4-methanesulfonylaniline (0.868 g, 3.47 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.0950 g, 0.104 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.101
g, 0.347 mmol) and sodium carbonate (1.287 g, 12.15 mmol) were
combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (35 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred at 60.degree. C. for 4 hours,
diluted with water and filtered to collect a solid. The solid was
dissolved in 100 mL of hot 1:1 ethyl acetate/methanol, filtered to
remove the solid palladium, and the filtrate was concentrated to
afford the title compound (0.98 g, 85%).
Example 1d
11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[c-
d,h]azulen-1-one
[0659] A 5 mL vial was charged with Example 1c (40 mg, 0.12 mmol),
paraformaldehyde (18 mg, 0.60 mmol) and methanol (1 mL). To this
suspension was added 4M HCl in dioxane (0.60 mL, 2.4 mmol). The
vial was closed and stirred at 90.degree. C. for 1 hour. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was purified by flash chromatography
(silica gel, 2-8% methanol in dichloromethane) to afford the title
compound (12 mg, 30%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.74 (d, J=5.09 Hz, 1H) 8.10 (d, J=2.37 Hz, 1H) 7.93 (s, 1H) 7.46
(dd, J=8.48, 2.03 Hz, 1H) 7.07 (d, J=8.48 Hz, 1H) 6.78 (d, J=5.43
Hz, 1H) 6.66 (s, 1H) 4.12 (s, 3H) 4.03 (s, 2H) 3.17 (s, 3H). MS
(ESI+) m/z 330 (M+H).sup.+.
Example 2
5-(cyclopropylmethyl)-11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H--
2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 2a
N-(cyclopropylmethyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-
-4-(methylsulfonyl)aniline
[0660] Example 1c (0.100 g, 0.302 mmol), cyclopropanecarboxaldehyde
(0.063 g, 0.91 mmol) and sodium triacetoxyhydroborate (0.192 g,
0.905 mmol) were combined in dichloromethane (1.0 mL) and acetic
acid (1.0 mL) under nitrogen, stirred for 6 hours and partitioned
in water/ethyl acetate. The organic layer was washed with 5%
aqueous sodium bicarbonate, saturated aqueous sodium chloride,
dried with anhydrous sodium sulfate, filtered, and concentrated to
afford the title compound (0.116 g, 100%).
Example 2b
3-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-1-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0661] Example 2a (0.035 g, 0.091 mmol) and 4M HCl in dioxane (5
mL, 20 mmol) were combined and heated at 70.degree. C. for 24
hours, cooled and concentrated. Purification by reverse phase
chromatography (C18, CH.sub.3CN/water (0.1% TFA), 10-100%) afforded
the title compound (0.024 g, 53%) as the TFA salt.
Example 2c
5-(cyclopropylmethyl)-11-methyl-8-(methylsulfonyl)-2,4,5,11-tetrahydro-1H--
2,5,11-triazadibenzo[cd,h]azulen-1-one
[0662] A 5 mL vial was charged with Example 2b (17 mg, 0.035 mmol),
paraformaldehyde (5.3 mg, 0.18 mmol) and methanol (1 mL). To this
suspension was added 4M HCl in dioxane (0.175 mL, 0.700 mmol). The
vial was closed and stirred at 90.degree. C. for 2 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was purified by flash chromatography
(silica gel, 2-8% methanol in dichloromethane) to afford the title
compound (9.0 mg, 67%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.74 (d, J=4.7 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.59
(dd, J=8.6, 2.2 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.79 (d, J=5.4 Hz,
1H), 4.06-4.15 (m, 5H), 3.09-3.27 (m, 5H), 0.90-1.06 (m, 1H),
0.39-0.48 (m, 2H), 0.14-0.23 (m, 2H). MS (ESI+) m/z 384
(M+H).sup.+.
Example 3
5-(cyclopropylmethyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrah-
ydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 3a
1-((methylsulfonyl)methyl)-4-nitrobenzene
[0663] To a solution of 4-nitrobenzyl bromide (10.0 g, 46.4 mmol)
in dimethylformamide (25 mL) was added sodium methanesulfinate
(7.10 g, 69.6 mmol). The reaction mixture was stirred at 65.degree.
C. for 1 hour. The reaction mixture was cooled to ambient
temperature, diluted with water, stirred for 10 minutes and
filtered to give the title compound (9.27 g, 93%).
Example 3b
4-((methylsulfonyl)methyl)aniline
[0664] Example 3a (8.2 g, 38 mmol) and tetrahydrofuran (200 mL)
were added to wet 5% Pd/C (1.6 g, 0.376 mmol) in a pressure bottle.
The reaction mixture was stirred at 50.degree. C. for 2 hours under
30 psi of hydrogen. The reaction mixture was filtered through a
nylon membrane, washed with a mixture of tetrahydrofuran and
methanol, and concentrated to give the title compound (6.21 g,
88%).
Example 3C
2-iodo-4-((methylsulfonyl)methyl)aniline
[0665] To a solution of Example 3b (1.12 g, 6.03 mmol) in
dimethylformamide (60.3 mL) was added N-iodosuccinimide (1.49 g,
6.63 mmol). The reaction mixture was stirred at ambient temperature
for 90 minutes. The reaction mixture was quenched with 10% sodium
thiosulfate and saturated aqueous sodium bicarbonate, and extracted
with ethyl acetate three times. The combined organic layers were
washed with saturated aqueous sodium chloride, dried with anhydrous
magnesium sulfate, filtered, and concentrated. Water was added to
the residue, and the mixture was stirred at ambient temperature for
10 minutes and filtered to give the title compound (1.55 g,
83%).
Example 3d
N-(cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline
[0666] Example 3c (311 mg, 1.00 mmol), cyclopropanecarbaldehyde
(0.187 mL, 2.50 mmol) and acetic acid (0.572 mL, 10.0 mmol) were
combined in a mixture of dichloromethane (5 mL) and methanol (5
mL). The reaction mixture was heated at 50.degree. C. for 30
minutes, and then cooled to ambient temperature.
MP-cyanoborohydride (1.27 g, 2.36 mmol/g, 3.00 mmol) was added and
the reaction mixture was stirred at ambient temperature for 3
hours. The reaction mixture was filtered, washed with
dichloromethane and concentrated. The residue was purified by flash
chromatography (silica gel, 20-60% ethyl acetate in heptanes) to
afford the title compound (296 mg, 81%).
Example 3e
N-(cyclopropylmethyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-
-4-((methylsulfonyl)methyl)aniline
[0667] Example 3d (183 mg, 0.500 mmol), Example 1b (173 mg, 0.600
mmol), sodium carbonate (185 mg, 1.75 mmol),
tris(dibenzylideneacetone)dipalladium (13.7 mg, 0.0150 mmol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (13.1
mg, 0.0450 mmol) were combined in a microwave tube and purged with
nitrogen for 15 minutes. A mixture of dioxane (2 mL) and water (0.5
mL) was purged with nitrogen for 15 minutes and transferred to the
microwave tube. The reaction mixture was heated at 60.degree. C.
for 4 hours. The reaction mixture was partitioned in ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride, dried with anhydrous sodium sulfate, treated with
3-mercaptopropyl functionalized silica gel, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 20-50% ethyl acetate in heptanes) to afford the title
compound (140 mg, 70%).
Example 3f
3-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-1-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0668] Example 3e (136 mg, 0.340 mmol) in a solution of 4M HCl in
dioxane (5 mL, 20.0 mmol) was heated at 70.degree. C. for 2 hours.
The reaction mixture was cooled and concentrated. The residue was
purified by flash chromatography (silica gel, 2-6% methanol in
dichloromethane) to afford the title compound (130 mg, 91%) as the
HCl salt.
Example 3g
5-(cyclopropylmethyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrah-
ydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0669] A 5 mL vial was charged with Example 3f (104 mg, 0.246
mmol), paraformaldehyde (37.0 mg, 1.23 mmol) and methanol (1 mL).
To this suspension was added 4M HCl in dioxane (1.23 mL, 4.92
mmol). The vial was closed and stirred at 90.degree. C. for 2
hours. The reaction mixture was cooled to ambient temperature and
concentrated. The residue was purified by flash chromatography
(silica gel, 2-8% methanol in dichloromethane) to give a solid. The
solid was partitioned in saturated sodium bicarbonate and ethyl
acetate. The organic layer was dried with anhydrous sodium sulfate,
filtered, and concentrated to afford the title compound (41 mg,
42%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.68 (d, J=5.43
Hz, 1H) 7.68 (s, 1H) 7.63 (s, 1H) 7.09-7.17 (m, 2H) 6.72 (d, J=5.43
Hz, 1H) 4.39 (s, 2H) 4.11 (s, 3H) 4.03 (s, 2H) 2.96 (d, J=6.44 Hz,
2H) 2.91 (s, 3H) 0.82-0.99 (m, 1H) 0.35-0.46 (m, 2H) 0.05-0.12 (m,
2H). MS (ESI+) m/z 398 (M+H).sup.+.
Example 4
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahydr-
o-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 4a
2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-((methylsulfonyl)me-
thyl)aniline
[0670] Example 3c (1.25 g, 4.00 mmol), Example 1b (1.15 g, 4.00
mmol), potassium phosphate (2.97 g, 14.0 mmol),
tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120 mmol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.105 g, 0.360 mmol) were combined in a microwave tube and purged
with nitrogen for 15 minutes. A mixture of dioxane (12 mL) and
water (3 mL) was purged with nitrogen for 15 minutes and
transferred via cannula to the microwave tube. The reaction mixture
was heated at 60.degree. C. for 4 hours. The reaction mixture was
partitioned in ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride, dried with anhydrous
sodium sulfate, treated with 3-mercaptopropyl functionalized silica
gel, filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 20-80% ethyl acetate in heptanes) to
afford the title compound (0.985 g, 71%).
Example 4b
N-(4-fluorophenyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4--
((methylsulfonyl)methyl)aniline
[0671] Example 4a (104 mg, 0.300 mmol), 1-bromo-4-fluorobenzene
(105 mg, 0.600 mmol), diacetoxypalladium (2.7 mg, 0.012 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(11.4 mg, 0.0239 mmol) and cesium carbonate (195 mg, 0.600 mmol)
were combined in a mixture of toluene (2.4 mL) and tert-butanol
(0.6 mL). The reaction mixture was heated in a microwave reactor at
150.degree. C. for 30 minutes. The reaction mixture was partitioned
in ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, treated with 3-mercaptopropyl functionalized silica gel,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 2-4% methanol in dichloromethane) to
afford the title compound (112 mg, 85%).
Example 4c
3-{2-[4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-1-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0672] Example 4b (110 mg, 0.250 mmol) in a solution of 4M HCl in
dioxane (5.0 mL, 20 mmol) was heated at 70.degree. C. for 2 hours.
The reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2-4% methanol in dichloromethane)
to afford the title compound (86 mg, 81%).
Example 4d
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahydr-
o-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0673] A 5 mL vial was charged with Example 4c (73 mg, 0.17 mmol),
paraformaldehyde (52 mg, 1.7 mmol) and methanol (1 mL). To this
suspension was added 4M HCl in dioxane (0.858 mL, 3.43 mmol). The
vial was closed and stirred at 90.degree. C. for 4 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. To the residue was added water, and the pH was
adjusted to about 7 by the addition of saturated aqueous sodium
bicarbonate. The mixture was sonicated for 5 minutes and filtered
to give a solid. The solid was purified by flash chromatography
(silica gel, 2-4% methanol in dichloromethane) to afford the title
compound (44 mg, 59%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.84 (d, J=5.43 Hz, 1H) 7.88 (s, 1H) 7.73 (s, 1H) 7.25-7.33 (m,
2H) 7.05 (d, J=5.76 Hz, 1H) 6.77-6.90 (m, 2H) 6.40-6.59 (m, 2H)
5.04 (s, 1H) 4.54 (s, 2H) 4.18 (s, 1H) 4.05 (s, 3H) 2.99 (s, 3H).
MS (ESI+) m/z 438 (M+H).sup.+.
Example 5
5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetra-
hydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 5a
N-(2,4-difluorophenyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl-
)-4-((methylsulfonyl)methyl)aniline
[0674] Example 4a (104 mg, 0.300 mmol), 1-bromo-2,4-difluorobenzene
(116 mg, 0.600 mmol), diacetoxypalladium (2.7 mg, 0.012 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(11.4 mg, 0.0239 mmol) and cesium carbonate (195 mg, 0.600 mmol)
were combined in a mixture of toluene (2.4 mL) and tert-butanol
(0.6 mL). The reaction mixture was heated in a microwave reactor at
150.degree. C. for 1 hour. The reaction mixture was partitioned in
ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, treated with 3-mercaptopropyl functionalized silica gel,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 1-2% methanol in dichloromethane) to
afford the title compound (62 mg, 45%).
Example 5b
3-{2-[(2,4-difluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-1-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0675] Example 5a (60.0 mg, 0.131 mmol) in a solution of 4M HCl in
dioxane (5.0 mL, 20 mmol) was heated at 70.degree. C. for 2 hours.
The reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2-4% methanol in dichloromethane)
to afford the title compound (46 mg, 79%).
Example 5c
5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetra-
hydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0676] A 5 mL vial was charged with Example 5b (37 mg, 0.083 mmol),
paraformaldehyde (25 mg, 0.83 mmol) and methanol (1 mL). To this
suspension was added 4M HCl in dioxane (0.417 mL, 1.67 mmol). The
vial was closed and stirred at 90.degree. C. for 4 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. To the residue was added water, and the pH was
adjusted to about 7 by the addition of saturated aqueous sodium
bicarbonate. The mixture was sonicated for 5 minutes and filtered
to give a solid. The solid was purified by flash chromatography
(silica gel, 2-4% methanol in dichloromethane) to afford the title
compound (16 mg, 42%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.75 (d, J=5.43 Hz, 1H) 7.69-7.93 (m, 2H) 7.05-7.22 (m, 2H)
6.80-6.98 (m, 2H) 6.66-6.76 (m, 2H) 4.57 (s, 2H) 4.46 (s, 2H) 4.11
(s, 3H) 2.95 (s, 3H). MS (ESI+) m/z 456 (M+H).sup.+.
Example 6
5-(cyclopropanecarbonyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tet-
rahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 6a
11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-1-one
[0677] A 20 mL vial was charged with Example 4a (380 mg, 1.10
mmol), paraformaldehyde (330 mg, 11.0 mmol) and methanol (5 mL). To
this suspension was added 4M HCl in dioxane (5.5 mL, 22 mmol). The
vial was closed and stirred at 90.degree. C. for 6 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. Water was added to the residue, and the pH was
adjusted to about 7 by the addition of saturated aqueous sodium
bicarbonate. The mixture was sonicated for 5 minutes and filtered
to give a solid. The solid was triturated with
methanol/dichloromethane (1%) to afford the title compound (295 mg,
78%).
Example 6b
5-(cyclopropanecarbonyl)-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tet-
rahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0678] Example 6a (24 mg, 0.070 mmol), cyclopropanecarbonyl
chloride (7.0 .mu.L, 0.077 mmol) and triethylamine (0.029 mL, 0.210
mmol) were combined in dimethylformamide (2 mL). The reaction
mixture was stirred at ambient temperature for 3 hours. Then
another batch of cyclopropanecarbonyl chloride (3.2 .mu.L, 0.035
mmol) was added. The reaction mixture was stirred at ambient
temperature for another 3 hours. The reaction mixture was
partitioned in ethyl acetate and 1M HCl. The organic layer was
washed twice with saturated aqueous sodium chloride, dried with
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by reverse phase HPLC (C8, CH.sub.3CN/water (0.1%
TFA), 20-55%) to afford the title compound (12 mg, 42%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 10.83 (d, J=5.76 Hz, 1H) 7.86
(d, J=2.03 Hz, 1H) 7.83 (s, 1H) 7.44 (d, J=8.16, 1H) 7.31 (dd,
J=8.14, 1.70 Hz, 1H) 6.82 (d, J=5.09 Hz, 1H) 5.34 (d, J=14.92 Hz,
1H) 4.42-4.63 (m, 2H) 4.13 (s, 3H) 3.81 (dd, J=14.92, 1.36 Hz, 1H)
2.98 (s, 3H) 1.13-1.34 (m, 1H) 0.55-0.85 (m, 3H) 0.37-0.49 (m, 1H).
MS (ESI+) m/z 412 (M+H).sup.+.
Example 7
5-benzoyl-11-methyl-8-((methylsulfonyl)methyl)-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-1-one
[0679] Example 7 was prepared according to the procedure used for
the preparation of Example 6b, substituting benzoyl chloride for
cyclopropanecarbonyl chloride, to provide the title compound (10
mg, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.91 (d,
J=5.49 Hz, 1H) 7.94 (s, 1H) 7.83 (d, J=1.83 Hz, 1H) 7.18-7.26 (m,
1H) 7.08-7.15 (m, 2H) 6.79-7.00 (m, 5H) 5.65 (d, J=14.65 Hz, 1H)
4.30-4.53 (m, 2H) 4.18 (s, 3H) 3.96 (d, J=14.65 Hz, 1H) 2.82 (s,
3H). MS (ESI+) m/z 448 (M+H).sup.+.
Example 8
5-(4-fluorophenyl)-4-(2-methoxyethyl)-11-methyl-8-((methylsulfonyl)methyl)-
-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0680] A 5 mL vial was charged with Example 4b (22 mg, 0.050 mmol),
3-methoxypropanal (44 mg, 0.50 mmol) and methanol (1 mL). To this
suspension was added 4M HCl in dioxane (0.25 mL, 1.0 mmol). The
vial was closed and stirred at 90.degree. C. for 2 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2-4% methanol in dichloromethane)
to afford the title compound (3 mg, 12%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.84 (d, J=5.49 Hz, 1H) 7.88 (d, J=1.83 Hz,
1H) 7.76 (s, 1H) 7.23-7.38 (m, 2H) 6.97 (d, J=5.80 Hz, 1H)
6.79-6.88 (m, 2H) 6.40-6.56 (m, 2H) 5.18 (t, J=7.48 Hz, 1H)
4.46-4.61 (m, 2H) 4.06 (s, 3H) 3.20-3.30 (m, 2H) 3.18 (s, 3H) 2.98
(s, 3H) 1.57-1.74 (m, 1H) 1.31-1.45 (m, 1H). MS (ESI+) m/z 496
(M+H).sup.+.
Example 9
methyl
3-(5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-1-oxo-2,-
4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-4-yl)propanoate
[0681] A 5 mL vial was charged with Example 4b (22 mg, 0.050 mmol),
methyl 4-oxobutanoate (58 mg, 0.50 mmol) and methanol (1 mL). To
this suspension was added 4M HCl in dioxane (0.25 mL, 1.0 mmol).
The vial was closed and stirred at 90.degree. C. for 2 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2-4% methanol in dichloromethane)
to afford the title compound (7 mg, 27%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.86 (d, J=5.49 Hz, 1H) 7.89 (d, J=1.83 Hz,
1H) 7.76 (s, 1H) 7.26-7.36 (m, 2H) 7.00 (d, J=5.80 Hz, 1H)
6.79-6.91 (m, 2H) 6.43-6.54 (m, 2H) 5.09 (t, J=7.48 Hz, 1H)
4.46-4.61 (m, 2H) 4.06 (s, 3H) 3.49 (s, 3H) 2.97 (s, 3H) 2.24-2.45
(m, 2H) 1.61-1.74 (m, 1H) 1.36-1.54 (m, 1H). MS (ESI+) m/z 524
(M+H).sup.+.
Example 10
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-4-((tetrahydro-2H--
pyran-4-yl)methyl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-
-1-one
[0682] A 5 mL vial was charged with Example 4b (22 mg, 0.050 mmol),
2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (64 mg, 0.50 mmol) and
methanol (1 mL). To this suspension was added 4M HCl in dioxane
(0.25 mL, 1.0 mmol). The vial was closed and was heated in a
microwave reactor at 120.degree. C. for 4 hours. The reaction
mixture was cooled to ambient temperature and concentrated. The
residue was partitioned in ethyl acetate and saturated aqueous
sodium bicarbonate. The organic layer was washed with saturated
aqueous sodium chloride, dried with anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 2-4% methanol in dichloromethane) to
afford the title compound (9 mg, 34%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.84 (d, J=5.43 Hz, 1H) 7.87 (d, J=1.70 Hz,
1H) 7.74 (s, 1H) 7.25-7.37 (m, 2H) 7.08 (d, J=5.76 Hz, 1H)
6.74-6.89 (m, 2H) 6.47-6.59 (m, 2H) 5.18 (t, J=7.46 Hz, 1H)
4.45-4.65 (m, 2H) 4.06 (s, 3H) 3.69-3.81 (m, 2H) 3.14-3.27 (m, 2H)
2.96 (s, 3H) 0.95-1.61 (m, 7H). MS (ESI+) m/z 536 (M+H).sup.+.
Example 11
5-(cyclopropylmethyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenz-
o[cd,h]azulen-1-one
Example 11a
2-bromo-N-(cyclopropylmethyl)aniline
[0683] A 100 mL flask was charged with 2-bromoaniline (1.720 g,
10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), acetic
acid (2.86 mL, 50.0 mmol) and dichloromethane (50 mL). The mixture
was heated at 50.degree. C. for 1 hour. The mixture was then cooled
in an ice bath and the sodium triacetoxyborohydride (2.119 g, 10.00
mmol) was added in portionwise over a few minutes. After 15
minutes, the ice bath was removed and the mixture was stirred for 2
hours at ambient temperature. The reaction mixture was quenched
with 2.5 M sodium hydroxide (16 mL) and then partitioned between
saturated sodium bicarbonate solution (100 mL) and ethyl acetate
(100 mL). The layers were separated and the organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 0-10%
ethyl acetate in heptanes) to provide the title compound (1.05 g,
93%).
Example 11b
N-(cyclopropylmethyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-
aniline
[0684] A 25 mL vial was charged with Example 1b (160 mg, 0.556
mmol), Example 11a (128.8 mg, 0.570 mmol),
tris(dibenzylideneacetone)dipalladium (0) (15.27 mg, 0.017 mmol),
(1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamanta-
ne (17.87 mg, 0.061 mmol) and potassium phosphate (354 mg, 1.667
mmol). This mixture was stirred under a stream of argon for 30
minutes. To this mixture was added a mixture of dioxane (4 mL) and
water (1 mL) which had been degassed with argon for 30 minutes. The
mixture was heated at 75.degree. C. for 18 hours. Upon cooling to
ambient temperature, the reaction mixture was partitioned between
ethyl acetate (75 mL) and 50% saturated aqueous sodium chloride
(100 mL). The organic layer was treated with 3-mercaptopropyl
functionalized silica gel, dried over anhydrous sodium sulfate,
filtered, and concentrated. This residue was purified by flash
chromatography (silica gel, 0-5% methanol in dichloromethane) to
provide the title compound (154 mg, 90%).
Example 11c
3-(2-((cyclopropylmethyl)amino)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-
(6H)-one
[0685] A 25 mL flask was charged with Example 11b (150 mg, 0.488
mmol), dioxane (4 mL) and hydrogen chloride (4M in dioxane, 4.88
mL, 19.52 mmol). The reaction mixture was heated at 70.degree. C.
overnight. Upon cooling, the reaction mixture was concentrated. The
residue was purified by flash chromatography (silica gel, 0-7.5%
methanol in dichloromethane) to provide the title compound (141 mg,
98%).
Example 11d
5-(cyclopropylmethyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenz-
o[cd,h]azulen-1-one
[0686] A 5 mL vial was charged Example 11c (60 mg, 0.205 mmol),
paraformaldehyde (92 mg, 1.023 mmol), methanol (2 mL) and hydrogen
chloride, 4M in dioxane (1.023 mL, 4.09 mmol). The reaction mixture
was heated at 90.degree. C. for 2 hours. Upon cooling, the reaction
mixture was partitioned between 50% saturated sodium bicarbonate
solution (100 mL) and ethyl acetate (75 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2.times.50 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by flash chromatography (silica gel, Gold Rf cartridge
(12 g) eluting with a 0-5% methanol in dichloromethane) to provide
the title compound (20.3 mg, 32%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.67 (d, J=4.88 Hz, 1H) 7.71 (s, 1H) 7.64
(dd, J=7.78, 1.37 Hz, 1H) 7.06-7.15 (m, 2H) 7.00-7.06 (m, 1H) 6.70
(d, J=5.19 Hz, 1H) 4.10 (s, 3H) 4.02 (s, 2H) 2.88 (d, J=6.41 Hz,
2H) 0.84-0.97 (m, 1H) 0.35-0.42 (m, 2H) 0.02-0.08 (m, 2H). MS
(ESI+) m/z 306.1 (M+H).sup.+.
Example 12
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)ethanesulfonamide
[0687] Example 23e (0.0395 g, 0.11 mmol) in 1,2-dichloroethane (3
mL) was treated with ethanesulfonyl chloride (0.03 mL, 0.33 mmol)
and triethylamine (0.06 mL, 0.44 mmol) and stirred at ambient
temperature for 1 hour. Additional ethanesulfonyl chloride (0.03
mL, 0.33 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added
and stirring was continued overnight. The reaction mixture was
concentrated. The residue was then treated with ethanesulfonyl
chloride (0.3 mL, 3.3 mmol) and triethylamine (0.6 mL, 4.4 mmol),
stirred for 7 hours and concentrated to dryness. The residue was
taken up in tetrahydrofuran (3 mL), treated with sodium hydroxide
(4 M aqueous solution, 0.14 mL, 0.55 mmol) and heated at 50.degree.
C. for 1.5 hours. The reaction mixture was then cooled to ambient
temperature and neutralized with 2 N hydrochloric acid (aqueous).
The reaction mixture was partitioned between ethyl acetate and
water, washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 0-17%
methanol in dichloromethane) to provide 0.0069 g (14%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.80 (d,
J=5.49 Hz, 1H), 9.87 (m, 1H), 7.63 (s, 1H), 7.60 (d, J=2.44 Hz,
1H), 7.21 (d, J=8.24 Hz, 1H), 7.09 (dd, J=8.54, 2.44 Hz, 1H), 7.03
(d, J=5.80 Hz, 1H), 6.82 (m, 2H), 6.49 (m, 2H), 5.01 (d, J=15.56
Hz, 1H), 4.16 (d, J=13.12 Hz, 1H), 4.05 (s, 3H), 3.18 (q, J=7.32
Hz, 2H), 1.27 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 453.1
(M+H).sup.+.
Example 13
8-chloro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-1-one
Example 13a
4-chloro-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)aniline
[0688] 2-Amino-5-chlorophenylboronic acid, pinacol ester (1.0 g,
3.94 mmol), Example 1a (1.136 g, 3.94 mmol),
tris(dibenzylideneacetone)dipalladium (0) (0.108 g, 0.118 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.115 g, 0.394 mmol) and sodium carbonate (1.463 g, 13.80 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (12 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 18 hours at 25.degree. C.,
cooled to ambient temperature, and partitioned in 100 mL of water
and 120 mL of ethyl acetate. The organic layer was washed with
water, saturated aqueous sodium chloride, dried (Na.sub.2SO.sub.4),
treated with 3-mercaptopropyl functionalized silica, filtered, and
concentrated. Purification by chromatography (silica gel, 0-50%
ethyl acetate in heptanes) afforded the title compound (0.8 g,
70%).
Example 13b
4-chloro-N-(4-fluorophenyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-
-3-yl)aniline
[0689] Example 13b was prepared according to the procedure used for
the preparation of Example 4b, substituting Example 13a for Example
4a. Purification by chromatography (silica gel, 0-40% ethyl acetate
in heptanes) afforded the title compound (0.153 g, 77%).
Example 13c
8-chloro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-1-one
[0690] A mixture of Example 13b (0.075 g, 0.196 mmol) and
paraformaldehyde (0.059 g, 1.964 mmol) in methanol (1.964 mL) was
treated with 4M hydrogen chloride in dioxane (1.47 mL, 5.89 mmol),
heated to 95.degree. C. for 3 hours in a sealed tube, cooled and
concentrated. The residue was diluted with methanol (2 mL) and 5%
aqueous sodium bicarbonate (10 mL), sonicated and the solid was
collected by filtration to afford the title compound (0.072 g,
97%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.82 (d, J=5.43
Hz, 1H), 7.75-8.06 (m, 2H), 7.19-7.37 (m, 2H), 7.04 (d, J=5.76 Hz,
1H), 6.77-6.94 (m, 2H), 6.36-6.58 (m, 2H), 5.02 (s, 1H), 4.19-4.32
(m, 1H), 4.03 (s, 3H). MS (ESI+) m/z 379 (M+H).sup.+.
Example 14
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetra-
azadibenzo[cd,h]azulen-1-one
Example 14a
3-bromo-N-(4-fluorophenyl)-5-nitropyridin-2-amine
[0691] 3-Bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol),
4-fluoroaniline (5.53 g, 49.7 mmol) and dimethylsulfoxide (33.2 mL)
were combined and stirred at 120.degree. C. for 1 hour. The
reaction mixture was cooled to ambient temperature producing a
solid. Precipitation was induced further by the addition of 150 mL
of water. The solid was collected by filtration and rinsed with 600
mL of water. The solid was purified by flash chromatography (silica
gel, 0 to 20% ethyl acetate in heptanes) and then triturated in 15%
ethyl acetate in heptanes to give 4.2 g (81%) of the title
compound.
Example 14b
N-(4-fluorophenyl)-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-5--
nitropyridin-2-amine
[0692] Example 14b was prepared according to the procedure used for
the preparation of Example 23a, substituting Example 1b for Example
1a and Example 14a for (2-fluoro-5-nitrophenyl)boronic acid.
Purification by flash chromatography (silica gel, 0 to 15% ethyl
acetate in dichloromethane) gave 0.5 g (38%) of the title
compound.
Example 14c
3-(2-((4-fluorophenyl)amino)-5-nitropyridin-3-yl)-1-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0693] A solution of Example 14b (0.5 g, 1.27 mmol) in 1,4-dioxane
(7 mL) was treated with hydrogen chloride solution (4 M in
1,4-dioxane, 3.2 mL, 12.7 mmol) and stirred at 90.degree. C. for 2
hours. The reaction mixture was concentrated and then treated again
with hydrogen chloride solution (4 M in 1,4-dioxane, 3.2 mL, 12.7
mmol). The mixture was heated for 2 hours at 90.degree. C. and then
concentrated to dryness to give 0.482 g (100%) of the title
compound.
Example 14d
5-(4-fluorophenyl)-11-methyl-8-nitro-2,4,5,11-tetrahydro-1H-2,5,6,11-tetra-
azadibenzo[cd,h]azulen-1-one
[0694] To Example 14c (0.48 g, 1.27 mmol) in acetic acid (12.7 mL)
was added paraformaldehyde (0.191 g, 6.36 mmol). The reaction
mixture was heated at 90.degree. C. for 15 minutes, partially
concentrated and then slowly neutralized with saturated sodium
carbonate solution. The resulting mixture was partitioned between
ethyl acetate and water and washed with saturated aqueous sodium
chloride. The combined aqueous layers were exhaustively extracted
with ethyl acetate. The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 0 to 60%
ethyl acetate in dichloromethane, then 10% ethyl acetate in
dichloromethane with 3-15% methanol) to give the title compound as
an impure mixture. The impure mixture was slurried in methanol (5
mL), treated with excess sodium hydroxide solution (4 M, aqueous)
and heated at 70.degree. C. for 1 hour. The reaction mixture was
then cooled to ambient temperature, neutralized with hydrochloric
acid solution (2 M, aqueous), and concentrated. The resulting solid
was slurried in water, collected by filtration and dried under
vacuum to give 0.187 g (38%) of the title compound.
Example 14e
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetra-
azadibenzo[cd,h]azulen-1-one
[0695] Example 14d (0.17 g, 0.43 mmol) in a mixture of ethanol (4
mL), tetrahydrofuran (4 mL) and water (1 mL) was treated with
ammonium chloride (0.23 g, 4.3 mmol) and zinc dust (0.43 g, 6.5
mmol) and stirred at ambient temperature for 23 minutes and then
filtered. The filtrate was evaporated and then slurried in ethyl
acetate and water. The solid was collected by filtration. The
filtrate was poured into a separatory funnel and the layers were
separated. The organic layer was washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The two solids were combined and dried under
vacuum to give 0.126 g (80%) of the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 10.78 (d, J=5.43 Hz, 1H), 7.73 (d,
J=2.71 Hz, 1H), 7.65 (s, 1H), 7.32 (d, J=3.05 Hz, 1H), 7.03 (d,
J=5.76 Hz, 1H), 6.80 (m, 2H), 6.45 (m, 2H), 5.36 (s, 2H), 4.91 (m,
1H), 4.28 (m, 1H), 4.04 (s, 3H). MS (ESI+) m/z 362.2
(M+H).sup.+.
Example 15
ethyl
5-(4-fluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)-1-oxo-2,4,5,-
11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-4-carboxylate
[0696] A 5 mL vial was charged with Example 4c (85 mg, 0.20 mmol),
50% ethyl 2-oxoacetate in toluene (0.396 mL, 2.00 mmol) and ethanol
(2 mL). To this suspension was added 4M HCl in dioxane (1.0 mL, 4.0
mmol). The vial was closed and stirred at 90.degree. C. for 4
hours. The reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2-4% methanol in dichloromethane)
to afford the title compound (21 mg, 21%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.90 (d, J=5.76 Hz, 1H) 7.79 (d, J=2.03 Hz,
1H) 7.71 (s, 1H) 7.16-7.30 (m, 2H) 7.10 (d, J=5.76 Hz, 1H)
6.85-6.96 (m, 2H) 6.59-6.68 (m, 2H) 6.18 (s, 1H) 4.39-4.58 (m, 2H)
4.07 (s, 3H) 3.72-3.90 (m, 2H) 2.91 (s, 3H) 0.86 (t, J=7.12 Hz,
3H). MS (ESI+) m/z 510 (M+H).sup.+.
Example 16
8-fluoro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-1-one
Example 16a
5-fluoro-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridin-2-ami-
ne
[0697] 3-Bromo-5-fluoropyridin-2-amine (0.25 g, 1.309 mmol),
Example 1b (0.377 g, 1.309 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.039 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.038 g, 0.131 mmol) and sodium carbonate (0.486 g, 4.58 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (9 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 4 hours at 60.degree. C.,
cooled to ambient temperature, and partitioned in water and ethyl
acetate. The organic layer was washed with water, saturated aqueous
sodium chloride, dried (anhydrous Na.sub.2SO.sub.4), treated with
3-mercaptopropyl functionalized silica gel, filtered, and
concentrated. Purification by chromatography (silica gel, 0-3%
methanol in dichloromethane) afforded the title compound (0.23 g,
64%).
Example 16b
5-fluoro-N-(4-fluorophenyl)-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-
-3-yl)pyridin-2-amine
[0698] 1-Bromo-4-fluorobenzene (0.129 g, 0.735 mmol), Example 16a
(0.1 g, 0.367 mmol), diacetoxypalladium (3.30 mg, 0.015 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.014 g, 0.029 mmol) and cesium carbonate (0.239 g, 0.735 mmol)
were combined in t-butanol (0.360 mL)/toluene (1.80 mL) and heated
by microwave at 150.degree. C. for 40 minutes. The reaction mixture
was cooled to ambient temperature and partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried (anhydrous Na.sub.2SO.sub.4),
treated with 3-mercaptopropyl functionalized silica gel, filtered,
and concentrated. Purification by chromatography (silica gel, 0-40%
ethyl acetate in heptanes) afforded the title compound (0.097 g,
72%).
Example 16c
3-(5-fluoro-2-((4-fluorophenyl)amino)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-
-c]pyridin-7(6H)-one
[0699] Example 16b (0.097 g, 0.265 mmol) and 4M hydrogen chloride
in dioxane (5 mL, 20.00 mmol) were heated at 90.degree. C. for 4
hours, cooled and concentrated. Purification by trituration in
diethyl ether afforded the title compound (0.11 g, 100%).
Example 16d
8-fluoro-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-1-one
[0700] Example 16c (0.04 g, 0.114 mmol), paraformaldehyde (0.068 g,
2.271 mmol) and 4M hydrogen chloride in dioxane (1.135 mL, 4.54
mmol) were heated in a sealed tube by microwave at 125.degree. C.
for 3 hours, cooled and concentrated. Purification by reverse phase
HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) afforded
the title compound as a TFA salt (0.01 g, 18%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.54 (s, 1H), 8.21 (d, J=3.05 Hz, 1H),
8.10 (dd, J=9.61, 2.90 Hz, 1H), 7.87 (s, 1H), 6.99 (d, J=2.44 Hz,
1H), 6.81-6.87 (m, 2H), 6.62-6.67 (m, 2H), 4.60 (s, 2H), 4.07 (s,
3H). MS (ESI+) m/z 365 (M+H).sup.+.
Example 17
2-(2-chloro-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide
[0701] A stock solution of Example 14e and
N,N-diisopropylethylamine (0.11 M and 0.33 M in
N,N-dimethylacetamide, respectively, 350 .mu.L, 0.038 mmol Example
14e and 0.11 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 .mu.L,
0.046 mmol), and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in
N,N-dimethylacetamide, 113 .mu.L, 0.050 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified by reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to give 0.0062 g (30%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.54
(d, J=2.75 Hz, 1H), 8.44 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.53
(dd, J=8.85, 5.19 Hz, 1H), 7.37 (dd, J=9.46, 3.05 Hz, 1H), 7.21 (m,
1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.62 (m, 2H), 4.05
(s, 3H), 3.94 (s, 2H). MS (APCI+) m/z 532.0 (M+H).sup.+.
Example 18
2-(1,5-dimethyl-1H-pyrazol-3-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4-
,5,11-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide
[0702] Example 18 was prepared according to the procedure used for
the preparation of Example 17, substituting
2-(1,5-dimethyl-1H-pyrazol-3-yl)acetic acid for
2-(2-chloro-5-fluorophenyl)acetic acid, to give 0.0053 g (28%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.50 (d, J=2.75 Hz, 1H), 8.45 (d, J=2.44 Hz, 1H), 7.77 (s,
1H), 7.07 (s, 1H), 6.86 (m, 2H), 6.57 (m, 2H), 6.02 (s, 1H), 4.61
(m, 2H), 4.06 (s, 3H), 3.67 (s, 3H), 3.59 (s, 2H), 2.23 (s, 3H). MS
(APCI+) m/z 498.1 (M+H).sup.+.
Example 19
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-8-yl)-2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)acetam-
ide
[0703] Example 19 was prepared according to the procedure used for
the preparation of Example 17, substituting
2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)acetic acid for
2-(2-chloro-5-fluorophenyl)acetic acid, to give 0.0108 g (50%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.55 (d, J=2.44 Hz, 1H), 8.44 (d, J=2.75 Hz, 1H), 7.92 (m,
2H), 7.77 (s, 1H), 7.39 (m, 1H), 7.28 (m, 2H), 7.07 (s, 1H), 6.88
(m, 2H), 6.72 (dd, J=3.66, 2.44 Hz, 1H), 6.59 (m, 2H), 5.20 (s,
2H), 4.62 (s, 2H), 4.05 (s, 3H). MS (APCI+) m/z 564.0
(M+H).sup.+.
Example 20
2-(4-chloro-2-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide
[0704] A stock solution of Example 14e and
N,N-diisopropylethylamine (0.11 M and 0.33 M in
N,N-dimethylacetamide, respectively, 350 .mu.L, 0.038 mmol Example
14e and 0.11 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 .mu.L,
0.046 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in
N,N-dimethylacetamide, 113 .mu.L, 0.050 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified by reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to yield the title compound as an impure
mixture. The material was dissolved in methanol (1 mL) and manually
injected into the HPLC (C8, acetonitrile/water (0.1% ammonium
acetate), 5-100%) to give 0.0036 g (19%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.52 (d,
J=2.75 Hz, 1H), 8.43 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.47 (t,
J=8.24 Hz, 1H), 7.42 (dd, J=9.77, 1.83 Hz, 1H), 7.30 (dd, J=8.09,
1.68 Hz, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.61 (s,
2H), 4.05 (s, 3H), 3.82 (s, 2H). MS (APCI+) m/z 532.0
(M+H).sup.+.
Example 21
2-(chroman-6-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-
-1H-2,5,6,11-tetraazadibenzo[cd,h]azulen-8-yl)acetamide
[0705] Example 21 was prepared according to the procedure used for
the preparation of Example 20, substituting 2-(chroman-6-yl)acetic
acid for 2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0066 g
(34%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 8.51 (d, J=2.44 Hz, 1H), 8.45 (d,
J=2.44 Hz, 1H), 7.76 (s, 1H), 7.06 (d, J=6.71 Hz, 3H), 6.86 (m,
2H), 6.70 (m, 1H), 6.56 (m, 2H), 4.61 (m, 2H), 4.11 (m, 2H), 4.06
(s, 3H), 3.58 (s, 2H), 2.74 (t, J=6.41 Hz, 2H), 1.91 (m, 2H). MS
(APCI+) m/z 535.7 (M+H).sup.+.
Example 22
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide
[0706] A stock solution of Example 14e and
N,N-diisopropylethylamine (0.11 M and 0.33 M in
N,N-dimethylacetamide, respectively, 350 .mu.L, 0.038 mmol Example
14e and 0.11 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 .mu.L,
0.046 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in
N,N-dimethylacetamide, 113 .mu.L, 0.050 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified by reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to yield the title compound as an impure
mixture. The material was dissolved in methanol (1 mL) and manually
injected into the HPLC (C8, acetonitrile/water (0.1% ammonium
acetate), 5-100%) give 0.0067 g (38%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.49 (d,
J=2.44 Hz, 1H), 8.45 (d, J=2.75 Hz, 1H), 7.77 (s, 1H), 7.63 (s,
1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.60
(m, 2H), 4.07 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H). MS (APCI+) m/z
484.1 (M+H).sup.+.
Example 23
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-1-one
Example 23a
3-(2-fluoro-5-nitrophenyl)-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine
[0707] Example 1a (2 g, 6.94 mmol), (2-fluoro-5-nitrophenyl)boronic
acid (1.412 g, 7.64 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.191 g, 0.208 mmol),
(1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamanta-
ne (0.203 g, 0.694 mmol) and potassium phosphate (5.16 g, 24.3
mmol) were combined and sparged with nitrogen for 30 minutes. To
this mixture were added nitrogen-sparged dioxane (32 mL) and water
(8 mL). The reaction mixture was stirred at 60.degree. C. for 4
hours, partitioned between ethyl acetate and water and washed with
saturated aqueous sodium chloride. The combined aqueous layers were
exhaustively extracted with ethyl acetate. The combined organic
layers were treated with 3-mercaptopropyl-functionalized silica gel
for 20 minutes, dried over anhydrous magnesium sulfate, filtered
through a plug of Celite and concentrated. The residue was purified
by flash chromatography (silica gel, 0-3% ethyl acetate in
dichloromethane) to give 1.9 g (91%) of the title compound.
Example 23b
N-(4-fluorophenyl)-2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4--
nitroaniline
[0708] Example 23a (1.07 g, 3.55 mmol) and 4-fluoroaniline (0.434
g, 3.91 mmol) were dissolved in dimethyl sulfoxide (35.5 mL),
treated with potassium 2-methylpropan-2-olate (0.8 g, 7.1 mmol) and
stirred overnight at ambient temperature. The reaction mixture was
partitioned between ethyl acetate and water and washed with
saturated aqueous sodium chloride. The combined aqueous layers were
extracted with ethyl acetate (2.times.150 mL). The combined organic
layers were dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-2% ethyl acetate in dichloromethane) to provide 1.13
g (81%) of the title compound.
Example 23c
3-(2-((4-fluorophenyl)amino)-5-nitrophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyri-
din-7(6H)-one
[0709] Example 23b (1.126 g, 2.87 mmol) was treated with hydrogen
chloride solution (4 M in 1,4-dioxane, 10.8 mL, 43 mmol) and heated
at 90.degree. C. for 1 hour. The reaction mixture was concentrated
to dryness to give 1.09 g (100%) of the title compound.
Example 23d
5-(4-fluorophenyl)-11-methyl-8-nitro-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-1-one
[0710] To Example 23c (1.09 g, 2.87 mmol) in acetic acid (16 mL)
was added paraformaldehyde (0.215 g, 7.18 mmol). The reaction
mixture was heated at 90.degree. C. for 13 minutes, cooled to
ambient temperature, and diluted with water. The resulting solid
was collected by filtration and dried under vacuum. The solid was
then slurried in methanol (8 mL), treated with sodium hydroxide (4
M aqueous solution, 3 mL, 12 mmol) and heated at 70.degree. C. for
2 hours. Methanol was removed under vacuum. Water was added to
further induce precipitation and the solid was collected by
filtration. The solid was then triturated with acetonitrile,
collected by filtration and dried under high vacuum to give 0.93 g
(83%) of the title compound.
Example 23e
8-amino-5-(4-fluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-1-one
[0711] Example 23d (0.93 g, 2.38 mmol) was slurried in a mixture of
tetrahydrofuran (8 mL), ethanol (4 mL) and water (2 mL), treated
with ammonium chloride (1.274 g, 23.82 mmol) and zinc dust (2.336
g, 35.7 mmol), and stirred at ambient temperature for 30 minutes.
The solids were removed by filtration. The filtrate was
concentrated and the resulting solid was purified by sequential
triturations with water, acetonitrile and diethyl ether to give
0.76 g (89%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.73 (d, J=5.49 Hz, 1H), 7.54 (s, 1H), 6.98
(d, J=5.49 Hz, 1H), 6.95 (d, J=2.44 Hz, 1H), 6.90 (d, J=8.24 Hz,
1H), 6.78 (m, J=8.85, 8.85 Hz, 2H), 6.49 (dd, J=8.39, 2.59 Hz, 1H),
6.45 (m, 2H), 5.11 (s, 2H), 4.95 (d, J=16.17 Hz, 1H), 4.14 (d,
J=15.87 Hz, 1H), 4.03 (s, 3H). MS (ESI+) m/z 361.2 (M+H).sup.+.
Example 24
8-chloro-5-(4-fluorophenyl)-11-methyl-4-phenyl-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-1-one
Example 24a
3-(5-chloro-2-((4-fluorophenyl)amino)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0712] Example 13b (0.76 g, 1.990 mmol) and 4M hydrogen chloride in
dioxane (20 mL, 80 mmol) were heated at 70.degree. C. for 18 hours,
cooled, concentrated and azeotroped two times with toluene to
afford the title compound (0.73 g, 100%).
Example 24b
8-chloro-5-(4-fluorophenyl)-11-methyl-4-phenyl-2,4,5,11-tetrahydro-1H-2,5,-
11-triazadibenzo[cd,h]azulen-1-one
[0713] Example 24a (0.05 g, 0.136 mmol) and benzaldehyde (0.041 mL,
0.408 mmol) in acetic acid (1 mL) were heated in a sealed tube at
100.degree. C. for 2 hours, cooled and concentrated. Purification
by reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%
gradient) afforded the title compound (0.002 g, 3%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.66 (s, 1H), 7.82 (s, 1H), 7.64
(d, J=2.44 Hz, 1H), 6.91-7.10 (m, 8H), 6.80-6.86 (m, 2H), 6.66-6.70
(m, 2H), 6.50 (s, 1H), 4.09 (s, 3H). MS (ESI+) m/z 456
(M+H).sup.+.
Example 25
11-methyl-8-((methylsulfonyl)methyl)-4-phenyl-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-1-one
[0714] A 5 mL vial was charged with Example 4a (104 mg, 0.300
mmol), benzaldehyde (159 mg, 1.50 mmol) and acetic acid (2 mL). The
vial was closed and stirred at 80.degree. C. for 6 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was partitioned in ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
reverse phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium
carbonate), 20-100%) to afford the title compound (19 mg, 15%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.72 (d, J=5.76 Hz,
1H) 7.68 (s, 1H) 7.57 (s, 1H) 7.03-7.29 (m, 5H) 6.90 (s, 2H) 6.41
(d, J=5.76 Hz, 1H) 6.28 (d, J=4.41 Hz, 1H) 5.30 (d, J=4.41 Hz, 1H)
4.26 (s, 2H) 4.16 (s, 3H) 2.80 (s, 3H). MS (ESI+) m/z 420
(M+H).sup.+.
Example 26
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)benzenesulfonamide
[0715] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane,
respectively, 500 .mu.L, 0.042 mmol Example 23e and 0.083 mmol
N,N-diisopropylethylamine), and benzenesulfonyl chloride (0.40 M in
dichloromethane, 239 .mu.L, 0.096 mmol) were mixed and stirred at
ambient temperature overnight. The reaction mixture was
concentrated, dissolved in methanol (1 mL) and injected on the
reverse phase HPLC (C8, acetonitrile/water (0.1% TFA), 5-100%) to
yield the title compound as an impure mixture. The material was
dissolved in methanol (1 mL) and manually injected into the HPLC
(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0031 g (17%)
of the title compound as the TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 8.03 (m, 1H), 7.85 (m, 2H), 7.63 (m,
3H), 7.50 (d, J=2.44 Hz, 1H), 7.11 (d, J=8.54 Hz, 1H), 7.02 (s,
1H), 6.96 (dd, J=8.54, 2.44 Hz, 1H), 6.81 (m, 2H), 6.38 (m, 2H),
4.96 (s, 1H), 4.11 (s, 1H), 4.04 (s, 3H). MS (APCI+) m/z 501.0
(M+H).sup.+.
Example 27
N-(4-(N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11--
triazadibenzo[cd,h]azulen-8-yl)sulfamoyl)phenyl)acetamide
[0716] A stock solution of Example 14e and
N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane,
respectively, 500 .mu.L, 0.042 mmol Example 14e and 0.083 mmol
N,N-diisopropylethylamine), and 4-acetamidobenzene-1-sulfonyl
chloride (0.40 M in dichloromethane, 239 .mu.L, 0.096 mmol) were
mixed and stirred at ambient temperature overnight. The reaction
mixture was concentrated, dissolved in methanol (1 mL) and injected
on the reverse phase HPLC (C8, acetonitrile/water (0.1% TFA),
5-100%) to yield the title compound as an impure mixture. The
material was dissolved in methanol (1 mL) and manually injected
into the HPLC (C8, acetonitrile/water (0.1% TFA), 5-100%) to give
0.0071 g (32%) of the title compound as the TFA salt. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.75 (q, J=9.16 Hz, 4H),
7.57 (s, 1H), 7.48 (d, J=2.44 Hz, 1H), 7.11 (d, J=8.54 Hz, 1H),
7.02 (s, 1H), 6.95 (dd, J=8.54, 2.44 Hz, 1H), 6.80 (m, J=8.85, 8.85
Hz, 2H), 6.37 (m, 2H), 4.97 (s, 1H), 4.12 (m, 1H), 4.04 (s, 3H),
2.06 (s, 3H). MS (APCI+) m/z 558.0 (M+H).sup.+.
Example 28
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)acetamide
[0717] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.165 M and 0.47 M in
N,N-dimethylacetamide, respectively, 275 .mu.L, 0.042 mmol Example
23e and 0.13 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 .mu.L,
0.063 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in
N,N-dimethylacetamide, 125 .mu.L, 0.05 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified using reverse phase HPLC (C8, acetonitrile/water (0.1%
TFA), 5-100%) to give 0.0168 g (68%) of the title compound as the
TFA salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.03
(d, J=2.14 Hz, 1H), 7.57 (s, 2H), 7.42 (dd, J=8.54, 2.44 Hz, 1H),
7.38 (s, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H),
6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.52 (s,
2H). MS (APCI+) m/z 483.1 (M+H).sup.+.
Example 29
2-(4-chloro-2-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0718] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.165 M and 0.47 M in
N,N-dimethylacetamide, respectively, 275 .mu.L, 0.042 mmol Example
23e and 0.13 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 .mu.L,
0.063 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in
N,N-dimethylacetamide, 125 .mu.L, 0.05 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified using reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to give 0.0126 g (57%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.06
(d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.45 (t, J=8.24 Hz, 1H), 7.40
(dd, J=8.54, 2.44 Hz, 1H), 7.31 (dd, J=9.77, 2.14 Hz, 1H), 7.25
(dd, J=8.24, 2.14 Hz, 1H), 7.17 (d, J=8.54 Hz, 1H), 6.97 (s, 1H),
6.78 (m, 2H), 6.50 (m, 2H), 4.58 (m, 2H), 4.05 (s, 3H), 3.77 (s,
2H). MS (APCI+) m/z 531.1 (M+H).sup.+.
Example 30
2-(2-chloro-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-
-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0719] Example 30 was prepared according to the procedure used for
the preparation of Example 29, substituting
2-(2-chloro-5-fluorophenyl)acetic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0108 g (49%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.07 (d, J=2.44 Hz, 1H), 7.57 (s, 1H), 7.48 (dd, J=8.85,
5.19 Hz, 1H), 7.41 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (dd, J=9.61,
3.20 Hz, 1H), 7.15 (m, 2H), 6.97 (s, 1H), 6.78 (m, 2H), 6.51 (m,
2H), 4.59 (m, 2H), 4.05 (s, 3H), 3.88 (m, 2H). MS (APCI+) m/z 531.0
(M+H).sup.+.
Example 31
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)acetamide
[0720] Example 31 was prepared according to the procedure used for
the preparation of Example 29, substituting
2-(3-(2-fluorophenyl)-1H-pyrazol-1-yl)acetic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0169 g (72%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.09 (d, J=2.44 Hz, 1H), 7.91 (td, J=7.86, 1.98 Hz, 1H),
7.86 (d, J=2.14 Hz, 1H), 7.57 (s, 1H), 7.41 (dd, J=8.54, 2.44 Hz,
1H), 7.35 (m, 1H), 7.23 (m, 3H), 6.97 (s, 1H), 6.78 (m, 2H), 6.69
(dd, J=3.66, 2.44 Hz, 1H), 6.51 (m, 2H), 5.12 (s, 2H), 4.59 (m,
2H), 4.05 (s, 3H). MS (APCI+) m/z 563.0 (M+H).sup.+.
Example 32
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-2-(2-methylthiazol-5-yl)acetamide
[0721] Example 32 was prepared according to the procedure used for
the preparation of Example 29, substituting
2-(2-methylthiazol-5-yl)acetic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0173 g (83%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.03 (d, J=2.44 Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.41
(dd, J=8.54, 2.44 Hz, 1H), 7.18 (d, J=8.54 Hz, 1H), 6.97 (s, 1H),
6.78 (m, 2H), 6.50 (m, 2H), 4.58 (m, 2H), 4.06 (s, 3H), 3.90 (m,
2H), 2.61 (s, 3H). MS (APCI+) m/z 500.1 (M+H).sup.+.
Example 33
2-(1,5-dimethyl-1H-pyrazol-3-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4-
,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0722] Example 33 was prepared according to the procedure used for
the preparation of Example 29, substituting
2-(1,5-dimethyl-1H-pyrazol-3-yl)acetic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0165 g (80%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.04 (d, J=2.44 Hz, 1H), 7.57 (s, 1H), 7.42 (dd, J=8.54,
2.44 Hz, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H),
6.50 (m, 2H), 6.00 (s, 1H), 4.58 (m, 2H), 4.06 (s, 3H), 3.68 (s,
3H), 3.57 (s, 2H), 2.22 (s, 3H). MS (APCI+) m/z 497.1
(M+H).sup.+.
Example 34
[0723]
N.sup.1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H--
2,5,11-triazadibenzo[cd,h]azulen-8-yl)-N.sup.5-phenylglutaramide
[0724] Example 34 was prepared according to the procedure used for
the preparation of Example 29, substituting
5-oxo-5-(phenylamino)pentanoic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0158 g (69%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.05 (d, J=2.44 Hz, 1H), 7.56 (m, 3H), 7.43 (dd, J=8.54,
2.44 Hz, 1H), 7.28 (m, 2H), 7.15 (d, J=8.54 Hz, 1H), 7.04 (m, 1H),
6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s,
3H), 2.44 (q, J=7.02 Hz, 4H), 1.99 (m, 2H). MS (APCI+) m/z 550.1
(M+H).sup.+.
Example 35
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-5-methylpyrazine-2-carboxamide
[0725] Example 35 was prepared according to the procedure used for
the preparation of Example 29, substituting
5-methylpyrazine-2-carboxylic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0066 g (33%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 9.18 (d, J=1.22 Hz, 1H), 8.67 (d, J=0.92 Hz, 1H), 8.28 (d,
J=2.44 Hz, 1H), 7.74 (dd, J=8.54, 2.44 Hz, 1H), 7.67 (s, 1H), 7.25
(d, J=8.54 Hz, 1H), 6.99 (s, 1H), 6.80 (m, 2H), 6.55 (m, 2H), 4.62
(m, 2H), 4.08 (s, 3H), 2.65 (s, 3H). MS (APCI+) m/z 481.1
(M+H).sup.+.
Example 36
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide
[0726] Example 36 was prepared according to the procedure used for
the preparation of Example 29, substituting
2-(4-methylpiperazin-1-yl)acetic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0111 g (53%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.03 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.48 (dd, J=8.54,
2.44 Hz, 1H), 7.18 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H),
6.51 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.16 (s, 2H), 2.60 (m,
4H), 2.45 (m, 4H), 2.21 (s, 3H). MS (APCI+) m/z 501.1
(M+H).sup.+.
Example 37
8-(((1-ethyl-1H-pyrazol-3-yl)methyl)amino)-5-(4-fluorophenyl)-11-methyl-2,-
4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0727] A stock solution of Example 23e (0.164 M in
N,N-dimethylacetamide, 255 .mu.L, 0.042 mmol), acetic acid (4 M in
methanol, 200 .mu.L, 0.84 mmol), sodium cyanoborohydride (0.31 M in
methanol, 200 .mu.L, 0.063 mmol) and
1-ethyl-1H-pyrazole-3-carbaldehyde (0.40 M in
N,N-dimethylacetamide, 156 .mu.L, 0.063 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 50.degree. C., and passed through the reactor at 180 .mu.L,
min.sup.-1 (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified by reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to give 0.0081 g (41%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.57
(m, 2H), 7.07 (d, J=2.75 Hz, 1H), 6.95 (m, 2H), 6.74 (m, 2H), 6.60
(dd, J=8.54, 2.75 Hz, 1H), 6.46 (m, 2H), 6.22 (d, J=2.14 Hz, 1H),
4.28 (s, 2H), 4.10 (q, J=7.12 Hz, 2H), 4.04 (s, 3H), 2.88 (d,
J=53.41 Hz, 2H), 1.38 (m, 3H). MS (APCI+) m/z 469.1
(M+H).sup.+.
Example 38
5-(4-fluorophenyl)-11-methyl-8-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-2-
,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0728] Example 38 was prepared according to the procedure used for
the preparation of Example 37, substituting
1-methyl-1H-pyrazole-5-carbaldehyde for
1-ethyl-1H-pyrazole-3-carbaldehyde, to give 0.0057 g (30%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.58 (s, 1H), 7.31 (d, J=1.83 Hz, 1H), 7.07 (d, J=2.75 Hz,
1H), 6.97 (d, J=8.54 Hz, 1H), 6.94 (s, 1H), 6.74 (m, 2H), 6.62 (dd,
J=8.54, 2.75 Hz, 1H), 6.47 (m, 2H), 6.27 (d, J=1.83 Hz, 1H), 4.59
(m, 2H), 4.39 (s, 2H), 4.05 (s, 3H), 3.85 (s, 3H). MS (APCI+) m/z
455.1 (M+H).sup.+.
Example 39
8-((3-(1H-pyrazol-1-yl)propyl)amino)-5-(4-fluorophenyl)-11-methyl-2,4,5,11-
-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0729] Example 39 was prepared according to the procedure used for
the preparation of Example 37, substituting
3-(1H-pyrazol-1-yl)propanal for 1-ethyl-1H-pyrazole-3-carbaldehyde,
to give 0.0072 g (37%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.68 (d, J=2.44 Hz, 1H), 7.57 (s,
1H), 7.46 (d, J=1.83 Hz, 1H), 6.94 (m, 3H), 6.74 (m, 2H), 6.50 (dd,
J=8.39, 2.59 Hz, 1H), 6.46 (m, 2H), 6.26 (t, J=2.14 Hz, 1H), 4.64
(m, 2H), 4.26 (t, J=6.87 Hz, 2H), 4.05 (s, 3H), 3.13 (t, J=6.87 Hz,
2H), 2.12 (m, 2H). MS (APCI+) m/z 469.1 (M+H).sup.+.
Example 40
5-(4-fluorophenyl)-11-methyl-8-(((6-methylpyridin-2-yl)methyl)amino)-2,4,5-
,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0730] A stock solution of Example 23e (0.164 M in
N,N-dimethylacetamide, 255 .mu.L, 0.042 mmol), acetic acid (4 M in
methanol, 200 .mu.L, 0.84 mmol), sodium cyanoborohydride (0.31 M in
methanol, 200 .mu.L, 0.063 mmol) and 6-methylpicolinaldehyde (0.40
M in N,N-dimethylacetamide, 156 .mu.L, 0.063 mmol) were aspirated
from their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 50.degree. C., and passed through the reactor at 180 .mu.L
per minute (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified by reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to give 0.0085 g (44%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta.
10.85 (s, 1H), 8.41 (d, J=1.83 Hz, 1H), 7.96 (s, 1H), 7.81 (dd,
J=8.24, 1.83 Hz, 1H), 7.38 (m, 2H), 7.04 (s, 1H), 6.87 (m, J=9.00,
9.00 Hz, 3H), 6.58 (m, 3H), 4.58 (m, 2H), 4.06 (s, 3H), 3.90 (s,
3H), 3.17 (s, 2H). MS (APCI+) m/z 466.1 (M+H).sup.+.
Example 41
methyl
4-((5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)amino)butanoate
[0731] Example 41 was prepared according to the procedure used for
the preparation of Example 37, substituting methyl 4-oxobutanoate
for 1-ethyl-1H-pyrazole-3-carbaldehyde, to give 0.0049 g (26%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.60 (s, 1H), 6.95 (m, 3H), 6.74 (m, 2H), 6.53 (dd, J=8.54,
2.75 Hz, 1H), 6.47 (m, 2H), 4.62 (m, 2H), 4.04 (s, 3H), 3.63 (s,
3H), 3.15 (t, J=6.87 Hz, 2H), 2.45 (t, J=7.17 Hz, 2H), 1.88 (m,
2H). MS (APCI+) m/z 461.1 (M+H).sup.+.
Example 42
5-(4-fluorophenyl)-11-methyl-8-(((1-methyl-1H-imidazol-5-yl)methyl)amino)--
2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0732] Example 42 was prepared according to the procedure used for
the preparation of Example 37, substituting
1-methyl-1H-imidazole-5-carbaldehyde for
1-ethyl-1H-pyrazole-3-carbaldehyde, to give 0.0056 g (30%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.59 (s, 1H), 7.52 (s, 1H), 7.08 (d, J=2.75 Hz, 1H), 6.97
(d, J=8.54 Hz, 1H), 6.93 (d, J=7.93 Hz, 2H), 6.75 (m, 2H), 6.63
(dd, J=8.54, 2.75 Hz, 1H), 6.47 (m, 2H), 4.45 (m, 2H), 4.33 (s,
2H), 4.05 (s, 3H), 3.67 (s, 3H). MS (APCI+) m/z 455.1
(M+H).sup.+.
Example 43
5-(4-fluorophenyl)-11-methyl-8-(((3-methylpyridin-2-yl)methyl)amino)-2,4,5-
,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0733] Example 43 was prepared according to the procedure used for
the preparation of Example 37, substituting 3-methylpicolinaldehyde
for 1-ethyl-1H-pyrazole-3-carbaldehyde, to give 0.0086 g (45%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.40 (dd, J=4.73, 1.07 Hz, 1H), 7.63 (s, 1H), 7.60 (dd,
J=7.48, 0.76 Hz, 1H), 7.23 (dd, J=7.48, 4.73 Hz, 1H), 7.16 (d,
J=2.75 Hz, 1H), 6.98 (d, J=8.54 Hz, 1H), 6.94 (s, 1H), 6.74 (m,
2H), 6.68 (dd, J=8.39, 2.59 Hz, 1H), 6.47 (m, 2H), 4.43 (s, 2H),
4.06 (s, 3H), 4.25 (m, 2H), 2.41 (s, 3H). MS (APCI+) m/z 466.1
(M+H).sup.+.
Example 44
1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-3-(3-phenoxyphenyl)urea
[0734] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.0875 M and 0.042 in
N,N-dimethylacetamide, respectively, 497 .mu.L, 0.042 mmol Example
23e and 0.126 mmol N,N-diisopropylethylamine) and
1-isocyanato-3-phenoxybenzene (0.40 M in N,N-dimethylacetamide, 208
.mu.L, 0.084 mmol) were aspirated from their respective source
vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner
diameter), and loaded into an injection loop. The reaction segment
was injected into the flow reactor (Hastelloy coil, 0.75 mm inner
diameter, 1.8 mL internal volume) set at 150.degree. C., and passed
through the reactor at 180 .mu.L per minute (10 minute residence
time). Upon exiting the reactor, the reaction mixture was loaded
directly into an injection loop and purified by reverse phase HPLC
(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give
0.0067 g (28%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.90 (d, J=2.44 Hz, 1H), 7.60 (s,
1H), 7.40 (m, 2H), 7.27 (m, 3H), 7.16 (m, 3H), 7.03 (m, 2H), 6.97
(s, 1H), 6.78 (m, 2H), 6.64 (m, 1H), 6.51 (m, 2H), 4.60 (m, 2H),
4.06 (s, 3H). MS (APCI+) m/z 572.1 (M+H).sup.+.
Example 45
1-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-3-(3-methoxyphenyl)urea
[0735] Example 45 was prepared according to the procedure used for
the preparation of Example 44, substituting
1-isocyanato-3-methoxybenzene for 1-isocyanato-3-phenoxybenzene, to
give 0.0013 g (6%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.92 (d, J=2.75 Hz, 1H), 7.62 (s,
1H), 7.29 (m, 1H), 7.18 (m, 3H), 6.99 (m, 2H), 6.78 (m, 2H), 6.59
(m, 1H), 6.52 (m, 2H), 4.60 (s, 2H), 4.07 (s, 3H), 3.77 (s, 3H). MS
(APCI+) m/z 510.1 (M+H).sup.+.
Example 46
2-(chroman-6-yl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-
-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0736] Example 46 was prepared according to the procedure used for
the preparation of Example 29, substituting 2-(chroman-6-yl)acetic
acid for 2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0081 g
(37%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 8.05 (d, J=2.44 Hz, 1H), 7.56 (s,
1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.15 (d, J=8.54 Hz, 1H), 7.05
(m, 2H), 6.97 (s, 1H), 6.77 (m, 2H), 6.68 (m, 1H), 6.50 (m, 2H),
4.58 (m, 2H), 4.11 (m, 2H), 4.05 (s, 3H), 3.55 (s, 2H), 2.74 (t,
J=6.41 Hz, 2H), 1.93 (m, 2H). MS (APCI+) m/z 535.1 (M+H).sup.+.
Example 47
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-3-(4-methylpiperazin-1-yl)propanamide
[0737] Example 47 was prepared according to the procedure used for
the preparation of Example 29, substituting
3-(4-methylpiperazin-1-yl)propanoic acid for
2-(4-chloro-2-fluorophenyl)acetic acid, to give 0.0054 g (25%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.03 (d, J=2.75 Hz, 1H), 7.56 (s, 1H), 7.39 (dd, J=8.54,
2.44 Hz, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.77 (m, 2H),
6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 4.04 (m, 2H), 2.70 (t,
J=6.87 Hz, 2H), 2.49 (m, J=5.80 Hz, 4H), 2.37 (m, 4H), 2.18 (s,
3H). MS (APCI+) m/z 515.2 (M+H).sup.+.
Example 48
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-3-(piperidin-1-yl)propanamide
[0738] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.165 M and 0.47 M in
N,N-dimethylacetamide, respectively, 275 .mu.L, 0.042 mmol Example
23e and 0.13 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 .mu.L,
0.063 mmol), and 3-(piperidin-1-yl)propanoic acid (0.40 M in
N,N-dimethylacetamide, 125 .mu.L, 0.05 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
min.sup.-1 (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified using reverse phase HPLC (C8, acetonitrile/water (0.1%
ammonium acetate), 5-100%) to give 0.0009 g (4%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 8.03
(d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.38 (dd, J=8.54, 2.44 Hz, 1H),
7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, J=8.85, 8.85 Hz,
2H), 6.51 (m, J=9.31, 4.43 Hz, 2H), 4.59 (m, 2H), 4.06 (s, 3H),
2.71 (s, 1H), 2.67 (m, 3H), 2.44 (m, 4H), 1.54 (m, 4H), 1.43 (m,
2H). MS (APCI+) m/z 500.2 (M+H).sup.+.
Example 49
2-(2-bromo-5-fluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11--
tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0739] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.14 M and 0.40 M in
N,N-dimethylacetamide, respectively, 287 .mu.L) and
2-(2-bromo-5-fluorophenyl)acetic acid (0.4 M in
N,N-dimethylacetamide, 124 .mu.L), and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.21 M in N,N-dimethylacetamide, 287 .mu.L)
were aspirated from their respective source vials, mixed through a
perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded
into an injection loop. The reaction segment was injected into the
flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL
internal volume) set at 100.degree. C. and passed through the
reactor at 180 .mu.L per minute (10 minute residence time). Upon
exiting the reactor, the reaction mixture was loaded directly into
an injection loop and purified by reverse phase HPLC (C8,
acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0058
g (24%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 8.14 (d, J=2.44 Hz, 1H), 7.68 (dd,
J=8.85, 5.49 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H),
7.36 (dd, J=9.61, 3.20 Hz, 1H), 7.21 (d, J=8.54 Hz, 1H), 7.14 (td,
J=8.54, 3.36 Hz, 1H), 7.04 (s, 1H), 6.82 (m, 2H), 6.49 (m, 2H),
5.02 (d, J=15.87 Hz, 1H), 4.18 (d, J=16.78 Hz, 1H), 4.03 (s, 3H),
3.92 (s, 2H). MS (APCI+) m/z 575.1 (M+H).sup.+.
Example 50
2-(2,5-dichlorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetr-
ahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0740] Example 50 was prepared according to the procedure used for
the preparation of Example 49, substituting
2-(2,5-dichlorophenyl)acetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0041 g (18%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.13 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.57 (d, J=2.44 Hz,
1H), 7.52 (m, 1H), 7.41 (m, 2H), 7.21 (d, J=8.54 Hz, 1H), 7.04 (s,
1H), 6.82 (m, 2H), 6.48 (m, 2H), 5.02 (d, J=16.17 Hz, 1H), 4.18 (d,
J=17.09 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 2H). MS (APCI+) m/z 547.1
(M+H).sup.+.
Example 51
2-(5-fluoro-2-(trifluoromethyl)phenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-o-
xo-2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0741] Example 51 was prepared according to the procedure used for
the preparation of Example 49, substituting
2-(5-fluoro-2-(trifluoromethyl)phenyl)acetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0111 g (47%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.13 (d, J=2.44 Hz, 1H), 7.83 (dd, J=8.85, 5.49 Hz, 1H),
7.64 (s, 1H), 7.45 (dd, J=9.77, 2.44 Hz, 1H), 7.37 (m, 2H), 7.21
(d, J=8.54 Hz, 1H), 7.04 (s, 1H), 6.83 (m, 2H), 6.48 (m, 2H), 5.02
(d, J=16.78 Hz, 1H), 4.18 (d, J=16.48 Hz, 1H), 4.03 (s, 3H), 4.01
(s, 2H). MS (APCI+) m/z 565.2 (M+H).sup.+.
Example 52
2-(2,5-difluorophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetr-
ahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0742] Example 52 was prepared according to the procedure used for
the preparation of Example 49, substituting
2-(2,5-difluorophenyl)acetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0061 g (29%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.12 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54,
2.44 Hz, 1H), 7.25 (m, 4H), 7.04 (s, 1H), 6.83 (m, 2H), 6.48 (m,
2H), 5.02 (d, J=15.56 Hz, 1H), 4.18 (d, J=16.48 Hz, 1H), 4.04 (s,
3H), 3.80 (s, 2H). MS (APCI+) m/z 515.2 (M+H).sup.+.
Example 53
2-(2,5-dimethylphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetr-
ahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0743] Example 53 was prepared according to the procedure used for
the preparation of Example 49, substituting
2-(2,5-dimethylphenyl)acetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0086 g (41%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.12 (d, J=2.14 Hz, 1H), 7.65 (s, 1H), 7.44 (dd, J=8.54,
2.44 Hz, 1H), 7.20 (d, J=8.54 Hz, 1H), 7.08 (m, 2H), 7.04 (s, 1H),
6.99 (dd, J=7.48, 1.37 Hz, 1H), 6.82 (m, 2H), 6.48 (m, 2H), 5.02
(d, J=17.09 Hz, 1H), 4.18 (d, J=16.17 Hz, 1H), 4.03 (s, 3H), 3.69
(s, 2H), 2.28 (s, 3H), 2.27 (s, 3H). MS (APCI+) m/z 507.3
(M+H).sup.+.
Example 54
N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triaza-
dibenzo[cd,h]azulen-8-yl)-2-phenylacetamide
[0744] Example 54 was prepared according to the procedure used for
the preparation of Example 49, substituting 2-phenylacetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0089 g, (44%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.09 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.45 (dd, J=8.54,
2.44 Hz, 1H), 7.38 (m, 4H), 7.28 (m, 1H), 7.20 (d, J=8.54 Hz, 1H),
7.04 (s, 1H), 6.82 (m, 2H), 6.47 (m, 2H), 5.01 (d, J=16.17 Hz, 1H),
4.17 (d, J=16.17 Hz, 1H), 4.04 (s, 3H), 3.69 (s, 2H). MS (APCI+)
m/z 479.2 (M+H).sup.+.
Example 55
2-(5-chloro-2-phenoxyphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0745] Example 55 was prepared according to the procedure used for
the preparation of Example 49, substituting
2-(5-chloro-2-phenoxyphenyl)acetic acid for
2-(2-bromo-5-fluorophenyl)acetic acid, to give 0.0027 g (11%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.03 (d, J=2.44 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=2.44 Hz,
1H), 7.36 (m, 4H), 7.16 (d, J=8.54 Hz, 1H), 7.12 (m, 1H), 7.04 (s,
1H), 6.99 (m, 2H), 6.88 (d, J=8.55 Hz, 1H), 6.81 (m, 2H), 6.46 (m,
2H), 5.01 (d, J=18.62 Hz, 1H), 4.17 (d, J=15.56 Hz, 1H), 4.04 (s,
3H), 3.79 (s, 2H). MS (APCI+) m/z 605.1 (M+H).sup.+.
Example 56
N-(5-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-t-
etrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
Example 56a
methyl
4-amino-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)benzoat-
e
[0746] Example 56a was prepared according to the procedure used for
the preparation of Example 23a, substituting Example 1b for Example
1a and methyl 4-amino-3-bromobenzoate for
(2-fluoro-5-nitrophenyl)boronic acid. Purification by flash
chromatography (silica gel, 0 to 45% ethyl acetate in
dichloromethane) gave 0.44 g (81%) of the title compound.
Example 56b
methyl
4-((4-fluorophenyl)amino)-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]py-
ridin-3-yl)benzoate
[0747] Example 56a (0.44 g, 1.413 mmol), 1-bromo-4-fluorobenzene
(0.495 g, 2.83 mmol), diacetoxypalladium (0.016 g, 0.071 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(X-PHOS) (0.067 g, 0.14 mmol) and cesium carbonate (0.921 g, 2.83
mmol) were combined. Toluene (6.5 mL) and tert-butanol (1.3 mL)
were added. The mixture was reacted at 150.degree. C. in a Biotage
microwave reactor for 45 minutes. The mixture was cooled to ambient
temperature, treated with 3-mercaptopropyl-functionalized silica
gel for 10 minutes, filtered through a pad of Celite and
concentrated. The residue was purified by flash chromatography
(silica gel, 0 to 15% ethyl acetate in dichloromethane) to provide
0.55 g (96%) of the title compound.
Example 56c
methyl
4-((4-fluorophenyl)amino)-3-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-3-yl)benzoate
[0748] Example 56b (0.546 g, 1.347 mmol) in methanol (4 mL) was
treated with hydrogen chloride solution (4 M in 1,4-dioxane, 10 mL,
40 mmol) and heated at 60.degree. C. for 1.5 hours. Additional
hydrogen chloride solution (4 M in 1,4-dioxane, 6 mL, 24 mmol) was
added and heating was continued at 65-70.degree. C. The reaction
mixture was concentrated, treated with hydrogen chloride solution
(4 M in 1,4-dioxane, 6 mL, 24 mmol) and stirred at 80.degree. C.
for 2 hours and then at ambient temperature for 4 hours. The
reaction mixture was concentrated, neutralized with saturated
sodium bicarbonate solution, and partitioned between ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The concentrate was triturated with
dichloromethane and dried under vacuum to give 0.47 g (88%) of the
title compound.
Example 56d
5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11-triazadib-
enzo[cd,h]azulene-8-carboxylic acid
[0749] Example 56c (0.504 g, 1.25 mmol) in a mixture of methanol (8
mL), dioxane (4 mL) and water (1 mL) was treated with lithium
hydroxide monohydrate (0.524 g, 12.5 mmol) and heated at 80.degree.
C. for 1 hour. The reaction mixture was cooled to ambient
temperature and neutralized with 2 N aqueous hydrochloric acid
solution. A solid precipitated out of solution upon partitioning
between ethyl acetate and water, and was isolated by filtration.
The organic layer was concentrated to dryness. This residue was
combined with the solid precipitate and the mixture was
sequentially triturated with water, acetonitrile and methanol and
then dried under high vacuum to give 0.25 g (52%) of the title
compound.
Example 56e
N-(5-fluoro-2-methoxybenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-t-
etrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0750] A stock solution of Example 56d and
N,N-diisopropylethylamine (0.15 M and 0.42 M in
N,N-dimethylacetamide, respectively, 254 .mu.L) and
(5-fluoro-2-methoxyphenyl)-methanamine (0.4 M in
N,N-dimethylacetamide, 115 .mu.L), and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.22 M in N,N-dimethylacetamide, 254 .mu.L)
were aspirated from their respective source vials, mixed through a
perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded
into an injection loop. The reaction segment was injected into the
flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL
internal volume) set at 100.degree. C., and passed through the
reactor at 180 .mu.L min.sup.-1 (10 minute residence time). Upon
exiting the reactor, the reaction mixture was loaded directly into
an injection loop and purified by reverse phase HPLC (C8,
acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0016
g (8%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 8.39 (d, J=2.14 Hz, 1H), 7.88 (s,
1H), 7.79 (dd, J=8.24, 2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.05
(m, 4H), 6.87 (m, 2H), 6.56 (m, 2H), 4.49 (s, 2H), 4.07 (s, 3H),
4.61 (m, 2H), 3.85 (s, 3H). MS (APCI+) m/z 527.2 (M+H).sup.+.
Example 57
N-(5-fluoro-2-methylbenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0751] Example 57 was prepared according to the procedure used for
the preparation of Example 56e, substituting
(5-fluoro-2-methylphenyl)methanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0032 g (16%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.39 (d, J=2.14 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J=8.24,
2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.24 (dd, J=8.24, 6.10 Hz,
1H), 7.06 (s, 1H), 7.01 (m, 2H), 6.87 (m, 2H), 6.56 (m, 2H), 4.50
(s, 2H), 4.64 (m, 2H), 4.07 (s, 3H), 2.33 (s, 3H). MS (APCI+) m/z
511.2 (M+H).sup.+.
Example 58
N-(2-bromo-5-fluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tet-
rahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0752] Example 58 was prepared according to the procedure used for
the preparation of Example 56e, substituting
(2-bromo-5-fluorophenyl)methanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0037 g (17%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.41 (d, J=2.14 Hz, 1H), 7.87 (s, 1H), 7.80 (dd, J=8.24,
2.14 Hz, 1H), 7.71 (dd, J=8.70, 5.34 Hz, 1H), 7.38 (d, J=8.24 Hz,
1H), 7.16 (m, 2H), 7.06 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.55
(s, 2H), 4.07 (s, 3H), 4.56 (m, 2H). MS (APCI+) m/z 575.1
(M+H).sup.+.
Example 59
5-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-11-methyl-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0753] Example 59 was prepared according to the procedure used for
the preparation of Example 56e, substituting
1-(4-fluorophenyl)ethanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0085 g (43%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.33 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.75 (dd, J=8.09,
1.98 Hz, 1H), 7.47 (m, 2H), 7.34 (d, J=8.24 Hz, 1H), 7.18 (m, 2H),
7.06 (s, 1H), 6.86 (m, 2H), 6.54 (m, 2H), 5.21 (q, J=7.02 Hz, 1H),
4.56 (m, 2H), 4.07 (s, 3H), 1.53 (d, J=7.02 Hz, 3H). MS (APCI+) m/z
511.1 (M+H).sup.+.
Example 60
N-(2-chloro-5-fluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-te-
trahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0754] Example 60 was prepared according to the procedure used for
the preparation of Example 56e, substituting
(2-chloro-5-fluorophenyl)methanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0044 g (22%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.40 (d, J=2.14 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J=8.09,
2.29 Hz, 1H), 7.54 (m, 1H), 7.38 (d, J=8.24 Hz, 1H), 7.21 (d,
J=8.85 Hz, 2H), 7.06 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.59 (s,
2H), 4.07 (s, 3H), 4.66 (m, 2H). MS (APCI+) m/z 531.1
(M+H).sup.+.
Example 61
N-(1-(2,4-dichlorophenyl)ethyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0755] Example 61 was prepared according to the procedure used for
the preparation of Example 56e, substituting
1-(2,4-dichlorophenyl)ethanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0082 g (38%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.34 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.75 (dd, J=8.24,
2.14 Hz, 1H), 7.59 (m, 2H), 7.45 (dd, J=8.54, 2.14 Hz, 1H), 7.35
(d, J=8.24 Hz, 1H), 7.06 (s, 1H), 6.87 (m, 2H), 6.55 (m, 2H), 5.43
(m, 1H), 4.08 (s, 3H), 4.40 (m, 2H), 1.50 (d, J=7.02 Hz, 3H). MS
(APCI+) m/z 561.1 (M+H).sup.+.
Example 62
N-((1-benzyl-1H-pyrazol-4-yl)methyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,-
4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0756] Example 62 was prepared according to the procedure used for
the preparation of Example 56e, substituting
(1-benzyl-1H-pyrazol-4-yl)methanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0089 g (42%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.32 (d, J=2.14 Hz, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.72
(dd, J=8.24, 2.14 Hz, 1H), 7.47 (s, 1H), 7.32 (m, 6H), 7.05 (s,
1H), 6.86 (m, 2H), 6.54 (m, 2H), 5.28 (s, 2H), 4.37 (s, 2H), 4.06
(s, 3H), 4.44 (m, 2H). MS (APCI+) m/z 559.2 (M+H).sup.+.
Example 63
N-benzyl-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,11--
triazadibenzo[cd,h]azulene-8-carboxamide
[0757] Example 63 was prepared according to the procedure used for
the preparation of Example 56e, substituting phenylmethanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0034 g (18%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.37 (d, J=2.14 Hz, 1H), 7.86 (s, 1H), 7.77 (dd, J=8.24,
2.14 Hz, 1H), 7.37 (m, J=4.27 Hz, 5H), 7.28 (m, 1H), 7.06 (s, 1H),
6.86 (m, 2H), 6.55 (m, 2H), 4.55 (s, 2H), 4.06 (s, 3H), 4.58 (m,
2H). MS (APCI+) m/z 479.3 (M+H).sup.+.
Example 64
N-(2,5-difluorobenzyl)-5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahy-
dro-1H-2,5,11-triazadibenzo[cd,h]azulene-8-carboxamide
[0758] Example 64 was prepared according to the procedure used for
the preparation of Example 56e, substituting
(2,5-difluorophenyl)methanamine for
(5-fluoro-2-methoxyphenyl)-methanamine, to give 0.0043 g (22%) of
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 8.37 (d, J=2.14 Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J=8.24,
2.14 Hz, 1H), 7.36 (m, 1H), 7.22 (m, 3H), 7.06 (s, 1H), 6.87 (m,
2H), 6.56 (m, 2H), 4.56 (s, 2H), 4.07 (s, 3H), 4.48 (m, 2H). MS
(APCI+) m/z 515.2 (M+H).sup.+.
Example 65
2-(5-fluoro-2-methoxyphenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,1-
1-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0759] A stock solution of Example 23e and
N,N-diisopropylethylamine (0.09 M and 0.25 M in
N,N-dimethylacetamide, respectively, 450 .mu.L, 0.2 mmol Example
23e and 0.6 mmol N,N-diisopropylethylamine),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.14 M in N,N-dimethylacetamide, 450 .mu.L,
0.3 mmol), and 2-(5-fluoro-2-methoxyphenyl)acetic acid (0.40 M in
N,N-dimethylacetamide, 125 .mu.L, 0.24 mmol) were aspirated from
their respective source vials, mixed through a perfluoroalkoxy
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 100.degree. C., and passed through the reactor at 180 .mu.L
min.sup.-1 (10 minute residence time). Upon exiting the reactor,
the reaction mixture was loaded directly into an injection loop and
purified using reverse phase HPLC (C8, acetonitrile/water (0.1%
TFA), 5-100%) to give 0.0243 g (91%) of the title compound as the
TFA salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta.
10.28 (s, 1H), 8.12 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.42 (dd,
J=8.54, 2.44 Hz, 1H), 7.20 (d, J=8.54 Hz, 1H), 7.11 (m, 2H), 7.04
(s, 1H), 7.01 (m, 1H), 6.83 (m, 2H), 6.48 (m, 2H), 5.02 (d, J=15.56
Hz, 1H), 4.18 (d, J=15.87 Hz, 1H), 4.04 (s, 3H), 3.79 (s, 3H), 3.70
(s, 2H). MS (APCI+) m/z 527.1 (M+H).sup.+.
Example 66
2-(5-fluoro-2-nitrophenyl)-N-(5-(4-fluorophenyl)-11-methyl-1-oxo-2,4,5,11--
tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0760] Example 66 was prepared according to the procedure used for
the preparation of Example 65, substituting
2-(5-fluoro-2-nitrophenyl)acetic acid for
2-(5-fluoro-2-methoxyphenyl)acetic acid, to give 0.0171 g (63%) of
the title compound as the TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 10.47 (s, 1H), 8.23 (dd, J=9.00,
5.34 Hz, 1H), 8.08 (d, J=2.44 Hz, 1H), 7.63 (s, 1H), 7.52 (dd,
J=9.46, 2.75 Hz, 1H), 7.44 (m, 1H), 7.39 (dd, J=8.54, 2.44 Hz, 1H),
7.21 (d, J=8.54 Hz, 1H), 7.04 (s, 1H), 6.83 (m, 2H), 6.49 (m, 2H),
5.02 (d, J=15.87 Hz, 1H), 4.18 (m, 3H), 4.03 (s, 3H). MS (APCI+)
m/z 542.0 (M+H).sup.+.
Example 67
8-amino-5-(2,4-difluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-t-
etraazadibenzo[cd,h]azulen-1-one
Example 67a
3-bromo-N-(2,4-difluorophenyl)-5-nitropyridin-2-amine
[0761] A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10
mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in dimethylsufoxide
(20 mL) was heated at 100.degree. C. for 2 hours. After cooling,
the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was separated, and the aqueous layer was
extracted with additional ethyl acetate twice. The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate filtered, and concentrated. The
residue was purified on silica gel eluting with 1:20 ethyl
acetate/heptanes to give the title compound (1.75 g, 5.30 mmol,
53.0% yield) as yellow crystals.
Example 67b
N-(2,4-difluorophenyl)-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl-
)-5-nitropyridin-2-amine
[0762] A mixture of Example 1b (0.1 g, 0.347 mmol), Example 67a
(0.137 g, 0.416 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.012 g, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0)
(9.53 mg, 10.41 .mu.mol), and potassium phosphate (0.184 g, 0.868
mmol) in dioxane (2 mL) and water (0.5 mL) was degassed and
back-filled with nitrogen several times. The reaction was heated at
60.degree. C. for 4 hours, during which time a solid formed. The
reaction mixture was partitioned between water and ethyl acetate.
Enough ethyl acetate was used to dissolve the solid completely. The
aqueous layer was extracted with additional ethyl acetate twice.
The combined organic layers were washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue triturated with 1:1 ethyl
acetate/hexanes to give the title compound (0.095 g, 0.231 mmol,
66.5% yield).
Example 67c
[0763] A mixture of Example 67b (0.09 g, 0.219 mmol) and hydrogen
chloride (5.47 mL, 21.88 mmol, 4 M) in dioxane (10 mL) was heated
at 90.degree. C. overnight. The solvent was evaporated to give the
title compound, which was used directly for the next reaction.
Example 67d
5-(2,4-difluorophenyl)-11-methyl-8-nitro-2,4,5,11-tetrahydro-1H-2,5,6,11-t-
etraazadibenzo[cd,h]azulen-1-one
[0764] A mixture of Example 67c (0.09 g, 0.227 mmol) and
formaldehyde (0.034 g, 1.133 mmol) in acetic acid (5 mL) was heated
at 100.degree. C. for three days. The solvent was removed under
reduced pressure to give the crude product, which was used for the
next reaction directly.
Example 67e
8-amino-5-(2,4-difluorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-t-
etraazadibenzo[cd,h]azulen-1-one
[0765] A mixture of Example 67d, iron powder (0.061 g, 1.099 mmol),
and ammonia hydrochloride (0.024 g, 0.440 mmol) in tetrahydrofuran
(2 mL), water (0.2 mL) and ethanol (2 mL) was heated at 90.degree.
C. for 2 hours. The solid was filtered off, and washed with ethyl
acetate several times. The eluant was then poured into water. The
organic layer was separated, and the aqueous layer was extracted
with ethyl acetate several times. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA),
0-100%) to give the title compound as a bis TFA salt (0.045 g,
0.074 mmol, 33.7% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.83 (d, J=5.8 Hz, 1H), 7.83 (s, 1H), 7.68 (m, 1H), 7.59
(d, J=2.75 Hz, 1H), 7.10-7.16 (m, 1H), 6.90-7.02 (m, 2H), 6.82 (d,
J=5.8 Hz, 1H), 4.62 9S, 2 h), 4.12 (s, 3H). MS (DCI+) m/z 380.1
(M+H).sup.+.
Example 68
N-(5-(2,4-difluorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11--
tetraazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide
[0766] A mixture of Example 67e (0.045 g, 0.074 mmol),
ethanesulfonyl chloride (0.038 g, 0.296 mmol), and triethylamine
(0.060 g, 0.593 mmol) in dichloromethane (3 mL) was stirred at
ambient temperature for 3 hours. The solvent was evaporated, and
the residue was taken up in dioxane (4 mL) and 2.0 N NaOH (2 mL).
The reaction mixture was heated at 90.degree. C. for 1 hour. The
solvents were partially removed, and the residue was partitioned
between water and ethyl acetate. The aqueous layer was neutralized
with 10% HCl and extracted with additional ethyl acetate twice. The
combined organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%) to
afford 0.029 g (67%) of the title compound as a mono TFA salt.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.78 (d, J=5.49, 1H),
9.75 (s, 1H), 7.91 (d, J=2.44 Hz, 1H), 7.83 (s, 1H), 7.80 (d,
J=2.44 Hz, 1H), 7.23-7.33 (m, 1H), 7.11-7.16 (m, 1H), 7.01-7.05 (m,
1H), 6.81 (d, J=5.49 Hz, 1H), 4.61 (s, 2H), 4.14 (s, 3H), 3.12 (q,
J=7.43 Hz, 2H), 1.25 (t, J=7.32 Hz, 3H). MS (DCI+) m/z 472.1
(M+H).sup.+.
Example 69
8-amino-5-(4-chlorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetra-
azadibenzo[cd,h]azulen-1-one
Example 69a
3-bromo-N-(4-chlorophenyl)-5-nitropyridin-2-amine
[0767] A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10
mmol) and 4-chloroaniline (2.55 g, 20.00 mmol) in dimethylsulfoxide
(20 mL) was heated at 90.degree. C. for 2 hours. After cooling to
ambient temperature, the reaction mixture was partitioned between
water and ethyl acetate. The organic layer was separated, and the
aqueous layer was extracted with additional ethyl acetate twice.
The combined organic layers were washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue was purified on silica gel eluting
with 1:20 ethyl acetate/heptanes to give the crude product. This
material was then triturated with 10% ethyl acetate in heptanes to
give title compound (2.25 g, 6.85 mmol, 68.5% yield).
Example 69b
N-(4-chlorophenyl)-3-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-5--
nitropyridin-2-amine
[0768] A mixture of Example 1b (0.2 g, 0.694 mmol), Example 69a
(0.274 g, 0.833 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.024 g, 0.081 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.019 g, 0.021 mmol), and potassium phosphate (0.368 g, 1.735
mmol) in dioxane (4 mL) and water (1 mL) was degassed and
back-filled with nitrogen several times. The reaction mixture was
heated at 60.degree. C. for 4 hours. The reaction mixture was
partitioned between water and ethyl acetate. The aqueous layer was
extracted with additional ethyl acetate three times. The combined
organic layers were washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel eluting with 60% ethyl acetate in hexanes to give the title
product (0.25 g, 0.610 mmol, 88% yield).
Example 69c
3-(2-((4-chlorophenyl)amino)-5-nitropyridin-3-yl)-1-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0769] A mixture of Example 69b (0.25 g, 0.610 mmol) and hydrogen
chloride (12.20 mL, 48.8 mmol, 4 M in dioxane) was heated at
90.degree. C. overnight. The reaction mixture was cooled to ambient
temperature, and the solvent was removed under reduced pressure to
give the crude product, which was used directly for the next
reaction.
Example 69d
[0770] A mixture of Example 69c (0.250 g, 0.632 mmol) and
formaldehyde (0.095 g, 3.16 mmol) in acetic acid (15 mL) was heated
at 90.degree. C. for 2 hours. The reaction mixture was cooled to
ambient temperature. The solvent was removed under reduced pressure
to give the crude product, which was used directly for the next
reaction.
Example 69e
8-amino-5-(4-chlorophenyl)-11-methyl-2,4,5,11-tetrahydro-1H-2,5,6,11-tetra-
azadibenzo[cd,h]azulen-1-one
[0771] A mixture of Example 69d (0.25 g, 0.613 mmol), iron (0.171
g, 3.07 mmol), and ammonia hydrochloride (0.066 g, 1.226 mmol) in
tetrahydrofuran (5 mL), water (1 mL) and ethanol (5 mL) was heated
at 90.degree. C. for 2 hours. The solid was filtered off, and
washed with ethyl acetate several times. The eluant was then poured
into water. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate several times. The combined
organic layers were washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was purified by flash chromatography on silica gel
eluting with 20% methanol in ethyl acetate to give the title
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.90 (d,
J=5.49, 1H), 7.76-7.77 (m, 2H), 7.61 (d, J=1.83 Hz, 1H), 7.05-7.09
(m, 1H), 6.55 (d, J=9.16 Hz, 2H), 4.88 (s, 2H), 4.06 (s, 3H). MS
(DCI+) m/z 378.2 (M+H).sup.+.
Example 70
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide
[0772] A mixture of Example 69e (0.04 g, 0.106 mmol),
ethanesulfonyl chloride (0.054 g, 0.2423 mmol), and triethylamine
(0.064 g, 0.635 mmol) in dichloromethane (3 mL) was stirred at
ambient temperature for 2 hours. The solvent was removed, and the
residue was treated with dioxane (3 mL) and 2.0 N NaOH (2 mL). The
reaction mixture was heated at 90.degree. C. for 2 hours. The
solvents were partially removed, and the residue was partitioned
between water and ethyl acetate. The aqueous layer was neutralized
with 10% HCl and extracted with additional ethyl acetate twice. The
combined organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%) to
afford 0.035 g (56.6%) of the title compound as the TFA salt.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.87 (d, J=5.8, 1H),
10.15 (s, 1H), 8.17 (d, J=2.75 Hz, 1H), 8.00 (d, J=2.75 Hz, 1H),
7.82 (s, 1H), 7.09 (d, J=5.8 Hz, 1H), 7.03-7.07 (m, 2H), 6.58-6.62
(m, 2H), 4.62 (s, 2H), 4.07 (s, 3H), 3.26 (q, J=7.32 Hz, 2H), 1.29
(t, J=7.32 Hz, 3H). MS (DCI+) m/z 470.1 (M+H).sup.+.
Example 71
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-8-yl)methanesulfonamide
[0773] Example 71 was prepared according to the procedure used for
the preparation of Example 68, substituting Example 69e for Example
67e, and methanesulfonyl chloride for ethanesulfonyl chloride,
respectively, to provide the mono TFA salt of the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.88 (d, J=5.49, 1H),
10.11 (s, 1H), 8.17 (d, J=2.44 Hz, 1H), 8.01 (d, J=2.44 Hz, 1H),
7.83 (s, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.03-7.07 (m, 2H), 6.59-6.63
(m, 2H), 4.63 (s, 2H), 4.07 (s, 3H), 3.17 (s, 3H). MS (DCI+) m/z
456.1 (M+H).sup.+.
Example 72
N-(5-(4-chlorophenyl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,6,11-tetr-
aazadibenzo[cd,h]azulen-8-yl)acetamide
[0774] A mixture of Example 69e (0.02 g, 0.053 mmol), triethylamine
(53.6 mg, 0.53 mmol), and acetyl chloride (0.019 mL, 0.265 mmol) in
dichloromethane (2 mL) was stirred at ambient temperature for 2
hours. Additional acetyl chloride (0.057 mL, 0.795 mmol) and
triethylamine (161 mg, 1.59 mmol) were added, and the reaction
mixture was stirred for additional 3 hours. The solvent was
evaporated, and the residue was treated with dioxane (3 mL) and 2.0
NaOH (1 mL). The reaction mixture was heated at 80.degree. C. for
three hours. The solvents were partially removed, and the residue
was partitioned between water and ethyl acetate. The aqueous layer
was neutralized with 10% HCl and extracted with additional ethyl
acetate twice. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by reverse phase HPLC (C18, CH.sub.3CN/water
(0.1% TFA), 0-100%) to afford 0.018 g (67.3%) of the title compound
as the TFA salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.87
(d, J=5.8, 1H), 10.31 (s, 1H), 8.53 (d, J=2.75 Hz, 1H), 8.42 (d,
J=2.44 Hz, 1H), 7.74 (s, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.03-7.07
(m, 2H), 6.57-6.60 (m, 2H), 4.65 (br s, 2H), 4.07 (s, 3H), 2.13 (s,
3H). MS (DCI+) m/z 420.2 (M+H).sup.+.
Example 73
5-(1-acetylpiperidin-4-yl)-8-amino-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-1-one
Example 73a
1-(4-((2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-nitrophenyl)-
amino)piperidin-1-yl)ethanone
[0775] Example 23a (0.1 g, 0.332 mmol) and
1-(4-aminopiperidin-1-yl)ethanone (0.052 g, 0.365 mmol) were
dissolved in dimethyl sulfoxide (0.6 mL), treated with
N-ethyl-N-isopropylpropan-2-amine (0.29 mL, 1.66 mmol) and stirred
at 90.degree. C. overnight. Additional
1-(4-aminopiperidin-1-yl)ethanone (0.052 g, 0.365 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.29 mL, 1.66 mmol) were added
and heating was continued at 90.degree. C. for another 24 hours.
The reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride, treated with mercapto-functionalized silica gel for 20
minutes, dried over anhydrous magnesium sulfate, filtered through a
plug of Celite and concentrated. The residue was purified by flash
chromatography (silica gel, 0-7% methanol in dichloromethane) to
provide 0.156 g (>100%) of the title compound with ethyl acetate
as an excipient.
Example 73b
3-(2-((1-acetylpiperidin-4-yl)amino)-5-nitrophenyl)-1-methyl-1H-pyrrolo[2,-
3-c]pyridin-7(6H)-one
[0776] Example 73a (0.99 g, 2.16 mmol) was dissolved in 1,4-dioxane
(5 mL) and treated with hydrogen chloride solution (4 M in
1,4-dioxane) (10.8 mL, 43.2 mmol). The mixture was stirred for 10
minutes at 80.degree. C. Methanol (1 mL) was added and heating was
continued at 80.degree. C. for two hours. The reaction mixture was
concentrated to dryness. The residue was converted to the free base
using a Varian ion exchange Bond Elut Plex column (1-7 N ammonia in
methanol). The material from the ion exchange procedure was
concentrated, slurried in methanol, and the solid collected by
filtration to give 0.092 g (>100%) of the title compound as the
ammonium salt.
Example 73c
5-(1-acetylpiperidin-4-yl)-11-methyl-8-nitro-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-1-one
[0777] To Example 73b (0.41 g, 1 mmol) and paraformaldehyde (0.06
g, 2 mmol) in a 20-mL microwave vial was added acetic acid (5 mL).
The vial was capped and heated at 90.degree. C. for 1 hour. The
reaction mixture was concentrated and dried under high vacuum to
give the title compound.
Example 73d
5-(1-acetylpiperidin-4-yl)-8-amino-11-methyl-2,4,5,11-tetrahydro-1H-2,5,11-
-triazadibenzo[cd,h]azulen-1-one
[0778] To Example 73c (0.421 g, 1 mmol) in tetrahydrofuran (4 mL),
ethanol (2 mL) and water (1 mL) was added zinc dust (0.981 g, 15
mmol) and ammonium chloride (0.535 g, 10 mmol). The mixture was
stirred for 45 minutes at ambient temperature. The reaction mixture
was filtered through Celite rinsing with tetrahydrofuran and
methanol. The filtrate was concentrated and partitioned between
ethyl acetate and water. The aqueous layer was exhaustively
extracted with ethyl acetate and combinations of dichloromethane
and isopropanol. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 0-20% methanol in
dichloromethane) to give 0.1 g (24%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.71 (d, J=5.19 Hz, 1H), 7.52
(s, 1H), 6.80 (d, J=2.44 Hz, 1H), 6.77 (dd, J=8.39, 1.68 Hz, 1H),
6.72 (d, J=5.19 Hz, 1H), 6.31 (dd, J=8.24, 2.75 Hz, 1H), 4.84 (s,
2H), 4.15 (m, 2H), 4.10 (s, 3H), 3.82 (d, J=15.87 Hz, 1H), 3.64
(dd, J=27.77, 13.73 Hz, 1H), 2.77 (m, 2H), 2.38 (m, 1H), 1.88 (m,
4H), 1.17 (m, 3H). MS (ESI+) m/z 392.2 (M+H).sup.+.
Example 74
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)ethanesulfonamide
[0779] Example 73d (0.02 g, 0.051 mmol) in pyridine (0.5 mL) was
treated sequentially with ethanesulfonyl chloride (0.015 ml, 0.153
mmol) and N,N-dimethylpyridin-4-amine (0.00156 g, 0.013 mmol). The
mixture was stirred at ambient temperature for 2 hours and 20
minutes. Ethanol (0.5 mL) and potassium carbonate (0.071 g, 0.511
mmol) were added and the mixture was stirred at ambient temperature
for 4.5 hours and then at 50.degree. C. overnight. The reaction
mixture was cooled to room temperature, partitioned between ethyl
acetate and water, washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was purified by flash chromatography (silica gel, 0-10%
methanol in dichloromethane) to give 0.0094 g (38%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.73 (d,
J=5.49 Hz, 1H), 9.59 (s, 1H), 7.56 (s, 1H), 7.44 (d, J=2.44 Hz,
1H), 7.06 (d, J=8.54 Hz, 1H), 6.92 (dd, J=8.39, 2.59 Hz, 1H), 6.77
(d, J=5.80 Hz, 1H), 4.25 (t, J=13.89 Hz, 2H), 4.11 (s, 3H), 3.72
(m, 2H), 3.07 (m, J=7.32, 7.32, 7.32 Hz, 3H), 2.87 (m, 1H), 2.42
(t, J=12.05 Hz, 1H), 1.93 (s, 3H), 1.75 (m, 1H), 1.30 (m, 3H), 1.23
(t, J=7.32 Hz, 3H). MS (ESI+) m/z 484.2 (M+H).sup.+.
Example 75
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)-2-(2-methylthiazol-5-yl)acetamide
[0780] A mixture of Example 73d (0.02 g, 0.051 mmol),
2-(2-methylthiazol-5-yl)acetic acid (0.012 g, 0.077 mmol), and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.029 g, 0.077 mmol) in N,N-dimethyl
acetamide (0.5 mL) was treated with
N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.153 mmol) and
stirred at ambient temperature for 22 hours. The reaction mixture
was partitioned between ethyl acetate and water and washed with
saturated aqueous sodium chloride. The aqueous layers were
combined, saturated with solid sodium chloride and extracted with
ethyl acetate (4.times.100 mL). The organic layers were combined,
dried over anhydrous magnesium sulfate, filtered and concentrated.
The residue was purified by flash chromatography (silica gel, 0-15%
methanol in dichloromethane). The material was further purified by
reverse phase HPLC (C18, acetonitrile/water (0.1% TFA), 10-100%) to
provide 0.0258 g (78%) of the title compound as the TFA salt.
.sup.1H NMR (400 MHz, PYRIDINE-d.sub.5) .delta. 11.24 (s, 1H),
10.34 (s, 1H), 8.34 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.54 (d,
J=2.75 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.54 Hz, 1H), 6.89 (s,
1H), 4.20 (s, 2H), 4.13 (s, 3H), 4.07 (s, 2H), 3.64 (m, 1H), 3.25
(m, 1H), 2.63 (m, 2H), 2.55 (s, 3H), 2.59 (m, 1H), 1.93 (s, 3H),
1.69 (m, 2H), 1.50 (m, 2H). MS (ESI+) m/z 531.1 (M+H).sup.+.
Example 76
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)-2-(2-chloro-5-fluorophenyl)acetamide
[0781] Example 73d (0.02 g, 0.051 mmol) in dichloromethane (0.5 mL)
was treated with a solution of 2-(2-chloro-5-fluorophenyl)acetyl
chloride (0.022 g, 0.106 mmol) in dichloromethane (0.2 mL) and
triethylamine (0.025 mL, 0.179 mmol) and stirred at ambient
temperature for 22 hours. The reaction mixture was concentrated.
The residue was purified by flash chromatography (silica gel, 0-10%
methanol in dichloromethane). It was further purified by reverse
phase HPLC (C18, acetonitrile/water (0.1% TFA), 0-90%) to provide
0.0228 g (66%) of the title compound as the TFA salt. .sup.1H NMR
(400 MHz, PYRIDINE-d.sub.5) .delta. 11.20 (s, 1H), 10.31 (s, 1H),
8.38 (d, J=2.44 Hz, 1H), 7.55 (dd, J=8.54, 2.44 Hz, 1H), 7.42 (dd,
J=9.46, 3.05 Hz, 1H), 7.32 (m, 2H), 7.21 (d, J=8.54 Hz, 1H), 6.93
(m, 1H), 6.89 (s, 1H), 4.50 (m, 1H), 4.20 (s, 2H), 4.13 (s, 3H),
4.04 (m, 2H), 3.65 (s, 1H), 3.25 (m, 1H), 2.62 (m, 2H), 1.93 (s,
3H), 1.69 (m, 2H), 1.49 (m, J=23.42, 11.83, 4.12 Hz, 2H). MS (ESI+)
m/z 562.1 (M+H).sup.+.
Example 77
N-(5-(1-acetylpiperidin-4-yl)-11-methyl-1-oxo-2,4,5,11-tetrahydro-1H-2,5,1-
1-triazadibenzo[cd,h]azulen-8-yl)acetamide
[0782] Example 23d (0.0278 g, 0.071 mmol) was treated with a
solution of acetyl chloride (0.0101 mL, 0.142 mmol) in
dichloromethane (1.5 mL), followed by triethylamine (0.059 mL,
0.426 mmol). The resulting mixture was stirred at ambient
temperature for 2.5 hours and then concentrated. The residue was
purified by flash chromatography (silica gel, 0-17% methanol in
dichloromethane). It was further purified by reverse phase HPLC
(C18, acetonitrile/water (0.1% TFA), 0-100%) to provide 0.0296 g
(78%) of the title compound as the TFA salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.42 (s, 1H), 9.54 (s, 1H), 7.86 (d, J=2.44
Hz, 1H), 7.48 (s, 1H), 7.22 (dd, J=8.54, 2.44 Hz, 1H), 7.05 (d,
J=8.54 Hz, 1H), 6.74 (s, 1H), 4.26 (m, 1H), 4.12 (s, 3H), 4.08 (m,
2H), 3.76 (m, 2H), 3.09 (m, 1H), 2.79 (m, 1H), 2.04 (s, 3H), 1.91
(s, 3H), 1.57 (m, 2H), 1.36 (m, J=1.22 Hz, 2H). MS (ESI+) m/z 434.1
(M+H).sup.+.
Example 78
6-cyclopropyl-5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)--
2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 78a
1-bromo-4-((methylsulfonyl)methyl)benzene
[0783] A 250 mL round-bottomed flask was charged with 4-bromobenzyl
bromide (5 g, 20 mmol) and N,N-dimethylformamide (10.81 mL). Sodium
methanesulfinate (3.06 g, 30 mmol) was added. The reaction mixture
was stirred at 65.degree. C. for 1 hour. The reaction mixture was
cooled to ambient temperature and diluted with water. The resulting
suspension was stirred for 10 minutes and filtered. The solid was
rinsed with water and dried under house vacuum over the weekend to
provide 4.75 g (95%) of the title compound.
Example 78b
2,4-difluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline
[0784] A 100 mL microwave tube was charged with 2,4-difluoroaniline
(1.235 mL, 12.26 mmol), Example 78a (3.05 g, 12.26 mmol),
diacetoxypalladium (0.055 g, 0.245 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1',1'-biphenyl]-2-yl)phosphine
(0.234 g, 0.49 mmol), cesium carbonate (5.59 g, 17.16 mmol),
toluene (40.9 mL) and t-butanol (8.17 mL). The tube was sealed, and
the reaction mixture was heated in a Milestone Ethos microwave, 5
minute ramp to 150.degree. C., then 10 minutes fixed hold time. The
reaction mixture was filtered through a 10 g Celite SPE column and
rinsed with ethyl acetate. The filtrate was concentrated. The
residue was purified by flash chromatography (20-100% ethyl acetate
in heptanes) to provide 3.44 g (94%) of the title compound.
Example 78c
2-bromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline
[0785] A 500 mL round-bottomed flask was charged with Example 78b
(3.44 g, 11.57 mmol) and acetic acid (116 mL). The reaction mixture
was placed into a water bath. N-bromosuccinimide (2.06 g, 11.57
mmol) was added in 2 portions 10 minutes apart. The reaction
mixture was stirred at ambient temperature for 1.5 hours. The
reaction mixture was quenched with 200 mL 10% aqueous sodium
thiosulfate solution and diluted with water. The reaction mixture
was extracted twice with ethyl acetate. The combined organic layers
were washed twice with 2 N aqueous sodium hydroxide solution (until
the pH of the aqueous was >7) and once with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate,
filtered and concentrated. The residue was taken up into ethyl
acetate, then treated with heptanes. The resulting slurry was
stirred for 30 minutes and filtered to provide 3.82 g (88% yield)
of the title compound.
Example 78d
2-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline
[0786] A 5 mL microwave vial was charged with Example 78c (0.2287
g, 0.608 mmol), cyclopropylboronic acid (0.209 g, 2.432 mmol),
cesium carbonate (0.99 g, 3.04 mmol) and
bis(triphenylphosphine)palladium(II) dichloride (0.021 g, 0.03
mmol). The tube was sealed and the mixture was sparged with
nitrogen for 30 minutes. Degassed 1,4-dioxane (2.53 mL) and water
(0.507 mL) were added. The reaction mixture was heated at
100.degree. C. overnight. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography (silica gel, 10-70% ethyl acetate
in heptanes) to provide 0.143 g (70%) of the title compound.
Example 78e
2-bromo-6-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)ani-
line
[0787] Example 78e was prepared according to the procedure used for
the preparation of Example 78c, substituting Example 78d for
Example 78b, to provide 0.111 g (63%) of the title compound.
Example 78f
2-cyclopropyl-N-(2,4-difluorophenyl)-6-(7-methoxy-1-methyl-1H-pyrrolo[2,3--
c]pyridin-3-yl)-4-((methylsulfonyl)methyl)aniline
[0788] Example 1b (0.066 g, 0.228 mmol), Example 78e (0.1 g, 0.24
mmol), tris(dibenzylideneacetone)dipalladium(0) (0.00627 g, 0.00685
mmol),
(1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamanta-
ne (0.00667 g, 0.023 mmol) and sodium carbonate (0.104 g, 0.982
mmol) were combined and sparged with nitrogen for 30 minutes. To
this were added nitrogen-sparged 1,4-dioxane (1.1 mL) and water
(0.275 mL) via syringe. The reaction mixture was stirred at
60.degree. C. for 5 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, treated with
3-mercaptopropyl-functionalized silica gel for 20 minutes, dried
over anhydrous magnesium sulfate, filtered through a plug of Celite
and concentrated. The residue was purified by flash chromatography
(silica gel, 0-10% ethyl acetate in dichloromethane) to give 0.0941
g (83%) of the title compound.
Example 78g
3-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)p-
henyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0789] Example 78f (0.094 g, 0.189 mmol) in methanol (2 mL) was
treated with hydrogen chloride solution (4 M in 1,4-dioxane) (0.945
mL, 3.78 mmol) and heated at 90.degree. C. for 3.67 hours. The
reaction mixture was cooled to ambient temperature and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-6% methanol in dichloromethane) to give 0.1 g
(>100%) of the title compound.
Example 78h
6-cyclopropyl-5-(2,4-difluorophenyl)-11-methyl-8-((methylsulfonyl)methyl)--
2,4,5,11-tetrahydro-1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0790] To a 5-mL microwave vial equipped with a magnetic stirbar
was added Example 78g (0.0541 g, 0.112 mmol), paraformaldehyde
(0.02 g, 0.671 mmol), and acetic acid (5 mL). The vial was capped
and heated at 70.degree. C. for 45 minutes. The reaction mixture
was concentrated. The residue was purified by reverse phase HPLC
(C18, acetonitrile/water (0.1% TFA), 10-90%). The material was then
taken up in tetrahydrofuran (1 mL) and methanol (0.1 mL), treated
with sodium hydroxide solution (4 M aqueous) (0.048 mL, 0.191 mmol)
and heated at 70.degree. C. for 2 hours. The reaction mixture was
cooled to ambient temperature and neutralized with hydrochloric
acid solution (2 M aqueous). The resulting mixture was partitioned
between ethyl acetate and water, washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered
and concentrated to provide 0.019 g (33.9%) of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.73 (d, J=5.19 Hz,
1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.06 (m, 1H), 6.83 (s, 1H), 6.75
(d, J=5.19 Hz, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.03 (d, J=16.17
Hz, 1H), 4.44 (m, 2H), 4.21 (d, J=16.17 Hz, 1H), 4.09 (s, 3H), 2.94
(s, 3H), 2.01 (m, 1H), 0.83 (m, 1H), 0.67 (m, 1H), 0.58 (m, 1H),
0.23 (m, 1H). MS (ESI+) m/z 496.1 (M+H).sup.+.
Example 79
11-methyl-8-((methylsulfonyl)methyl)-5-(pyridin-2-yl)-2,4,5,11-tetrahydro--
1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
Example 79a
N-(2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-((methylsulfonyl-
)methyl)phenyl)pyridin-2-amine
[0791] Example 4a (0.05 g, 0.145 mmol), 2-bromopyridine (0.028 mL,
0.29 mmol), diacetoxypalladium (0.0016 g, 0.00724 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.0069 g, 0.014 mmol), and cesium carbonate (0.094 g, 0.29 mmol)
were combined in a 5-mL microwave vial. Toluene (1.2 mL) and
t-butanol (0.3 mL) were added. The vial was capped and the mixture
was reacted at 150.degree. C. for 30 minutes in a Biotage microwave
reactor. Additional 2-bromopyridine (0.028 mL, 0.29 mmol),
diacetoxypalladium (0.0016 g, 0.00724 mmol) and
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.0069 g, 0.014 mmol) were added and the mixture was reacted in a
Biotage microwave reactor for another 40 minutes at 150.degree. C.
The reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride, treated with 3-mercaptopropyl-functionalized silica gel
for 20 minutes, dried over anhydrous magnesium sulfate, filtered
through a plug of Celite and concentrated. The residue was purified
by flash chromatography (silica gel, 0-90% ethyl acetate in
dichloromethane) to give 0.04 g (65.4%) of the title compound.
Example 79b
1-methyl-3-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyr-
rolo[2,3-c]pyridin-7(6H)-one
[0792] A mixture of Example 79a (0.062 g, 0.147 mmol) in methanol
(1 mL) was treated with hydrogen chloride solution (4 M in
1,4-dioxane) (1 mL, 4 mmol) and heated at 75.degree. C. for 2.5
hours. Additional hydrogen chloride solution (4 M in 1,4-dioxane)
(1 mL, 4 mmol) was added and heating was continued for another 3.5
hours. The reaction mixture was concentrated to dryness to provide
0.06 g (92%) of the title compound as the HCl salt.
Example 79c
11-methyl-8-((methylsulfonyl)methyl)-5-(pyridin-2-yl)-2,4,5,11-tetrahydro--
1H-2,5,11-triazadibenzo[cd,h]azulen-1-one
[0793] A mixture of Example 79b (0.06 g, 0.135 mmol) and
paraformaldehyde (0.066 g, 2.2 mmol) in acetic acid (1 mL) was
heated at 85.degree. C. for 1 hour. The reaction mixture was
concentrated to 1/3 of the original volume, treated with sodium
hydroxide solution (4 M aqueous) (0.169 mL, 0.674 mmol) until pH 10
was obtained and stirred overnight at ambient temperature. The
mixture was heated at 50.degree. C. for 1 hour, basified further to
pH 12 and heated at 70.degree. C. for 3 hours. The mixture was
cooled to ambient temperature, neutralized with hydrochloric acid
solution (2 M aqueous) and partitioned between ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate. The
organic layers were combined and concentrated. The residue was
purified by reverse phase HPLC (C18, acetonitrile/water (0.1% TFA),
0-45%) to provide 0.013 g (18%) of the title compound as the TFA
salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.86 (d, J=5.19
Hz, 1H), 8.00 (d, J=4.88 Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.54
(s, 1H), 7.41 (m, 1H), 7.35 (m, 1H), 7.00 (d, J=5.19 Hz, 1H), 6.70
(m, 1H), 6.54 (s, 1H), 5.52 (d, J=15.56 Hz, 1H), 4.56 (m, 2H), 4.19
(d, J=15.26 Hz, 1H), 4.08 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z
421.1 (M+H).sup.+.
Example 80
tert-butyl
4-(11-methyl-8-((methylsulfonyl)methyl)-1-oxo-1H-2,5,11-triazad-
ibenzo[cd,h]azulen-5(2H,4H,11H)-yl)piperidine-1-carboxylate
[0794] To a mixture of Example 6a (0.015 g, 0.044 mmol) and
tert-butyl 4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was
added dichloroethane (1 mL) and acetic acid (0.03 mL, 0.524 mmol).
The reaction mixture was heated at 50.degree. C. for 2 hours,
treated with sodium triacetoxyhydroborate (0.028 g, 0.131 mmol) and
heated overnight at 50.degree. C. Additional tert-butyl
4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was added and
the mixture was heated for 1 hour. Additional sodium
triacetoxyhydroborate (0.028 g, 0.131 mmol) was added and the
mixture was heated over a second night at 50.degree. C. The
reaction mixture was cooled to ambient temperature, partitioned
between ethyl acetate and water, washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered
and concentrated. The residue was purified by flash chromatography
(silica gel, 0-6% methanol in dichloromethane) to give 0.0194 g
(84%) of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.71 (d, J=5.49 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.13
(s, 1H), 6.79 (d, J=5.49 Hz, 1H), 4.40 (m, 2H), 4.11 (s, 3H), 3.87
(m, 2H), 3.73 (m, 1H), 3.63 (m, 1H), 3.19 (m, 1H), 2.91 (s, 3H),
2.66 (m, 2H), 1.67 (m, 1H), 1.58 (m, 1H), 1.45 (m, 2H), 1.38 (s,
9H), 1.23 (m, 1H). MS (ESI+) m/z 526.8 (M+H).sup.+.
Example 81
methyl
11-methyl-8-((methylsulfonyl)methyl)-1-oxo-4,11-dihydro-1H-2,5,11-t-
riazadibenzo[cd,h]azulene-5(2H)-carboxylate
[0795] A mixture of Example 6a (0.0145 g, 0.042 mmol) in
N,N-dimethylacetamide (0.5 mL) was treated sequentially with methyl
carbonochloridate (0.016 mL, 0.211 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.074 mL, 0.422 mmol) and
stirred overnight at ambient temperature. The reaction mixture was
then diluted with methanol (1.2 mL), treated with sodium carbonate
(0.011 g, 0.105 mmol) and stirred at ambient temperature for 4
hours. The reaction mixture was partitioned between ethyl acetate
and water and washed with saturated aqueous sodium chloride. The
aqueous layers were combined and exhaustedly extracted with ethyl
acetate. The combined organic layers were dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by reverse phase HPLC (C18, acetonitrile/water (0.1% TFA),
0-50%) to provide 0.0069 g (40.7%) of the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.51 (s, 1H), 7.76 (d, J=1.53
Hz, 1H), 7.69 (s, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.79 (s, 1H),
5.00 (d, J=15.56 Hz, 1H), 4.44 (m, 2H), 4.12 (s, 3H), 3.94 (d,
J=15.26 Hz, 1H), 3.50 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 402.1
(M+H).sup.+.
Example 82
N-(11-methyl-1-oxo-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadi-
benzo[cd,h]azulen-8-yl)ethanesulfonamide
Example 82a
N-(2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-nitrophenyl)pyri-
din-2-amine
[0796] A mixture of Example 23a (0.122 g, 0.405 mmol) and
2-aminopyridine (0.042 g, 0.445 mmol) in dimethyl sulfoxide (6 mL)
was treated with potassium 2-methylpropan-2-olate (0.091 g, 0.81
mmol) and stirred at ambient temperature for 23.5 hours. The
reaction mixture was partitioned between ethyl acetate and water,
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography (silica gel, 0-15% ethyl acetate
in dichloromethane) to give 0.117 g (77%) of the title
compound.
Example 82b
1-methyl-3-(5-nitro-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin--
7(6H)-one
[0797] A mixture of Example 82a (0.1163 g, 0.31 mmol) in methanol
(3.1 mL) was treated with hydrogen chloride solution (4 M in
1,4-dioxane) (1.55 mL, 6.2 mmol) and heated at 75.degree. C.
overnight and then for another 10 hours at 67.degree. C. The
reaction mixture was concentrated to give 0.151 g (>100%) of the
title compound as the HCl salt
Example 82c
11-methyl-8-nitro-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadib-
enzo[cd,h]azulen-1-one
[0798] To a 20-mL microwave vial equipped with a magnetic stirbar
was added Example 82b (0.132 g, 0.365 mmol), paraformaldehyde
(0.033 g, 1.1 mmol), and acetic acid (6 mL). The vial was capped
and heated at 75.degree. C. for 1 hour and 25 minutes. The reaction
mixture was concentrated, diluted with 1,4-dioxane, treated with
sodium hydroxide solution (4 N aqueous) (1.83 mL, 7.3 mmol) and
heated at 75.degree. C. for 1 hour. The reaction mixture was cooled
to ambient temperature and neutralized with hydrochloric acid
solution (2 N aqueous). The resulting mixture was partitioned
between ethyl acetate and water, washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered
and concentrated to give 0.104 g (76%) of the title compound as an
impure mixture.
Example 82d
8-amino-11-methyl-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadib-
enzo[cd,h]azulen-1-one
[0799] A mixture of Example 82c (0.09 g, 0.241 mmol), zinc dust
(0.236 g, 3.62 mmol) and ammonium chloride (0.129 g, 2.411 mmol) in
tetrahydrofuran (2.6 mL), ethanol (1.3 mL), and water (0.65 mL) was
stirred at ambient temperature for 1 hour and then filtered to
remove the solid. The filtrate was concentrated and then slurried
in water. The solid was collected by filtration and dried in a
vacuum oven at 70.degree. C. to give 0.0732 g (88%) of the title
compound as an impure mixture.
Example 82e
N-(11-methyl-1-oxo-5-(pyridin-2-yl)-2,4,5,11-tetrahydro-1H-2,5,11-triazadi-
benzo[cd,h]azulen-8-yl)ethanesulfonamide
[0800] A mixture of Example 82d (0.09 g, 0.262 mmol) in
dichloroethane (2 mL) and 1,4-dioxane (4 mL) was treated with
ethanesulfonyl chloride (0.075 mL, 0.786 mmol) and triethylamine
(0.183 mL, 1.31 mmol). The mixture was stirred at ambient
temperature overnight and then concentrated. The mixture was
redissolved in 1,4-dioxane (4 mL), treated with sodium hydroxide
solution (4 M aqueous) (0.655 ml, 2.62 mmol) and heated at
50.degree. C. for 1.75 hours. The mixture was then cooled to
ambient temperature and neutralized with hydrochloric acid solution
(2 M aqueous). The mixture was partitioned between ethyl acetate
and water. The aqueous layer was extracted with ethyl acetate
(2.times.60 mL). The organic layers were combined, dried over
anhydrous magnesium sulfate, filtered and concentrated. The residue
was purified by reverse phase HPLC (C18, acetonitrile/water (0.1%
TFA), 10-60%) to provide 0.0477 g (33%) of the title compound as
the TFA salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.48 (s,
1H), 9.56 (s, 1H), 7.98 (dd, J=5.19, 1.22 Hz, 1H), 7.64 (d, J=2.44
Hz, 1H), 7.58 (s, 1H), 7.41 (m, 1H), 7.27 (d, J=8.54 Hz, 1H), 7.13
(dd, J=8.54, 2.44 Hz, 1H), 6.90 (s, 1H), 6.60 (dd, J=6.56, 5.65 Hz,
1H), 6.42 (d, J=8.85 Hz, 1H), 5.53 (s, 1H), 4.08 (s, 3H), 3.97 (s,
1H), 3.19 (q, J=7.32 Hz, 2H), 1.29 (t, J=7.32 Hz, 3H). MS (ESI+)
m/z 436.2 (M+H).sup.+.
Biological Examples
Bromodomain Domain Binding Assay
[0801] A time-resolved fluorescence resonance energy transfer
(TR-FRET) assay was used to determine the affinities of compounds
of the Examples listed in Table 1 for each bromodomain of BRD4.
His-tagged first (BD1: amino acids K57-E168) and second (BD2: amino
acids E352-E168) bromodomains of BRD4 were expressed and purified.
An Alexa647-labeled BET-inhibitor was used as the fluorescent probe
in the assay.
Synthesis of Alexa647-labeled bromodomain inhibitor compound
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetic acid
[0802] Methyl
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetate (see e.g., WO
2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mL methanol to
which was added a freshly prepared solution of lithium hydroxide
monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient
temperature for 3 hours. The methanol was evaporated and the pH
adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and
extracted four times with ethyl acetate. The combined ethyl acetate
layers were dried over magnesium sulfate and evaporated to afford
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS
m/z=401.1 [(M+H).sup.+] which was used directly in the next
reaction.
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-tr-
imethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide
bis(2,2,2-trifluoroacetate)
[0803]
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4-
]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid) (85.3 mg, 0.213
mmol) was combined with 2,2'-(ethane-1,2-diylbis(oxy))diethanamine
(Sigma-Aldrich, 0.315 mg, 2.13 mmol) were combined in 5 mL
anhydrous dimethylformamide.
(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium
hexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg,
0.638 mmol) was added and the reaction shaken at ambient
temperature for 16 hours. The reaction was diluted to 6 mL with
dimethylsulfoxide:water (9:1, v:v) and purified in two injections
with time collection Waters Deltapak C18 200.times.25 mm column
eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in water
and acetonitrile. The fractions containing the two purified
products were lyophilized to afford
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-t-
rimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamid-
e bis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1
[(M+H).sup.+]; 529.1 [(M-H).sup.-] and
(S,Z)--N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6-
S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,-
3-a][1,4]diazepin-6-yl)acetamide) bis(2,2,2-trifluoroacetate) (3.0
mg, 1.5%); ESI-MS m/z=913.2 [(M+H).sup.+]; 911.0 [(M-H).sup.-].
N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophen-
yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6--
yl)acetamide(2,2,2-trifluoroacetate)
[0804]
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2-
,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ac-
etamide bis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was
combined with Alexa Fluor.RTM. 647 carboxylic Acid, succinimidyl
ester (Life Technologies, Grand Island, N.Y.; 3 mg, 0.0024 mmol)
were combined in 1 mL anhydrous dimethylsulfoxide containing
diisopropylethylamine (1% v/v) and shaken at ambient temperature
for 16 hours. The reaction was diluted to 3 mL with
dimethylsulfoxide:water (9:1, v:v) and purified in one injection
with time collection Waters Deltapak C18 200.times.25 mm column
eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in water
and acetonitrile. The fractions containing the purified product
were lyophilized to afford
N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophe-
nyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-
-yl)acetamide(2,2,2-trifluoroacetate) (1.8 mg); MALDI-MS
m/z=1371.1, 1373.1 [(M+H).sup.+] as a dark blue powder.
Assay
[0805] Compound dilution series were prepared in DMSO via an
approximately 3-fold serial dilution from one of the following:
Assay method C: 1250 .mu.M-21 nM Assay method D: 500 .mu.M-8.5 nM
Assay method E: 0.47 mM to 7.8 nM Assay method F: 250 .mu.M-4.2 nM
Assay method G: 0.047 mM to 0.78 nM or 5-fold serial dilution from
one of the following: Assay method A: 2.5 mM-800 nM Assay method B:
2.5 mM-797 nM
[0806] For Assay methods A, C, D, and F: Compounds were then
diluted 6:100 in assay buffer (20 mM Sodium Phosphate, pH 6.0, 50
mM NaCl, 1 mM Ethylenediaminetetraacetic acid, 0.01% Triton X-100,
1 mM DL-Dithiothreitol) to yield 3.times. working solutions. Six
microliters (.mu.L) of the working solution was then transferred to
white, low-volume assay plates (Costar #3673). A 1.5.times. assay
mixture containing His-tagged bromodomain, Europium-conjugated
anti-His antibody (Invitrogen PV5596) and the Alexa-647-conjugated
probe molecule was also prepared. Twelve .mu.L of this solution
were added to the assay plate to reach a final volume of 18
.mu.L.
[0807] For Assay methods B, E, and G: Compound dilutions were added
directly into white, low-volume assay plates (Perkin Elmer
Proxiplate 384 Plus #6008280) using a Labcyte Echo in conjunction
with Labcyte Access and Thermo Multidrop CombinL robotics.
Compounds were then suspended in eight microliters (.mu.L) of assay
buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mM
Ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01%
Triton X-100, 1 mM DL-Dithiothreitol) containing His-tagged
bromodomain, Europium-conjugated anti-His antibody (Invitrogen
PV5596) and Alexa-647-conjugated probe.
[0808] The final concentration of 1.times. assay mixture for assay
methods A, B, C, D, E, F, and G contains 2% DMSO, 8 nM His-tagged
bromodomain, 1 nM Europium-conjugated anti-His-tag antibody and 100
nM or 30 nM probe (for BDI or BDII, respectively) and compound
concentration in the range of: 50 .mu.M-16 nM for method A, 49.02
.mu.M-15.63 nM for method B, 25 .mu.M-423 pM for method C, 10
.mu.M-169 pM for method D, 9.19 .mu.M-150 pM for method E, 5
.mu.M-85 pM for method F, and 0.92 .mu.M-15 pM for method G.
[0809] After a one-hour equilibration at room temperature, TR-FRET
ratios were determined using an Envision multilabel plate reader
(Ex 340, Em 495/520).
[0810] TR-FRET data were normalized to the means of 24 no-compound
controls ("high") and 8 controls containing 1 .mu.M un-labeled
probe ("low"). Percent inhibition was plotted as a function of
compound concentration and the data were fit with the 4 parameter
logistic equation to obtain IC.sub.50s. Inhibition constants
(K.sub.i) were calculated from the IC.sub.50s, probe K.sub.d and
probe concentration. Typical Z' values were between 0.65 and 0.75.
The minimum significant ratio was determined to evaluate assay
reproducibility (Eastwood et al., (2006) J Biomol Screen, 11:
253-261). The MSR was determined to be 2.03 for BDI and 1.93 for
BDII, and a moving MSR (last six run MSR overtime) for both BDI and
BDII was typically <3. The K.sub.i values are reported in Table
1.
[0811] MX-1 Cell Line Proliferation Assay The impact of compounds
of the Examples on cancer cell proliferation was determined using
the breast cancer cell line MX-1 (ATCC) in a 3-day proliferation
assay and the data are reported in Table 1. MX-1 cells were
maintained in RPMI 1640 medium (Sigma) supplemented with 10% FBS at
37 C..degree. and an atmosphere of 5% CO.sub.2. For compound
testing, MX-1 cells were plated in 96-well black bottom plates at a
density of 5000 cells/well in 90 .mu.L of culture media and
incubated at 37.degree. overnight to allow cell adhesion and
spreading. Compound dilution series were prepared in DMSO via a
3-fold serial dilution from 3 mM to 0.1 .mu.M. The DMSO dilution
series were then diluted 1:100 in phosphate buffered saline, and 10
.mu.L of the resulted solution were added to the appropriate wells
of the MX-1 cell plate. The final compound concentrations in the
wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003 and
0.0001 .mu.M. After the addition of compounds, the cells were
incubated for 72 more hours and the amounts of viable cells were
determined using the Cell Titer Glo assay kit (Promega) according
to manufacturer suggested protocol.
[0812] Luminescence readings from the Cell Titer Glo assay were
normalized to the DMSO treated cells and analyzed using the
GraphPad Prism software with sigmoidal curve fitting to obtain
EC.sub.50s. The minimum significant ratio (MSR) was determined to
evaluate assay reproducibility (Eastwood et al., (2006) J Biomol
Screen, 11: 253-261). The overall MSR was determined to be 2.1 and
a moving MSR (last six run MSR overtime) has been <2.
TABLE-US-00001 TABLE 1 TR-FRET TR-FRET TR- Binding Ki: Binding Ki:
Compounds FRET BRD4 BRD4 Cellular of assay (BDI_K57- (BDII_E352-
proliferation: Example # protocol E168) (.mu.M) M457) (.mu.M)
EC.sub.50 (.mu.M) 1 D 1.35 2.82 >3 2 D 0.021 0.43 0.144 3 D
0.00439 0.00755 0.0193 4 F 0.00061 0.00215 0.00139 5 F 0.00176
0.00195 0.00395 6 F 0.00353 0.00244 0.0164 7 D 0.0591 0.0975 0.273
8 F 0.00581 0.0252 0.0466 9 F 0.00629 0.0182 0.805 10 F 0.00823
0.0574 0.0816 11 F 0.00714 0.0189 0.0568 12 F 0.00218 0.0043
0.00563 13 D 0.00274 0.0341 0.072 14 D 0.003 0.00369 0.00278 15 F
0.00914 0.0269 0.0363 16 D 0.00079 0.00507 0.00555 17 F 0.00143
0.00248 0.0199 18 D 0.00182 0.00346 0.00702 19 F 0.00132 0.0116
0.0687 20 D 0.00176 0.00469 0.0365 21 F 0.00105 0.00269 0.0166 22 D
0.00129 0.00303 0.0165 23 F 0.00138 0.00754 0.00479 24 F 0.178
>0.408 ND 25 F 0.192 0.124 >1 26 F 0.00027 0.00312 0.00948 27
F 0.0002 0.00173 0.00856 28 F 0.00117 0.00821 0.0135 29 F 0.00303
0.0224 ND 30 F 0.00353 0.0218 0.0512 31 F 0.0115 0.0795 ND 32 F
0.00137 0.0116 0.0123 33 F 0.00149 0.00639 0.0174 34 F 0.0022
0.0249 0.0479 35 F 0.00201 0.0189 0.0264 36 F 0.00134 0.0232 0.0168
37 F 0.00107 0.00742 0.019 38 F 0.00152 0.0093 0.0090 39 F 0.00194
0.0123 0.0232 40 F 0.00086 0.00727 0.0255 41 F 0.00173 0.0125
0.0556 42 F 0.00207 0.0134 0.00983 43 F 0.00125 0.00649 0.0173 44 F
0.0533 >0.408 >1 45 F 0.00712 0.13 ND 46 F 0.00329 0.0197 ND
47 F 0.00114 0.0133 0.0143 48 F 0.00239 0.0195 0.0295 49 F 0.00274
0.0298 0.0651 50 F 0.00594 0.0331 0.0637 51 F 0.00512 0.0848 ND 52
F 0.00276 0.0559 0.0559 53 F 0.00261 0.0501 ND 54 F 0.00207 0.0179
ND 55 F 0.00931 0.24 ND 56 F 0.00174 0.0574 ND 57 F 0.00172 0.029
0.0549 58 F 0.00183 0.0127 0.0633 59 F 0.00289 0.0715 ND 60 F
0.0032 0.0461 0.0755 61 F 0.00517 0.147 ND 62 F 0.00162 0.0331
0.0656 63 F 0.00198 0.022 0.0499 64 F 0.00173 0.0469 ND 65 F
0.00392 0.0449 0.0555 66 F 0.00214 0.0301 0.0446 67 F 0.0212 0.007
ND 68 F 0.00126 0.00179 0.0175 69 F 0.00078 0.00189 0.0044 70 F
0.00079 0.000708 0.0244 71 F 0.00165 0.00221 0.0356 72 F 0.00256
0.00441 0.0101 73 F 0.00708 0.0418 ND 74 F 0.00361 0.017 >1.0 75
F 0.00254 0.0546 >1.0 76 F 0.00346 0.0175 0.332 77 F 0.0046
0.112 >1.0 78 F 0.00129 0.00085 0.00628 79 F 0.00109 0.00208
0.00548 80 F 0.00304 0.0145 0.106 81 F 0.00497 0.0111 0.0779 82 F
0.00083 0.00147 0.00493 ND = Not Determined
LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay
[0813] Compounds of the Examples listed in Table 2 were assayed for
their ability to inhibit LPS (lipopolysaccharide) induced IL-6
(Interleukin-6) production in mice. Fox Chase SCID.RTM. female mice
(Charles Rivers Labs, 5 per group) or CD1 female mice (5 mice per
group) received an intraperitoneal challenge of lipopolysaccharide
(2.5 mg/kg, L2630 E. coli 0111:B4) one hour after oral
administration of compounds. Mice were euthanized 2 hours after
lipopolysaccharide injection, blood was removed by cardiac
puncture, and then the serum harvested from the blood samples was
frozen at -80.degree. C. On the day of the assay the serum samples
were brought to room temperature and then diluted 1:20 in
phosphate-buffered saline containing 2% bovine serum albumin.
Interleukin-6 measurements were performed using a cytokine assay
from Meso Scale Discovery (Gaithersburg, Md.) for mouse serum
analysis according to the manufacturer's protocol and read on a
SECTOR Imager 6000 (Meso Scale Discovery, Gaithersburg, Md.)
instrument. Statistical analysis was performed using Prism software
(version 5.0) incorporating Dunnett's one way ANOVA. The IL-6 mean
and standard deviation of the group of vehicle treated animals were
compared with the IL-6 mean and standard deviation of the group
treated with drug. A p value <0.05 means that there is less than
a 5% probability that the mean values in the two groups are equal.
The % inhibition values in Table 2 all exhibited a p value less
than 0.05.
TABLE-US-00002 TABLE 2 Inhibition of LPS induced IL-6 production
Compound of % inhibition Mouse Example # at 3 mg/kg Strain 4 70
SCID 5 71 SCID 36 68 CD1 72 63 CD1 79 61 CD1
Xenograft Tumor Growth Inhibition Assay
[0814] The effect of compounds of the examples to inhibit the
growth of OPM-2 xenograft tumors implanted in mice was evaluated. A
suspension of cancer cells (5.times.10.sup.6 per 0.1 mL) prepared
in RPMI culture medium (Invitrogen, Carlsbad, Calif.) was diluted
1:1 with a solution of Matrigel.TM. (BD Biosciences, Franklin
Lakes, N.J.) and inoculated subcutaneously into the right hind
flank of female SCID-beige (Charles River Labs) mice. Randomization
into treatment and vehicle control groups (9 or 10/group) occurred
when the mean tumor volume reached approximately 250 mm.sup.3.
Compounds were formulated in 2.5% DMSO, 10% EtOH, 27.5% PEG 400,
60% Phosol 53 MCT. Administration of compound or vehicle was
initiated on the day following randomization and continued for 21
days. Tumors were measured twice a week throughout the treatment
period using a pair of calipers and tumor volumes were calculated
according to the formula V=L.times.W.sup.2/2 (V: volume, mm.sup.3;
L: length, mm. W: width, mm). Tumor growth inhibition was
calculated based on the mean tumor volume measured on the first day
that the mean volume of the vehicle group exceeded 2000 mm.sup.3
according to the formula % TGI=100-mean tumor volume of treatment
group/mean tumor volume of control group.times.100. Results are
given in Table 3.
TABLE-US-00003 TABLE 3 OPM-2 human multiple myeloma cancer
xenograft model Compound Dose route, % removed of example # mg/kg
regimen %TGI.sup.a from study.sup.b 4 3.75 PO, QDx21 68*** 11 4 7.5
PO, QDx21 84*** 44 5 2.5 PO, QDx21 66*** 0 5 5.0 PO, QDx21 81*** 44
79 1.25 PO, QDx21 71*** 11 79 2.5 PO, QDx21 79*** 0 .sup.aThe p
values (as indicated by asterisks) are derived from Student's T
test comparison of treatment group vs. control group. ***p <
0.001. .sup.bPercentage of treatment group that were removed from
study due to morbidity or weight loss in excess of 20%.
[0815] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof. All
publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *