U.S. patent application number 16/018357 was filed with the patent office on 2018-10-18 for tetracyclic bromodomain inhibitors.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Andrew Bogdan, Yujia Dai, Justin D. Dietrich, Steven D. Fidanze, Lisa A. Hasvold, James H. Holms, Dachun Liu, Robert A. Mantei, Jasmina Marjanovic, Keith F. McDaniel, John Pratt, George S. Sheppard, Le Wang.
Application Number | 20180298003 16/018357 |
Document ID | / |
Family ID | 51535867 |
Filed Date | 2018-10-18 |
United States Patent
Application |
20180298003 |
Kind Code |
A1 |
Fidanze; Steven D. ; et
al. |
October 18, 2018 |
TETRACYCLIC BROMODOMAIN INHIBITORS
Abstract
The present invention provides for compounds of formula (I)
##STR00001## wherein R1, R2, R6, Y1, Y2, Y3, A1, A2, A3, and A4
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: |
Fidanze; Steven D.;
(Grayslake, IL) ; Liu; Dachun; (Vernon Hills,
IL) ; Mantei; Robert A.; (Franklin, WI) ;
McDaniel; Keith F.; (Wauconda, IL) ; Pratt; John;
(Kenosha, WI) ; Sheppard; George S.; (Wilmette,
IL) ; Wang; Le; (Vernon Hills, IL) ; Bogdan;
Andrew; (Evanston, IL) ; Holms; James H.;
(Gurnee, IL) ; Dietrich; Justin D.; (Lindenhurst,
IL) ; Marjanovic; Jasmina; (Chicago, IL) ;
Hasvold; Lisa A.; (Grayslake, IL) ; Dai; Yujia;
(Gurnee, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
51535867 |
Appl. No.: |
16/018357 |
Filed: |
June 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14774866 |
Sep 11, 2015 |
10035800 |
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PCT/CN2014/000258 |
Mar 12, 2014 |
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16018357 |
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61928779 |
Jan 17, 2014 |
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61777797 |
Mar 12, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 15/16 20180101;
C07D 471/16 20130101; A61P 13/12 20180101; A61P 31/18 20180101;
A61P 35/00 20180101; C07D 471/22 20130101 |
International
Class: |
C07D 471/22 20060101
C07D471/22; C07D 471/16 20060101 C07D471/16 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, ##STR00010## wherein Y.sup.1 is N or CH; R.sup.1 is
CD.sub.3, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl;
R.sup.2 is H or C.sub.1-C.sub.3 alkyl; Y.sup.3 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, --CN,
--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 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, --CN, --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.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)=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;
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, --CN, --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, and R.sup.5b, 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.5c, at
each occurrence, is 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, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1,
--(C.sub.1-C.sub.6 alkylenyl)-CN, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a;
R3d, at each occurrence, is independently C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G1, or --(C1-C6
alkylenyl)-G1; R.sup.5d, 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.1, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d,
or --(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.e)C(O)O(R.sup.b); 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, --CN, --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)=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.1, --S(O).sub.2NR.sup.y3R.sup.4, --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.2,
--(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.1, --(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.y3, --(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.3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)S(O).sub.2R.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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.3R.sup.4, --(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, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.Z3R.sup.z4, 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.z,
--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.4,
--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.
2. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, ##STR00011## wherein Y.sup.1 is N or CH; R.sup.1 is
CD.sub.3, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl;
R.sup.2 is H or C.sub.1-C.sub.3 alkyl; Y.sup.3 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,
--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, --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.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)=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;
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.2,
--(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.1, --(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.3)S(O).sub.2R.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.3R.sup.4, --(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.4,
--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.
3. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, ##STR00012## wherein Y.sup.1 is N or CH; R.sup.1 is
CD.sub.3, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl;
R.sup.2 is H or C.sub.1-C.sub.3 alkyl; Y.sup.3 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, --CN,
--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 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, --CN, --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.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)=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;
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, and R.sup.5b, 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.5c, at
each occurrence, is 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, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1,
--(C.sub.1-C.sub.6 alkylenyl)-CN, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.a;
R.sup.3d, 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.1, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1; R.sup.5d, 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.1, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6 alkylenyl)-NR.sup.cR.sup.d,
or --(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.e)C(O)O(R.sup.b); 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)=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.4, --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.2,
--(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.3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)S(O).sub.2R.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)C(O)NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2NR.sup.3R.sup.4, --(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.4,
--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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/774,866, filed Sep. 11, 2015, which is a National Stage
Entry of International PCT Application No. PCT/CN2014/00258, filed
on Mar. 12, 2014, which claims priority of U.S. Provisional
Application 61/928,779, filed Jan. 17, 2014, and U.S. Provisional
Application 61/777,797, filed Mar. 12, 2013. Each of the foregoing
references are incorporated by reference in their entireties.
BACKGROUND
[0002] 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
[0003] In one aspect the present invention relates to compounds of
formula (I) or a salt thereof,
##STR00002##
wherein [0004] Y.sup.1 is N or CH; [0005] R.sup.1 is CD.sub.3,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl; [0006] R.sup.2
is H or C.sub.1-C.sub.3 alkyl; [0007] Y.sup.3 is N or CR.sup.3;
[0008] 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, --CN, --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 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, --CN, --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.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)=NR.sup.3bR.sup.3c; [0009] Y.sup.2
is C(O), S(O).sub.2, or CR.sup.4R.sup.5; [0010] R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6
haloalkyl; [0011] 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, --CN, --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; [0012]
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.5a, and R.sup.5b, 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;
[0013] R.sup.5c, at each occurrence, is 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, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6 alkylenyl)-CN,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, or --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.a; [0014] R.sup.3d, 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.1, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1; [0015] R.sup.5d, 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.1, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b); [0016] 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; [0017] 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, --CN, --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)=NR.sup.6bR.sup.6c; [0018] 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; [0019] 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; [0020] 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; [0021] 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; [0022]
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.1, --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.2, --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.1, --(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.1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.3R.sup.4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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; [0023] 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; [0024] 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; [0025] 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; [0026] R.sup.10
is H, C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--CN; [0027] 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; [0028] 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, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.z1, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.z3R.sup.z4, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.z3R.sup.z4, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a; [0029] 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; [0030] 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; [0031] 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; [0032] 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 [0033] 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.
[0034] 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.
[0035] Some of the methods are directed to treating or preventing
an inflammatory disease or cancer or AIDS.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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 kidney disease. In
certain embodiments, the methods further comprise administering a
therapeutically effective amount of at least one additional
therapeutic agent.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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
[0045] Disclosed herein are compounds of formula (I)
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.6, Y.sup.1, Y.sup.2, Y.sup.3,
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.
[0046] 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
[0047] 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.
[0048] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0049] 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.
[0050] 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--.
[0051] 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" refers to an alkyl substituent
containing from 1 to 6 carbon atoms and "C.sub.1-C.sub.3 alkyl"
refers to 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.
[0052] 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--.
[0053] 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, 1-butynyl, and but-2-yn-1-yl.
[0054] 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.
[0055] The term "cycloalkyl" as used herein, refers to a radical
that is a monocyclic cyclic alkyl, a bicyclic cycloalkyl, or a
spiro cycloalkyl. A monocyclic cycloalkyl is a carbocyclic ring
system containing three to eight carbon atoms, zero heteroatoms and
zero double bonds, i.e., a C.sub.3-C.sub.8 cycloalkyl. In certain
embodiments, a cycloalkyl refers to a monocyclic C.sub.3-C.sub.7
cycloalkyl. Examples of monocyclic ring systems include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. A bicyclic cycloalkyl is a monocyclic cycloalkyl fused
to a monocyclic cycloalkyl ring. 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. 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.
[0056] The term "cycloalkenyl" as used herein, refers to a
monocyclic or a bicyclic hydrocarbon ring radical. A monocyclic
cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms
and zero heteroatoms, i.e., a C.sub.4-C.sub.8 cycloalkenyl. 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. A
bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a
monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to
a monocyclic cycloalkenyl group. 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. 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.
[0057] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0058] 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.
[0059] 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,
1,3-benzodioxolyl, benzopyranyl, benzothiopyranyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydro-1H-indolyl, dihydroisoindol-2-yl, 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.
[0060] The term "C.sub.4-C.sub.6 heterocycle" or "C.sub.4-C.sub.6
heterocyclic" as used herein, means a 4, 5, or 6 membered
monocyclic heterocycle as defined herein above. Non-limiting
examples of C.sub.4-C.sub.6 heterocycle include azetidinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,
piperidinyl, and morpholinyl.
[0061] 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.
[0062] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0063] The term "oxo" as used herein, means a .dbd.O group.
[0064] 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).
[0065] 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.
[0066] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0067] 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.
[0068] 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.
[0069] 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
[0070] Compounds of the invention have the general formula (I) as
described above.
[0071] 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.
[0072] In certain embodiments of formula (I), Y.sup.1 is N or
CH.
[0073] In certain embodiments, Y.sup.1 is N.
[0074] In certain embodiments, Y.sup.1 is CH.
[0075] In certain embodiments of formula (I), R.sup.1 is CD.sub.3,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl.
[0076] In certain embodiments, R.sup.1 is C.sub.1-C.sub.3 alkyl. In
some such embodiments, R.sup.1 is methyl.
[0077] In certain embodiments of formula (I), R.sup.2 is H or
C.sub.1-C.sub.3 alkyl.
[0078] In certain embodiments, R.sup.2 is H or methyl.
[0079] In certain embodiments, R.sup.2 is H.
[0080] In certain embodiments, R.sup.2 is C.sub.1-C.sub.3 alkyl. In
some such embodiments, R.sup.2 is methyl.
[0081] In certain embodiments of formula (I), Y.sup.3 is N or
CR.sup.3.
[0082] In certain embodiments, Y.sup.3 is N.
[0083] In certain embodiments, Y.sup.3 is CR.sup.3.
[0084] In certain embodiments of formula (I), R.sup.3 is H, --CN,
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, --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, --CN, --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.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.
[0085] In certain embodiments, R.sup.3 is H, --CN, --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. In some such
embodiments, the C.sub.1-C.sub.6 alkyl is substituted with a
G.sup.1 group, wherein the G.sup.1 group is piperidinyl,
piperazinyl, or morpholinyl, each of which is optionally
substituted with 1 or 2 C.sub.1-C.sub.6 alkyl. In some such
embodiments, the C.sub.1-C.sub.6 alkyl is substituted with a
G.sup.1 group, wherein the G.sup.1 group is piperazinyl or
morpholinyl, each of which is optionally substituted with 1 or 2
C.sub.1-C.sub.6 alkyl.
[0086] In certain embodiments, R.sup.3 is H,
--C(O)NR.sup.3bR.sup.3c, --CN, or C.sub.1-C.sub.6 alkyl which is
substituted with a G.sup.1 group. In some such embodiments, the
C.sub.1-C.sub.6 alkyl is substituted with a G.sup.1 group, wherein
the G.sup.1 group is an optionally substituted C.sub.4-C.sub.6
heterocycle. In some such embodiments, the C.sub.1-C.sub.6 alkyl is
substituted with a G.sup.1 group, wherein the G.sup.1 group is
piperidinyl, piperazinyl, or morpholinyl, each of which is
optionally substituted with 1 or 2 C.sub.1-C.sub.6 alkyl.
[0087] 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. In some such
embodiments, R.sup.3a is G.sup.1 wherein G.sup.1 is piperidinyl,
piperazinyl, or morpholinyl, each of which is optionally
substituted with 1 or 2 C.sub.1-C.sub.6 alkyl. In some such
embodiments, R.sup.3a is G.sup.1 wherein G.sup.1 is piperazinyl,
optionally substituted with 1 or 2 C.sub.1-C.sub.6 alkyl.
[0088] 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.
[0089] In certain embodiments, R.sup.3 is H.
[0090] 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.
[0091] In certain embodiments, R.sup.3 is G.sup.1. In some such
embodiments, G.sup.1 is optionally substituted monocyclic
heteroaryl. In some such embodiments, G.sup.1 is optionally
substituted pyrazolyl. In some such embodiments, G.sup.1 is
pyrazolyl substituted with 1 or 2 C.sub.1-C.sub.6 alkyl.
[0092] In certain embodiments of formula (I), Y.sup.2 is C(O),
S(O).sub.2, or CR.sup.4R.sup.5.
[0093] In certain embodiments, Y.sup.2 is C(O).
[0094] In certain embodiments, Y.sup.2 is S(O).sub.2.
[0095] In certain embodiments, Y.sup.2 is CR.sup.4R.sup.5.
[0096] In certain embodiments of formula (I), R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6
haloalkyl.
[0097] In certain embodiments, R.sup.4 is H or deuterium.
[0098] In certain embodiments, R.sup.4 is H.
[0099] In certain embodiments of formula (I), 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, --CN, --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.
[0100] 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.
[0101] In certain embodiments, R.sup.5 is C.sub.2-C.sub.6 alkenyl
optionally substituted with a G.sup.1 group, or R.sup.5 is H,
deuterium, C.sub.1-C.sub.6 alkyl, --C(O)R.sup.5a, --C(O)OR.sup.5a,
or G.sup.1; wherein the C.sub.1-C.sub.6 alkyl is unsubstituted or
substituted with a substituent 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, and
N(R.sup.5b)C(NR.sup.5bR.sup.5c).dbd.NR.sup.5bR.sup.5c.
[0102] 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.
[0103] In certain embodiments, R.sup.5 is H.
[0104] In certain embodiments of formula (I), 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, --CN, --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)=NR.sup.6bR.sup.6c.
[0105] 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, --CN,
--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.
[0106] In certain embodiments, R.sup.6 is H, C.sub.1-C.sub.6 alkyl,
--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
is unsubstituted or substituted with a substituent selected from
the group consisting of G.sup.2 and --C(O)OR.sup.6a.
[0107] In certain embodiments, R.sup.6 is --C(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, G.sup.2, or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with a
G.sup.2 group. In certain embodiments, R.sup.6a is G.sup.2 or
unsubstituted C.sub.1-C.sub.6 alkyl.
[0108] In certain embodiments, R.sup.6 is --C(O)OR.sup.6a. In some
such embodiments, R.sup.6a is C.sub.1-C.sub.6 alkyl.
[0109] 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 optionally substituted cycloalkyl; or
R.sup.6 is C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with a substituent selected from the group consisting
of heteroaryl, cycloalkyl, and heterocycle, each of which is
optionally substituted. In some such embodiments, R.sup.6 is
optionally substituted aryl, optionally substituted heteroaryl, or
optionally substituted cycloalkyl; or R.sup.6 is C.sub.1-C.sub.6
alkyl which is unsubstituted or substituted with a substituent
selected from the group consisting of cycloalkyl and heterocycle,
each of which is optionally substituted. In some such embodiments,
R.sup.6 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
indazolyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrrolidinyl, piperidinyl, or azepanyl, each of which is optionally
substituted; or R.sup.6 is C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a G.sup.1 group wherein the
G.sup.1 group is cyclopropyl, cyclohexyl, pyrrolidinyl,
piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,
3 dioxolyl, or pyrazolyl, each of which is optionally substituted.
In some such embodiments, R.sup.6 is optionally substituted phenyl,
optionally substituted pyridinyl, or optionally substituted
cyclohexyl; or R.sup.6 is C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a substituent selected from the
group consisting of cyclopropyl and tetrahydrofuranyl, each of
which is optionally substituted. 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), --N(H)C(O)O(C.sub.1-C.sub.6 alkyl),
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.
[0110] In certain embodiments of formula (I), 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.
[0111] 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).
[0112] 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).
[0113] 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).
[0114] 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).
[0115] In certain embodiments of formula (I), 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.2,
--(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.1, --(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.
[0116] In certain embodiments, R.sup.7 is H, halogen, --CN,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] In certain embodiments, R.sup.8 is H.
[0121] 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)-CN, --(--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.1,
--(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.3)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.
[0122] In certain embodiments, R.sup.9 is H, C.sub.1-C.sub.6 alkyl,
halogen, --S(O).sub.2R.sup.y1, --S(O).sub.2NR.sup.y3R.sup.y4,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)S(O).sub.2R.sup.y2,
--(C.sub.1-C.sub.6 alkylenyl)-CN, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1.
[0123] In certain embodiments, R.sup.9 is H, C.sub.1-C.sub.6 alkyl,
halogen, --S(O).sub.2R.sup.y1, --S(O).sub.2NR.sup.y3R.sup.y4,
--NR.sup.y3R.sup.y4, --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, R.sup.y3, and R.sup.y4, at each occurrence,
are each independently H or C.sub.1-C.sub.6 alkyl, and R.sup.y2 is
C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.y1 and
R.sup.y2 are C.sub.1-C.sub.3 alkyl, and R.sup.y3 and R.sup.y4 are
hydrogen.
[0124] 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.1.
[0125] In certain embodiments, R.sup.9 is halogen,
--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
and R.sup.y2 are C.sub.1-C.sub.6 alkyl, and R.sup.y3 is H. In some
such embodiments, the halogen is F. In some such embodiments,
R.sup.y1 and R.sup.y2 are each independently methyl or ethyl, and
R.sup.y3 is H.
[0126] In certain embodiments, R.sup.9 is
--(CH.sub.2)--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.y1 is methyl.
[0127] In certain embodiments of formula (I), R.sup.10 is H,
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--CN.
[0128] In certain embodiments, R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen.
[0129] In certain embodiments, R.sup.10 is H.
[0130] Various embodiments of substituents R.sup.1, R.sup.2,
R.sup.6, Y.sup.1, Y.sup.2, Y.sup.3, 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.
In certain embodiments,
[0131] Y.sup.1 is CH;
[0132] Y.sup.3 is CR.sup.3; and
[0133] Y.sup.2 is CR.sup.4R.sup.5.
In certain embodiments, [0134] Y.sup.1 is CH; [0135] Y.sup.3 is
CR.sup.3; [0136] Y.sup.2 is CR.sup.4R.sup.5; and [0137] R.sup.3 is
H, --CN, --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. [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). 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). 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). 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). In certain embodiments,
[0139] Y.sup.1 is CH; [0140] Y.sup.3 is CR.sup.3; [0141] Y.sup.2 is
CR.sup.4R.sup.5; [0142] R.sup.4 is H or deuterium; and [0143]
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. [0144] 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). 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). 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). 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). In certain embodiments,
[0145] Y.sup.1 is CH; [0146] Y.sup.3 is CR.sup.3; [0147] Y.sup.2 is
CR.sup.4R.sup.5; and [0148] 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, --CN,
--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. [0149] 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). 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). 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). 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). In certain embodiments,
[0150] Y.sup.1 is CH; [0151] Y.sup.3 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.3)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.3)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). 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). 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). 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). In certain
embodiments, [0155] Y.sup.1 is CH; [0156] Y.sup.3 is CR.sup.3;
[0157] Y.sup.2 is CR.sup.4R.sup.5; and [0158] 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 [0159] 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
[0160] 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). 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). 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). 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). In certain
embodiments, [0161] R.sup.1 is C.sub.1-C.sub.3 alkyl; [0162]
R.sup.2 is H; [0163] Y.sup.1 is CH; [0164] Y.sup.3 is CR.sup.3; and
[0165] Y.sup.2 is CR.sup.4R.sup.5. In some further embodiments,
R.sup.1 is methyl. In certain embodiments, [0166] R.sup.1 is
C.sub.1-C.sub.3 alkyl; [0167] R.sup.2 is H; [0168] Y.sup.1 is CH;
[0169] Y.sup.3 is CR.sup.3; [0170] Y.sup.2 is CR.sup.4R.sup.5;
[0171] R.sup.4 is H or deuterium; and [0172] R.sup.5 is
C.sub.2-C.sub.6 alkenyl optionally substituted with a G.sup.1
group, or R.sup.5 is H, deuterium, C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.5a, --C(O)OR.sup.5a, or G.sup.1; wherein the
C.sub.1-C.sub.6 alkyl is unsubstituted or substituted with a
substituent 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, and
N(R.sup.5b)C(NR.sup.5bR.sup.5c)=NR.sup.5bR.sup.5c. In some further
embodiments, R.sup.1 is methyl. [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); 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). 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). 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). 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). In certain embodiments,
[0174] R.sup.1 is C.sub.1-C.sub.3 alkyl; [0175] R.sup.2 is H;
[0176] Y.sup.1 is CH; [0177] Y.sup.3 is CR.sup.3; [0178] Y.sup.2 is
CR.sup.4R.sup.5; and [0179] R.sup.3 is H, --C(O)R.sup.3a, or
--C(O)NR.sup.3bR.sup.3c. 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). 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). 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). 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). In some further embodiments, R.sup.1 is
methyl. In some further embodiments, R.sup.1 is methyl, and
R.sup.3a is G.sup.1. In yet some further embodiments, R.sup.1 is
methyl, R.sup.3a is G.sup.1 wherein G.sup.1 is optionally
substituted heterocycle. In certain embodiments, [0180] R.sup.1 is
C.sub.1-C.sub.3 alkyl; [0181] R.sup.2 is H; [0182] Y.sup.1 is CH;
[0183] Y.sup.3 is CR.sup.3; [0184] Y.sup.2 is CR.sup.4R.sup.5; and
[0185] R.sup.6 is H, C.sub.1-C.sub.6 alkyl, --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 is unsubstituted or
substituted with a substituent selected from the group consisting
of G.sup.2 and --C(O)OR.sup.6a. [0186] 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). In some further embodiments, R.sup.1 is methyl. 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). 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). 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). In certain embodiments, [0187] R.sup.1 is
C.sub.1-C.sub.3 alkyl; [0188] R.sup.2 is H; [0189] Y.sup.1 is CH;
[0190] Y.sup.3 is CR.sup.3; [0191] Y.sup.2 is CR.sup.4R.sup.5; and
[0192] R.sup.9 is H, C.sub.1-C.sub.6 alkyl, halogen,
--S(O).sub.2R.sup.1, --S(O).sub.2NR.sup.y3R.sup.4,
--NR.sup.y3R.sup.y4, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.1. [0193] 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). 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). 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). 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). In some
further embodiments, R.sup.1 is methyl. In certain embodiments,
[0194] R.sup.1 is C.sub.1-C.sub.3 alkyl; [0195] R.sup.2 is H;
[0196] Y.sup.1 is CH; [0197] Y.sup.3 is CR.sup.3; [0198] Y.sup.2 is
CR.sup.4R.sup.5; and [0199] 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
[0200] 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). 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). 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). 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). In yet some further embodiments, R.sup.1 is
methyl. In certain embodiments, [0201] R.sup.1 is methyl; [0202]
R.sup.2 is H; [0203] Y.sup.1 is CH; [0204] Y.sup.3 is CR.sup.3;
[0205] Y.sup.2 is CR.sup.4R.sup.5; [0206] 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 [0207] 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 [0208] 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);
[0209] R.sup.4 is H or deuterium; [0210] R.sup.7 is H, halogen,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0211] 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 R.sup.10 is H, C.sub.1-C.sub.3 alkyl,
or halogen. 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). 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). 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). In one embodiment, the
invention is directed to compounds of formula (I), wherein [0212]
R.sup.1 is methyl; [0213] R.sup.2 is H; [0214] Y.sup.1 is CH;
[0215] Y.sup.3 is CR.sup.3; [0216] Y.sup.2 is CR.sup.4R.sup.5;
[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.0); 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.0); [0220] R.sup.4 is H or deuterium;
[0221] R.sup.7 is H, halogen, C.sub.1-C.sub.3 alkyl, or optionally
substituted cyclopropyl; [0222] 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.3)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; R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and R.sup.3 is H or --C(O)NR.sup.3bR.sup.3c. In
some further embodiments, R.sup.3b and R.sup.3c are each
independently H or C.sub.1-C.sub.6 alkyl. 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). 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). 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). In one embodiment, the invention is
directed to compounds of formula (I), wherein [0223] R.sup.1 is
methyl; [0224] R.sup.2 is H; [0225] Y.sup.1 is CH; [0226] Y.sup.3
is CR.sup.3; [0227] Y.sup.2 is CR.sup.4R.sup.5; [0228] 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.0); or [0229] 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
[0230] 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); [0231] R.sup.4 is H or deuterium; [0232]
R.sup.7 is H, halogen, C.sub.1-C.sub.3 alkyl, or optionally
substituted cyclopropyl; [0233] 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; [0234] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0235] 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 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). 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). 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). In yet some further
embodiments, R.sup.5a is C.sub.1-C.sub.6 alkyl. In one embodiment,
the invention is directed to compounds of formula (I), wherein
[0236] R.sup.1 is methyl; [0237] R.sup.2 is H; [0238] Y.sup.1 is
CH; [0239] Y.sup.3 is CR.sup.3; [0240] Y.sup.2 is CR.sup.4R.sup.5;
[0241] 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 [0242] 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 [0243] 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); [0244] R.sup.4 is H or deuterium;
[0245] R.sup.7 is H, halogen, C.sub.1-C.sub.3 alkyl, or optionally
substituted cyclopropyl; [0246] 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.3)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.3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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; [0247] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0248] R.sup.6 is --C(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, G.sup.2, or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with a
G.sup.2 group. In some further embodiments, R.sup.6a is G.sup.2 or
unsubstituted C.sub.1-C.sub.6 alkyl. 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). 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). 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). In one embodiment, the invention is
directed to compounds of formula (I), wherein [0249] R.sup.1 is
methyl; [0250] R.sup.2 is H; [0251] Y.sup.1 is CH; [0252] Y.sup.3
is CR.sup.3; [0253] Y.sup.2 is CR.sup.4R.sup.5; [0254] 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 [0255] 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
[0256] 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.0); [0257] R.sup.4 is H or deuterium; [0258]
R.sup.7 is H, halogen, C.sub.1-C.sub.3 alkyl, or optionally
substituted cyclopropyl; [0259] 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; [0260] R.sup.10 is H, C.sub.1-C.sub.3
alkyl, or halogen; and [0261] 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.1. 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); 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). 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). In certain
embodiments, [0262] R.sup.1 is methyl; [0263] R.sup.2 is H; [0264]
Y.sup.1 is CH; [0265] Y.sup.3 is CR.sup.3; [0266] Y.sup.2 is
CR.sup.4R.sup.5; [0267] 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.0); or
[0268] 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 [0269] 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.0); [0270] R.sup.4
is H or deuterium; [0271] R.sup.7 is H or halogen; [0272] R.sup.8
is H; and [0273] R.sup.10 is H. 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). 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). 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). In certain embodiments, [0274] R.sup.1 is
methyl; [0275] R.sup.2 is H; [0276] Y.sup.1 is CH; [0277] Y.sup.3
is CR.sup.3; [0278] Y.sup.2 is CR.sup.4R.sup.5; [0279] 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 [0280] 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
[0281] 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 [0282] R.sup.4 is H or deuterium;
[0283] R.sup.7 is H or halogen; [0284] R.sup.8 is H; [0285]
R.sup.10 is H; and [0286] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1. 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.0). 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). 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). 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. In certain embodiments, [0287] R.sup.1 is
methyl; [0288] R.sup.2 is H; [0289] Y.sup.1 is CH; [0290] Y.sup.3
is CR.sup.3; [0291] Y.sup.2 is CR.sup.4R.sup.5; [0292] 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 [0293] 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
[0294] 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); [0295] R.sup.4 is H or deuterium; [0296]
R.sup.7 is H or halogen; [0297] R.sup.8 is H; [0298] R.sup.10 is H;
[0299] R.sup.9 is halogen, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.1; and [0300] R.sup.6
is --C(O)R.sup.6a, --C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c,
G.sup.2, or C.sub.1-C.sub.6 alkyl which is unsubstituted or
substituted with a G.sup.2 group. In some further embodiments,
R.sup.6a is G.sup.2 or unsubstituted C.sub.1-C.sub.6 alkyl. 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). 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). 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). In some further embodiments, R.sup.y1 and
R.sup.y2 are C.sub.1-C.sub.6 alkyl, and R.sup.3 is H. In certain
embodiments, [0301] R.sup.1 is methyl; [0302] R.sup.2 is H; [0303]
Y.sup.1 is CH; [0304] Y.sup.3 is CR.sup.3; [0305] Y.sup.2 is
CR.sup.4R.sup.5; [0306] 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
[0307] 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 [0308] 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); [0309]
R.sup.4 is H or deuterium; [0310] R.sup.7 is H or halogen; [0311]
R.sup.8 is H; [0312] R.sup.10 is H; [0313] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R; [0314] R.sup.6 is --C(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, G.sup.2, or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with a
G.sup.2 group; and [0315] 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 further embodiments, R.sup.6a is G.sup.2 or
unsubstituted C.sub.1-C.sub.6 alkyl. 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). 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). 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). 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. In certain
embodiments, [0316] R.sup.1 is methyl; [0317] R.sup.2 is H; [0318]
Y.sup.1 is CH; [0319] Y.sup.3 is CR.sup.3; [0320] Y.sup.2 is
CR.sup.4R.sup.5; [0321] 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
[0322] 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 [0323] 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); [0324]
R.sup.4 is H or deuterium; [0325] R.sup.7 is H or halogen; [0326]
R.sup.8 is H; [0327] R.sup.10 is H; [0328] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1; [0329] R.sup.6 is --C(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, G.sup.2, or
C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with a
G.sup.2 group; [0330] 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; and [0331]
R.sup.3 is H or --C(O)NR.sup.3bR.sup.3c. In some further
embodiments, R.sup.6a is G.sup.2 or unsubstituted C.sub.1-C.sub.6
alkyl. 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).
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). 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). In certain embodiments, [0332] R.sup.1 is
methyl; [0333] R.sup.2 is H; [0334] Y.sup.1 is CH; [0335] Y.sup.3
is CR.sup.3; [0336] Y.sup.2 is CR.sup.4R.sup.5; [0337] 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 [0338] 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
[0339] 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); [0340] R.sup.4 is H or deuterium; [0341]
R.sup.7 is H or halogen; [0342] R.sup.8 is H; [0343] R.sup.10 is H;
[0344] R.sup.9 is halogen, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.y1; [0345] R.sup.6 is
--C(O)R.sup.6a, --C(O)OR.sup.6a, --C(O)NR.sup.6bR.sup.6c, G.sup.2,
or C.sub.1-C.sub.6 alkyl which is unsubstituted or substituted with
a G.sup.2 group; [0346] 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; [0347] R.sup.3
is H or --C(O)NR.sup.3bR.sup.3c; [0348] R.sup.3b and R.sup.3c are
each independently H or C.sub.1-C.sub.6 alkyl; [0349] R.sup.5a is
C.sub.1-C.sub.6 alkyl; [0350] R.sup.y1 and R.sup.y2 are
C.sub.1-C.sub.6 alkyl; and [0351] R.sup.y3 is H. In some further
embodiments, R.sup.6a is G.sup.2 or unsubstituted C.sub.1-C.sub.6
alkyl. 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).
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). 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). In certain embodiments, [0352] R.sup.1 is
methyl; [0353] R.sup.2 is H; [0354] Y.sup.1 is CH; [0355] Y.sup.3
is CR.sup.3; [0356] Y.sup.2 is CR.sup.4R.sup.5; [0357] 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 [0358] 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
[0359] 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); [0360] R.sup.4 is H or deuterium; [0361]
R.sup.7 is H or halogen; [0362] R.sup.8 is H; [0363] R.sup.10 is H;
[0364] R
.sup.9 is halogen, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.1; [0365] 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; [0366] 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; [0367] R.sup.3 is H or --C(O)NR.sup.3bR.sup.3c; [0368]
R.sup.3b and R.sup.3c are each independently H or C.sub.1-C.sub.6
alkyl; [0369] R.sup.5a is C.sub.1-C.sub.6 alkyl; [0370] R.sup.y1
and R.sup.y2 are C.sub.1-C.sub.6 alkyl; and [0371] R.sup.y3 is H.
In some further embodiments, R.sup.6 is optionally substituted
aryl, optionally substituted heteroaryl, or optionally substituted
cycloalkyl; or R.sup.6 is C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a substituent selected from the
group consisting of cycloalkyl and heterocycle, each of which is
optionally substituted. In some further embodiments, R.sup.6 is
optionally substituted phenyl, optionally substituted cyclohexyl,
optionally substituted pyridinyl, or C.sub.1-C.sub.6 alkyl which is
unsubstituted or substituted with a G.sup.2 group wherein G.sup.2
is cyclopropyl or tetrahydrofuranyl, each of which is optionally
substituted. 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). 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). 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). In certain embodiments,
[0372] R.sup.1 is methyl; [0373] R.sup.2 is H; [0374] Y.sup.1 is
CH; [0375] Y.sup.3 is CR.sup.3; [0376] Y.sup.2 is CR.sup.4R.sup.5;
[0377] 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 [0378] 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 [0379] 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); [0380] R.sup.3 is H,
--C(O)NR.sup.3bR.sup.3c, --CN, or C.sub.1-C.sub.6 alkyl which is
substituted with a G.sup.1 group; [0381] wherein G.sup.1 is an
optionally substituted C.sub.4-C.sub.6 heterocycle; [0382] R.sup.4
is H or deuterium; [0383] R.sup.7 is H, halogen, --CN,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0384] R.sup.8 is H; [0385] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1; and [0386] R.sup.10 is H. 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). 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). 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). In some further embodiments, R.sup.3b is H
or C.sub.1-C.sub.6 alkyl; and R.sup.3c is H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.1, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1. In some further embodiments, R.sup.3b and
R.sup.3c are each independently H or C.sub.1-C.sub.6 alkyl. 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. In certain embodiments, [0387] R.sup.1 is
methyl; [0388] R.sup.2 is H; [0389] Y.sup.1 is CH; [0390] Y.sup.3
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.3 is H,
--C(O)NR.sup.3bR.sup.3c, --CN, or C.sub.1-C.sub.6 alkyl which is
substituted with a G.sup.1 group; [0396] wherein G.sup.1 is an
optionally substituted C.sub.4-C.sub.6 heterocycle; [0397] R.sup.4
is H or deuterium; [0398] R.sup.7 is H, halogen, --CN,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0399] R.sup.8 is H; [0400] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1; [0401] R.sup.10 is H; and [0402]
R.sup.5 is H. 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). 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). 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). In some further
embodiments, R.sup.3b and R.sup.3c are each independently H or
C.sub.1-C.sub.6 alkyl. 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. In certain
embodiments, [0403] R.sup.1 is methyl; [0404] R.sup.2 is H; [0405]
Y.sup.1 is CH; [0406] Y.sup.3 is CR.sup.3; [0407] Y.sup.2 is
CR.sup.4R.sup.5; [0408] 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
[0409] 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 [0410] 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); [0411]
R.sup.3 is H, --C(O)NR.sup.3bR.sup.3c, --CN, or C.sub.1-C.sub.6
alkyl which is substituted with a G.sup.1 group; [0412] wherein
G.sup.1 is an optionally substituted C.sub.4-C.sub.6 heterocycle;
[0413] R.sup.4 is H or deuterium; [0414] R.sup.7 is H, halogen,
--CN, C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0415] R.sup.8 is H; [0416] R.sup.9 is halogen,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1; [0417] R.sup.10 is H; [0418] R.sup.5
is H; and [0419] R.sup.6 is phenyl, pyridinyl, or cyclohexyl; each
of which is optionally substituted; or R.sup.6 is
--C(O)O(C.sub.1-C.sub.6 alkyl); or R.sup.6 is
--CH.sub.2-(optionally substituted tetrahydropyranyl). 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). 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.0). 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). In some further embodiments, R.sup.3b and R.sup.3c are
each independently H or C.sub.1-C.sub.6 alkyl. 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. In certain embodiments, [0420] R.sup.1 is methyl;
[0421] R.sup.2 is H; [0422] Y.sup.1 is CH; [0423] Y.sup.3 is
CR.sup.3; [0424] Y.sup.2 is CR.sup.4R.sup.5; [0425] 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 [0426] 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
[0427] 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); [0428] R.sup.3 is G.sup.1; [0429] R.sup.4
is H or deuterium; [0430] R.sup.7 is H, halogen, --CN,
C.sub.1-C.sub.3 alkyl, or optionally substituted cyclopropyl;
[0431] R.sup.8 is H; [0432] R.sup.9 is --S(O).sub.2R.sup.1,
--N(R.sup.y3)S(O).sub.2R.sup.y2, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.1; and [0433] R.sup.10 is H. 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). 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). 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). 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. In certain
embodiments, [0434] R.sup.1 is methyl; [0435] R.sup.2 is H; [0436]
Y.sup.1 is CH; [0437] Y.sup.3 is CR.sup.3; [0438] Y.sup.2 is
CR.sup.4R.sup.5; [0439] 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
[0440] 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 [0441] 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); [0442]
R.sup.3 is G.sup.1; wherein G.sup.1 is optionally substituted
heteroaryl; [0443] R.sup.4 is H or deuterium; [0444] R.sup.7 is H,
halogen, --CN, C.sub.1-C.sub.3 alkyl, or optionally substituted
cyclopropyl; [0445] R.sup.8 is H; [0446] R.sup.9 is
--S(O).sub.2R.sup.1, --N(R.sup.y3)S(O).sub.2R.sup.y2, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.1; [0447] R.sup.10 is
H; and [0448] R.sup.5 is H. 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). 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). 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). 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. In certain embodiments, [0449] R.sup.1 is
methyl; [0450] R.sup.2 is H; [0451] Y.sup.1 is CH; [0452] Y.sup.3
is CR.sup.3; [0453] Y.sup.2 is CR.sup.4R.sup.5; [0454] 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 [0455] 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
[0456] 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); [0457] R.sup.3 is G.sup.1; wherein G.sup.1
is optionally substituted pyrazolyl; [0458] R.sup.4 is H or
deuterium; [0459] R.sup.7 is H, halogen, --CN, C.sub.1-C.sub.3
alkyl, or optionally substituted cyclopropyl; [0460] R.sup.8 is H;
[0461] R.sup.9 is --S(O).sub.2R.sup.y1; [0462] R.sup.10 is H;
[0463] R.sup.5 is H; and [0464] R.sup.6 is phenyl, pyridinyl, or
cyclohexyl; each of which is optionally substituted; or R.sup.6 is
--C(O)O(C.sub.1-C.sub.6 alkyl); or R.sup.6 is
--CH.sub.2-(optionally substituted tetrahydropyranyl). 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). 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). 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). In some further embodiments, R.sup.y1 is
C.sub.1-C.sub.6 alkyl. In certain embodiments, [0465] Y.sup.1 is N
or CH; [0466] R.sup.1 is CD.sub.3, C.sub.1-C.sub.3 alkyl, or
C.sub.1-C.sub.3 haloalkyl; [0467] R.sup.2 is H or C.sub.1-C.sub.3
alkyl; [0468] Y.sup.3 is N or CR.sup.3; [0469] 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, --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, --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.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)=NR.sup.3bR.sup.3c; [0470] Y.sup.2
is C(O), S(O).sub.2, or CR.sup.4R.sup.5; [0471] R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6
haloalkyl; [0472] 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; [0473]
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;
[0474] 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; [0475] 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; [0476] 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; [0477]
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; [0478] 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; [0479] 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; [0480] 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; [0481]
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, --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.2,
--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.1, --(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.3)C(O)R.sup.y2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.y3)S(O).sub.2R.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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; [0482] 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; [0483] 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; [0484] 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; [0485] R.sup.10
is H, C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--CN; [0486] 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; [0487] 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; [0488] 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; [0489] 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; [0490] 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; [0491] 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 [0492] 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. In
certain embodiments, [0493] Y.sup.1 is N or CH; [0494] R.sup.1 is
CD.sub.3, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl;
[0495] R.sup.2 is H or C.sub.1-C.sub.3 alkyl; [0496] Y.sup.3 is N
or CR.sup.3; [0497] 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, --CN, --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 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, --CN, --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.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)=NR.sup.3bR.sup.3c; [0498] Y.sup.2
is C(O), S(O).sub.2, or CR.sup.4R.sup.5; [0499] R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl, halogen, or C.sub.1-C.sub.6
haloalkyl; [0500] 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; [0501]
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.5a, and R.sup.5b, 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; [0502]
R.sup.5c, at each occurrence, is 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, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6 alkylenyl)-CN,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.a, or --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.a; [0503] R.sup.3d, 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.1, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1; [0504] R.sup.5d, 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.1, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.cR.sup.d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.e)C(O)O(R.sup.b); [0505] 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; [0506] 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; [0507]
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; [0508] 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; [0509] 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; [0510] 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; [0511]
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.1,
--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.2,
--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.1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.y1, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.3R.sup.4, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.y3R.sup.y4, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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.3)C(O)O(R.sup.y2), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.3)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; [0512] 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; [0513] 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; [0514] 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; [0515] R.sup.10
is H, C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--CN; [0516] 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; [0517] 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; [0518] 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; [0519] 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; [0520] 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.3R.sup.4, --(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; [0521] 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 [0522] 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.
[0523] 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.
[0524] 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.
[0525] 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.
[0526] 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.
[0527] Compounds of the invention are named using ChemDraw Ultra
Version 12.0.
[0528] Exemplary compounds of formula (I) include, but are not
limited to: [0529]
4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0530]
4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-11(10H)-one; [0531]
4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0532]
10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azu-
len-11(10H)-one; [0533]
10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[-
cd,f]azulen-11(10H)-one; [0534]
4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0535] ethyl
4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;
[0536]
4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one; [0537]
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0538]
4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-t-
etraazadibenzo[cd,f]azulene-7-sulfonamide; [0539]
4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[-
cd,f]azulen-11(10H)-one; [0540]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0541]
4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]-
azulen-11(10H)-one; [0542] methyl
3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;
[0543]
4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfo-
nyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0544]
3-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one; [0545] methyl
3-(10-methyl-7-((methylsulfonyl)methyl)-1-oxo-3,4,10,11-tetrahydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-3-yl)propanoate; [0546]
10-methyl-7-((methylsulfonyl)methyl)-3-phenethyl-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one; [0547]
3-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one; [0548]
(E)-3-(4-fluorostyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0549]
7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibe-
nzo[cd,f]azulen-11(1 OH)-one; [0550]
N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-t-
etraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide; [0551]
N-(4-(2,4-difluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,5,1-
0-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide; [0552]
4-butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulen-11(10H)-one; [0553] tert-butyl
3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxylate;
[0554]
10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0555]
4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0556]
tert-butyl
4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylate;
[0557]
10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0558]
4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0559]
4-(4-fluorophenyl)-(3,3-.sup.2H.sub.2)-10-methyl-7-((methylsulfonyl)methy-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0560]
7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadib-
enzo[cd,f]azulen-11(10H)-one; [0561]
4-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraaz-
adibenzo[cd,f]azulen-11(10H)-one; [0562] ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11--
tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;
[0563] tert-butyl
4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-
-carboxylate; [0564]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0565]
10-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0566]
7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11-
(10H)-one; [0567] ethyl
7-fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenz-
o[cd,f]azulene-3-carboxylate; [0568]
4-(4-fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methy-
lsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)--
one; [0569]
4-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methyl-
sulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-o-
ne; [0570]
5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0571] ethyl
4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10--
tetraazadibenzo[cd,f]azulene-3-carboxylate; [0572]
N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0573]
N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-1-oxo-10,11-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0574]
N-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0575]
4-butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulen-11(10H)-one; [0576]
5,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]-
azulen-11(10H)-one; [0577]
4-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulen-11(10H)-one; [0578] methyl
4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd-
,f]azulen-4(3H)-yl)butanoate; [0579]
5,7-difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadib-
enzo[cd,f]azulen-11(10H)-one; [0580]
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0581]
2-ethylhexyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0582]
4-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-11(10H)-one; [0583]
5,7-difluoro-10-methyl-4-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd-
,f]azulen-11(10H)-one; [0584]
4-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0585]
4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dih-
ydro-H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0586]
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11--
tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0587]
4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0588]
4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-(-
(methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11-
(10H)-one; [0589]
N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0590]
N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0591]
N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0592]
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0593]
N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0594]
N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide; [0595]
N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0596]
N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0597]
N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0598]
N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0599]
N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methy-
l)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxa-
mide; [0600] ethyl
4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1-
,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxyla-
te; [0601]
N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;
[0602]
10-methyl-7-((methylsulfonyl)methyl)-4-tosyl-3,4-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-11(10H)-one; [0603]
4-([1,1'-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0604]
4-((4-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0605]
10-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0606]
4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0607]
10-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0608]
4-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0609]
4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one; [0610] methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;
[0611]
4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaaz-
adibenzo[cd,f]azulen-11(10H)-one; [0612] (R)-ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11--
tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;
[0613] (S)-ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;
[0614] 2-methoxyethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0615] ethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0616] pentyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0617] 4-chlorobutyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0618] naphthalen-2-yl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0619] p-tolyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0620] neopentyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0621] phenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0622] 4-fluorophenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0623] 2-methoxyphenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0624] 2-fluoroethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0625] 4-methoxyphenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0626] but-2-yn-1-yl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate; [0627]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;
[0628]
4-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0629]
4-(3-methoxypropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0630]
4-([1,1'-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0631]
4-(3-cyclopentylpropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0632]
4-(2-(3-methoxyphenyl)acetyl)-10-methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0633]
10-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one; [0634]
10-methyl-4-(3-methylbutanoyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0635]
4-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0636]
10-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0637]
4-benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one; [0638]
4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0639] methyl
4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-4(3H)-yl)-4-oxobutanoate; [0640]
4-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0641]
4-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0642]
4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one;
[0643]
4-(cyclopropanecarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0644]
10-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropanoyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0645]
2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindo-
line-1,3-dione; [0646]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropan-
amide; [0647]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpr-
opanamide; [0648]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholi-
no-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-on-
e; [0649]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-1-
1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(te-
trahydro-2H-pyran-4-yl)propanamide; [0650]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N'-methyl-N'-p-
henylpropanehydrazide; [0651]
N-benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-1-
1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propan-
amide; [0652]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxido-
tetrahydrothiophen-3-yl)propanamide; [0653] tert-butyl
4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)pi-
perazine-1-carboxylate; [0654] tert-butyl
4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamido)-
piperidine-1-carboxylate; [0655]
4-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulene-2-carboxamide; [0656]
6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexyl
acetate; [0657]
3-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfony-
l)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0658]
N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methy-
l)amino)(dimethylamino)methylene)-N-methylmethanaminium; [0659]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(p-
iperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one; [0660]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-
-yl)propanamide; [0661]
4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyl
diacetate; [0662] methyl
5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate;
[0663] tert-butyl
(2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino-
)-2-oxoethyl)carbamate; [0664]
4-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0665]
N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzami-
de; [0666]
1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-
-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)meth-
yl)-3-phenylurea; [0667]
2-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-1-
1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl-
)acetamide; [0668]
4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfony-
l)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0669]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;
[0670]
4-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsul-
fonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0671]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-p-
henoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0672]
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3--
(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)--
one; [0673]
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phen-
oxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0674]
4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,-
4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0675]
4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)m-
ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0676]
4-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0677]
4-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one; [0678]
4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,-
4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0679]
10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0680]
4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulf-
onyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0681]
4-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0682]
N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)meth-
yl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-car-
boxamide; [0683] methyl
2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)aceta-
te; [0684]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11--
oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene--
3-carboxamide; [0685]
N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;
[0686]
N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)m-
ethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3--
carboxamide; [0687]
N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide-
; [0688]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azu-
lene-3-carboxamide; [0689]
4-(2,4-difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-
-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxami-
de; [0690]
4-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methyls-
ulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulene-3-carboxamide; [0691]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-y-
lmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene--
3-carboxamide; [0692]
N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl-
)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene--
3-carboxamide; [0693]
4-(2,4-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methyls-
ulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulene-3-carboxamide; [0694]
4-(2,4-difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((met-
hylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd-
,f]azulene-3-carboxamide; [0695]
4-(2,4-difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfon-
yl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-
e-3-carboxamide; [0696]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-p-
henylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-ca-
rboxamide; [0697]
4-(3,3-dimethylbutanoyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one; [0698] tert-butyl
((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate; [0699]
4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0700]
4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0701] ethyl
5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]-
azulene-4(3H)-carboxylate; [0702]
4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulf-
onyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0703]
4-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((m-
ethylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1-
0H)-one; [0704]
4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methy-
lsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)--
one; [0705]
2-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-7-yl)acetonitrile; [0706]
4-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)m-
ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0707]
2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-4(3H)-yl)pyrrolidin-1-yl)acetic acid;
[0708]
10-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0709]
10-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0710]
10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0711]
4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0712]
10-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethy-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0713]
4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0714]
4-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0715]
10-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0716]
10-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0717]
10-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0718]
4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0719]
10-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0720]
4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile; [0721]
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinometh-
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0722]
N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0723]
5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)-
methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0724] tert-butyl
(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate; [0725]
tert-butyl
((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;
[0726]
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0727]
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11--
tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;
[0728]
4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)met-
hyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0729]
4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulene-2-carbonitrile; [0730]
4-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0731]
4-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11--
oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamid-
e; [0732]
(S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)meth-
yl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)m-
ethyl)isoindoline-1,3-dione; [0733]
(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)iso-
indoline-1,3-dione; [0734]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile;
[0735]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,-
10-triazadibenzo[cd,f]azulen-11(10H)-one; [0736] ethyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate;
[0737]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0738]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;
[0739]
10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0740]
4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0741]
4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0742]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0743]
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3--
phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0744]
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0745]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-
-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one; [0746]
4-(2,4-difluorophenyl)-(3,3-.sup.2H.sub.2)-10-methyl-7-((methylsul-
fonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0747]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neop-
entyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0748]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoi-
ndolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one; [0749]
4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfon-
yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0750]
4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methy-
lsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)--
one; [0751]
3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsu-
lfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one-
; [0752] methyl
(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate; [0753]
methyl
((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;
[0754] methyl
((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;
[0755]
2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl-
)isoindoline-1,3-dione; [0756]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-
-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-on-
e; [0757] benzyl
(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamat-
e; [0758]
3-([1,1'-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((me-
thylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10-
H)-one; [0759]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-
-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0760]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2--
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0761]
3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methy-
lsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)--
one; [0762]
4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;
[0763]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(-
pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1
(10H)-one; [0764]
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;
[0765]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2--
oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azule-
n-11(1 OH)-one; [0766] ethyl
4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-c-
arboxylate; [0767]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;
[0768] 4-(2,4-difluorophenyl)-N,
10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4-
,10-triazadibenzo[cd,f]azulene-5-carboxamide; [0769]
4-(2,4-difluorophenyl)-N,N,
10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,-
4,10-triazadibenzo[cd,f]azulene-5-carboxamide; [0770]
N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide; [0771]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,-
10-triazadibenzo[cd,f]azulen-11(10H)-one; [0772]
4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0773]
4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0774]
4-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulen-11(10H)-one; [0775]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0776]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0777]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0778]
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxo-
pyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1-
1(1 OH)-one; [0779]
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxo-
pyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1-
1(1 OH)-one; [0780]
10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0781]
4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0782]
10-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0783]
4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0784]
4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0785]
4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0786]
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0787]
4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methy-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0788]
2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-4(3H)-yl)-2-phenylacetonitrile; [0789]
2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide;
[0790]
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10-
,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic
acid; [0791]
10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)ben-
zyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0792]
(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-11(10H)-one; [0793]
10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4-
,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one; [0794]
(S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulen-11(10H)-one; [0795] (R)-methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;
[0796] (S)-methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;
[0797]
4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(m-
ethylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one-
; [0798]
4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(meth-
ylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
[0799]
(R)--N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;
[0800]
10-methyl-2-(1-methyl-H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-
-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one; [0801]
10-methyl-2-(1-methyl-H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; [0802]
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one; and
4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfo-
nyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;
or pharmaceutically acceptable salts thereof.
[0803] 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.
[0804] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[0805] 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.
[0806] 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.
[0807] 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.
[0808] 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.
[0809] The present invention contemplates compounds of formula (I)
formed by synthetic means or formed by in vivo biotransformation of
a prodrug.
[0810] 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
[0811] 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 1-6. The
variables A.sup.1, A.sup.2, A.sup.3, A.sup.4, Y.sup.1, Y.sup.2,
Y.sup.3, 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.
[0812] Abbreviations used in the descriptions of the schemes and
the specific examples have the following meanings: DMF for
dimethylformamide, DMSO for dimethyl sulfoxide, mCPBA for
3-chloroperbenzoic acid, Pd(OAc).sub.2 for palladium(II) acetate,
SFC for Supercritical Fluid Chromatography, THF for
tetrahydrofuran, TFA for trifluoroacetic acid, and HPLC for high
performance liquid chromatography.
##STR00004##
[0813] Compounds of general formula (I) wherein Y.sup.2 is
CR.sup.4R.sup.5 may be prepared by treating compounds of 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 a reagent such as titanium
tetrachloride in a solvent such as, but not limited to,
tetrahydrofuran or dichloromethane, at a temperature ranging from
0.degree. C. to 50.degree. C. Alternatively, this cyclization
reaction may also 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 50.degree. C. to 150.degree. C.
##STR00005##
[0814] Compounds of formula (1) wherein Y.sup.1 and Y.sup.3 are CH
and R.sup.2 is H may be prepared by general synthetic methods as
shown in Scheme 2. Treatment of compounds of formula (4) wherein X
is Br, Cl, or I, with 1,1-dimethoxy-N,N-dimethylmethanamine at
elevated temperature (e.g. about 60.degree. C. to about 100.degree.
C.), in the absence or presence of a base, and in a solvent such
as, but not limited to, DMF, provide compounds of formula (5).
Examples of suitable bases include, but are not limited to, lithium
or sodium methanolate. Catalytic hydrogenation of (5) in the
presence of a catalyst such as, but not limited to, Raney-Nickel
and under hydrogen atmosphere (about 30 psi) and in a solvent such
as, but not limited to, ethyl acetate, at about room temperature
generally affords compounds of formula (6). Protection of the
nitrogen atom with protecting group such as, but not limited to,
benzyl, tosyl, or (trimethylsilyl)ethoxy)methyl group may be
derived from reaction with an appropriate halide in the presence of
a strong base such as, but not limited to, sodium hydride, to
provide compounds of formula (7).
[0815] Treatment of (7) with an acid such as, but not limited to,
hydrochloric acid or hydrobromic acid and in a solvent such as, but
not limited to, dioxane or water, at about 40.degree. C. to about
100.degree. C., typically provides compounds of formula (8).
[0816] Alkylation of (8) with an halide or mesylate, in the
presence of a base such as, but not limited to, sodium hydride,
cesium carbonate, or potassium carbonate, and in a solvent such as,
but not limited to, dimethylformamide or dimethylsulfoxide at a
temperature of about 0.degree. C. to about 50.degree. C. provides
compounds of formula (9).
[0817] Treatment of the compounds of formula (9) with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) affords
compounds of formula (10). In general, the conversion may be
facilitated by a palladium catalyst such as, but not limited to,
tetrakis(triphenylphosphine)palladium(O),
tris(dibenzylideneacetone)dipalladium(O), or palladium(II)acetate,
an optional ligand such as, but not limited to,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), or
1,1'-bis(diphenylphosphanyl) ferrocene, and a base such as, but not
limited to, carbonates, acetates, or phosphates of sodium,
potassium, and cesium; and cesium fluoride. Non-limiting examples
of suitable solvents include methanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran,
and water, or a mixture thereof. Compounds of formula (13) may be
prepared by (a) treating compounds of formula (10) with compounds
of formula (11) wherein X.sup.101 is halide, mesylate, or triflate,
under Suzuki coupling conditions (N. Miyama and A. Suzuki, Chem.
Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148), to
provide compounds of formula (12), and (b) removal of the
protecting group (PG), as illustrated in Scheme 2. Removal of the
protecting group may also occur in situ under the Suzuki reaction
conditions. Generally, the coupling reaction is effected 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 (for example, at 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(O),
tris(dibenzylideneacetone)dipalladium(O), 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 not limited to,
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and
1,1'-bis(diphenylphosphanyl) ferrocene. Non-limiting examples of
suitable solvent include methanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran,
and water, or a mixture thereof.
[0818] Alternatively, treatment of compounds of formula (9) wherein
X is I, Br, Cl, or triflate with boronic acid or derivatives
thereof (e.g. boronic esters) of formula (14), under Suzuki
coupling conditions as described above, may also afford compounds
of formula (12). Removal of the protecting group may take place
under the Suzuki reaction conditions to provide compounds of
formula (13).
##STR00006##
[0819] Compounds of formula (11) wherein X.sup.101 is I, Br, or Cl
and formula (14) may be prepared according to the synthesis
outlined in Scheme 3. Reductive amination of amines (15) wherein
X.sup.101 is I, Br, or Cl with a suitable aldehyde or ketone in the
presence of a reducing agent such as, for example, sodium
triacetoxyhydroborate, sodium borohydride, or sodium
cyanoborohydride, and an acid (e.g. acetic acid), provides
compounds (11) 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.
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. Compounds of formula
(14) may be prepared from compounds of formula (11) under Suzuki
coupling conditions as described in Scheme 2.
[0820] Alternatively, compounds of formula (11) may be prepared
using Buchwald reaction conditions. Halides (16) may be treated
with a suitable amine (17) in the presence of a catalyst, a ligand,
a base, and in a solvent to provide compounds of formula (18).
Examples of catalysts that may be employed include, but are not
limited to, tetrakis(triphenylphosphine)palladium(O),
tris(dibenzylideneacetone)dipalladium(O),
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-phosphaadamante,
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 (18) by reaction with a reagent such as, but
not limited to, N-bromosuccinimide 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 (11) wherein X.sup.101 is I or Br.
##STR00007##
[0821] Compounds of general formula (3) wherein R.sup.2 is H may be
prepared according to the synthesis outlined in Scheme 4. Compounds
of formula (20) may be prepared by treating compounds of formula
(18) with (15) wherein X.sup.101 is halide, mesylate, or triflate
under Suzuki coupling conditions as described in Scheme 2.
Compounds of formula (20) may also be prepared by treating
compounds of formula (21), wherein X.sup.103 is halide, mesylate,
or triflate, with a boronic acid (or a boronic acid derivative)
(22) under Suzuki coupling conditions. Deprotection of compound
(20) under suitable conditions provides compounds of formula (23).
Compounds of formula (24) may be prepared by treating compounds of
the formula (23) with an aldehyde or ketone (2) using conditions
described in Scheme 1. Compounds of formula (25) 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 (24) with suitable aldehydes or ketones,
employing reaction conditions described in Scheme 3. Similarly,
reductive amination of compounds of formula (20) with suitable
aldehydes or ketones provides compounds of formula (26). Compounds
of general formula (25) 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 (24) 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##
[0822] Compounds of formula (21) wherein X.sup.103 is Cl, Y.sup.1
is N and Y.sup.3 is CH may be prepared according to the synthesis
described in Scheme 5. Treatment of (27) with ammonium hydroxide at
about 100.degree. C. to about 150.degree. C. affords amines of
formula (28).
[0823] Iodination of (28) with N-iodosuccinimide in a solvent such
as, but not limited to, acetonitrile or acetone, at a temperature
of about 40.degree. C. to about 85.degree. C., yields compounds of
formula (29). Subsequent coupling with
(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
utilizing Suzuki coupling reaction conditions as described above
provides compounds of formula (30). Cyclization of (30) followed by
protection of the nitrogen atom affords compounds of formula
(31).
[0824] Cyclization of (30) may be accomplished in the presence of
an acid such as, but not limited to, acetic acid or hydrochloric
acid and at an elevated temperature (e.g. about 50.degree. C. to
about 100.degree. C.).
##STR00009##
[0825] Compounds of formula (38) may be prepared according to
Scheme 6. Esters of formula (33) may be obtained from (a) treatment
of formula (4) with diethyl oxalate in the presence of a base such
as, but not limited to, potassium ethoxide or sodium ethoxide, in a
solvent such as, but not limited to, ethanol, dioxane, and diethyl
ether, and at a temperature of about 40.degree. C. to about
80.degree. C.; and (b) cyclization of the resulting intermediate
(32) in the presence of iron and in ethanol and acetic acid, at a
temperature of about 80.degree. C. to about 100.degree. C.
Conversion of (33) to (36) may be accomplished by employing
reaction conditions discussed above.
[0826] Utilizing reaction conditions described in Schemes 1-5,
intermediates (36) may be transformed to compounds (37). Hydrolysis
of the ester function of (37), followed by coupling of the
resulting acids with a suitable amines of formula
NHR.sup.3bR.sup.3c provides compounds of formula (38).
[0827] 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.
[0828] 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.
[0829] 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.
[0830] 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.
[0831] 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).
[0832] 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
[0833] 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.
[0834] 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.
[0835] 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.
[0836] 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.
[0837] 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.
[0838] 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.
[0839] 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.
[0840] 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.
[0841] 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.
[0842] 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.
[0843] 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.
[0844] 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.
[0845] 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.
[0846] 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.
[0847] 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.
[0848] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0849] 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.
[0850] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0851] 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.
[0852] 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.
[0853] 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.
[0854] 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.
[0855] 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
[0856] 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.
[0857] 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.
[0858] 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, cardiac myopathy, 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.
[0859] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat AIDS.
[0860] 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.
[0861] 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.
[0862] 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).
[0863] 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.
[0864] 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.
[0865] 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.
[0866] 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.
[0867] 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.
[0868] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0869] 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.
[0870] 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.
[0871] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[0872] 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.
[0873] 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.
[0874] 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.
[0875] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafamib), 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.
[0876] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0877] 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,
PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[0878] Inhibitors of inhibitors of apoptosis proteins include HGS
1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[0879] 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
[0880] 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.
[0881] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[0882] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[0883] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0884] 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.
[0885] 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.
[0886] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0887] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[0888] Polo-like kinase inhibitors include BI-2536 and the
like.
[0889] 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.
[0890] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0891] 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.
[0892] 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.
[0893] 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.
[0894] 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.
[0895] 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.
[0896] 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.
[0897] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[0898] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0899] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0900] 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-1 b) 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-muHMFGi),
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.
[0901] 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,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0902] 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.
[0903] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[0904] 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.
[0905] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[0906] 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.
[0907] Additionally, compounds having Formula (I) may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (famesyl 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, EP0906 (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.
[0908] 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 TGFP.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.
[0909] 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.
[0910] 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.1.alpha. (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.).
[0911] 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.
[0912] 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.).
[0913] 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.
[0914] 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.
[0915] 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.
[0916] 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.
[0917] 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-13 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.).
[0918] 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.
[0919] A compound of Formula (I) may also be co-administered with
insulin for the treatment of type I diabetes.
[0920] 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.
[0921] 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.
[0922] 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, glibomuride, gliclazide, glimepiride, glipizide,
gliquidone, glisoxepide, glyclopyramide, tolbutamide, and
tolazamide), nonsulfonylureas (e.g., nateglinide, and repaglinide),
and thiazolidinediones (e.g., pioglitazone).
[0923] 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.
[0924] 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.
[0925] The following Examples may be used for illustrative purposes
and should not be deemed to narrow the scope of the invention.
EXAMPLES
Example 1
4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
Example 1a
(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine
[0926] 5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7
mmol) was dissolved in dimethylformamide (300 mL), and lithium
methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction
mixture was heated at 100.degree. C. To this mixture was added
1,1-dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10
minutes. The reaction mixture was stirred at 95.degree. C. for 16
hours. The reaction mixture was cooled to ambient temperature and
water was added carefully (300 mL, exothermic). The resulting
precipitate was collected by vacuum filtration, washed with water,
and dried to provide the title compound (13.9 g, 45.9 mmol, 76%
yield).
Example 1b
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
[0927] Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL)
were added to Ra-Ni 2800 (pre-washed with ethanol), water slurry
(6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred
for 30 minutes at 30 psi and ambient temperature. The reaction
mixture was filtered, and concentrated. The residue was triturated
with dichloromethane, and the solid filtered to provide the title
compound (5.82 g). The mother liquor was concentrated and the
residue triturated again with dichloromethane and filtered to
provide an additional 1.63 g of the title compound. Total
yield=7.45 g, 72% yield
Example 1c
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[0928] A solution of Example 1b (7.42 g, 32.7 mmol) in
dimethylformamide (235 mL) was stirred at ambient temperature. To
this solution was added sodium hydride (1.18 g, 1.96 g of 60%
dispersion in oil, 49.0 mmol), and the reaction mixture was stirred
for 10 minutes. P-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was
then added portion-wise, and the mixture was stirred at ambient
temperature under nitrogen for 16 hours. The reaction mixture was
quenched carefully with water and the resulting beige solid
collected by vacuum filtration on a Buchner funnel, and washed with
water. The solid was collected and dried in a vacuum oven at
50.degree. C. to provide 12.4 g (100%) of the title compound.
Example 1d
4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0929] A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140
mL) was stirred at ambient temperature. To this solution was added
4M HCl in dioxane (140 mL). The reaction mixture was stirred at
40.degree. C. for 16 hours. The reaction mixture was cooled to
ambient temperature and concentrated. The residue was triturated
with diethylether, filtered, and rinsed with additional
diethylether and dried to provide the title compound (11.23 g, 30.6
mmol, 94% yield) as a beige solid.
Example 1e
4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0930] Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil
dispersion) was added to a stirring solution of Example 1d (11.2 g,
30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30
minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the
solution was stirred at ambient temperature for 3 hours. Upon
addition of water (250 mL) a precipitate formed. The precipitate
was collected by vacuum filtration, rinsed with water (50 mL) and
dried in a vacuum oven at 55.degree. C. overnight to provide 11.2 g
of the title compound (96%).
Example 1f
6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrol-
o[2,3-c]pyridin-7(6H)-one
[0931] Example 1e (6.55 g, 17.2 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.73
g, 34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),
tris(dibenzylideneacetone)dipalladium(O) (0.393 g, 0.430 mmol) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS,
0.819 g, 1.72 mmol) were combined and sparged with argon for 1 hour
with stirring. Dioxane (86 mL) was sparged with nitrogen for 1
hour, transferred via cannula under nitrogen to the solid
components, and the mixture was heated under argon at 80.degree. C.
for 5 hours. The reaction mixture was cooled to ambient
temperature, partitioned between ethyl acetate and water, and
filtered through Celite. The ethyl acetate layer was washed twice
with saturated aqueous sodium chloride, dried (anhydrous sodium
sulfate), filtered and concentrated. The residue was purified by
chromatography (silica gel, 25-80% ethyl acetate in hexane). The
resulting material from chromatography was triturated with a
minimal amount of hexanes (30 mL) and the particulate solid was
collected by filtration, rinsed with a minimal amount of hexanes
and dried to constant mass to afford the title compound (5.4 g,
73%).
Example 1g
(3-bromo-4-fluorophenyl)(isopropyl)sulfane
[0932] A 250 mL round bottomed flask was charged with
3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol), sodium hydroxide
(3.95 mL, 19.73 mmol) and methanol. The reaction mixture was
stirred at 0.degree. C. for 10 minutes. To this solution was added
2-iodopropane (3.83 g, 22.54 mmol). The reaction mixture was
stirred at ambient temperature for 6 hours. The solvent was
removed, and the residue 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 to provide the title
compound.
Example 1h
2-bromo-1-fluoro-4-(isopropylsulfonyl)benzene
[0933] A 500 mL round bottomed flask was charged with Example 1g
(4.0 g, 16.06 mmol) and dichloromethane (200 mL). mCPBA (8.71 g,
35.3 mmol) was added. The reaction mixture was stirred at ambient
temperature for 6 hours. The reaction mixture was filtered, and the
solids were washed by additional dichloromethane. The filtrate was
washed with 10% NaOH (50 mL, twice), then saturated sodium
bicarbonate. The organic layer was concentrated, and the residue
was purified by flash chromatography on silica gel (15% ethyl
acetate in heptanes) to provide the title compound.
Example 1i
2-bromo-N-(cyclopropylmethyl)-4-(isopropylsulfonyl)aniline
[0934] A mixture of Example 1h (0.562 g, 2 mmol) and
cyclopropylmethanamine (0.427 g, 6.00 mmol) in dioxane (10 mL) was
heated at 100.degree. C. overnight. The solvent was removed, and
the residue was purified by flash chromatography (50% ethyl acetate
in heptanes) to provide the title compound.
Example 1j
4-(2-((cyclopropylmethyl)amino)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-p-
yrrolo[2,3-c]pyridin-7(6H)-one
[0935] A mixture of Example 1f (0.086 g, 0.2 mmol), Example 1i
(0.066 g, 0.2 mmol), cesium fluoride (0.091 g, 0.600 mmol), and
tetrakistriphenylphosphine palladium (0.012 g, 10.00 .mu.mol) in
dimethoxyethane (2 mL) and methanol (1 mL) was heated under
microwave conditions (120 C, 40 min). The reaction mixture was
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 residue was
purified by reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA),
0-100% gradient) to provide the title compound.
Example 1k
4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
[0936] A 4 mL vial was charged with Example 1j (0.0106 g, 0.027
mmol), paraformaldehyde (3.98 mg, 0.133 mmol) and methanol (0.265
mL) to give a white suspension. Hydrochloric acid (4N in dioxane,
0.133 mL, 0.531 mmol) was added. The vial was closed and the
reaction mixture was heated at 90.degree. C. for 1 hour. The
reaction mixture was cooled to ambient temperature and diluted with
ether. The resulting suspension was filtered, and the solid was
rinsed with ether, collected, and dried in a 60.degree. C. vacuum
oven overnight to provide a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.83 (s, 1H), 8.04 (d, J=2.04 Hz, 1H), 7.65
(m, 2H), 7.41 (d, J=8.82 Hz, 1H), 7.18 (d, J=2.03 Hz, 1H), 4.26 (s,
2H), 3.64 (s, 3H), 3.49 (m, 1H), 3.03 (d, J=6.1 Hz, 2H), 1.20 (d,
J=6.78 Hz, 6H), 0.90 (m, 1H), 0.41 (m, 2H), 0.09 (q, J=4.63 Hz,
2H). MS (ESI+) m/z 412.1 (M+H).sup.+.
Example 2
4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
Example 2a
(3-bromo-4-fluorophenyl)(ethyl)sulfane
[0937] A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79
mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in methanol was
stirred at 0.degree. C. for 10 minutes. To this solution was added
iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred
at ambient temperature for 6 hours. The solvent was removed, and
the residue was partitioned between water and ethyl acetate. The
aqueous layer was extracted with addition ethyl acetate three
times. The combined organic layers were washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated to give the title compound (4.35 g,
18.50 mmol, 98% yield).
Example 2b
2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
[0938] Example 2a (4.4 g, 18.71 mmol) in dichloromethane (250 mL)
was cooled to 0.degree. C. To this solution was treated with mCPBA
(10.15 g, 41.2 mmol) portionwise. The reaction mixture was stirred
at ambient temperature for 6 hours. The solid from the reaction
mixture was removed by filtration. The filtrate was washed with
saturated aqueous sodium bicarbonate several times. The aqueous
layer was then extracted with additional dichloromethane 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
chromatography on silica gel eluting with 15% ethyl acetate/hexanes
to afford the title compound (4.4 g, 16.47 mmol, 88% yield).
Example 2c
2-bromo-N-(cyclopropylmethyl)-4-(ethylsulfonyl)aniline
[0939] Example 2c was prepared according to the procedure used for
the preparation of Example 1i, substituting Example 2b for Example
1h, to provide the title compound.
Example 2d
4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[0940] Example 2d was prepared according to the procedure used for
the preparation of Example 1j, substituting Example 2c for Example
1i, to provide the title compound.
Example 2e
4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
[0941] A mixture of Example 2d (0.03 g, 0.078 mmol) and
paraformaldehyde (0.012 g, 0.389 mmol) in methanol (0.778 mL) was
treated with 4M hydrogen chloride (0.389 mL, 1.557 mmol). The
mixture was heated at 90.degree. C. for 1 hour, cooled, and
concentrated. Purification by chromatography (silica gel, 1-5%
methanol in dichloromethane) afforded the title compound (0.022 g,
71%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.51 (s, 1H),
8.08 (d, J=2.14 Hz, 1H), 7.66 (dd, J=8.54, 2.14 Hz, 1H), 7.58 (s,
1H), 7.44 (d, J=8.54 Hz, 1H), 7.12 (d, J=2.75 Hz, 1H), 4.27 (s,
2H), 3.64 (s, 3H), 3.28 (d, J=7.32 Hz, 2H), 3.03 (d, J=6.10 Hz,
2H), 1.18 (t, J=7.32 Hz, 3H), 0.83-0.98 (m, 1H), 0.33-0.43 (m, 2H),
0.04-0.11 (m, 2H). MS (ESI+) m/z 398 (M+H).sup.+.
Example 3
4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0942] A mixture of Example 2d (0.045 g, 0.117 mmol) and
propionaldehyde (0.136 g, 2.335 mmol) in methanol (1.167 mL) was
treated with 4M hydrogen chloride (0.584 mL, 2.34 mmol). The
mixture was heated at 90.degree. C. for 3 hours, cooled and
concentrated. The residue was dissolved in ethyl acetate, washed
with 5% aqueous sodium bicarbonate, saturated aqueous sodium
chloride, dried (anhydrous Na.sub.2SO.sub.4), filtered and
concentrated. Purification by chromatography (silica gel, 0-5%
methanol in dichloromethane) afforded a solid that was triturated
in a minimal amount of 30% ethyl acetate in heptanes to afford the
title compound (0.017 g, 34%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.83 (s, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.65 (dd,
J=8.31, 2.20 Hz, 1H), 7.41 (d, J=8.48 Hz, 1H), 7.14 (d, J=2.37 Hz,
1H), 4.37 (s, 1H), 3.64 (s, 3H), 3.37 (q, J=7.29 Hz, 2H), 3.13 (s,
1H), 2.93 (s, 1H), 1.41-1.59 (m, 1H), 1.14 (t, J=7.29 Hz, 3H),
1.03-1.09 (m, 1H), 0.86 (t, J=6.78 Hz, 3H), 0.77-0.88 (m, 1H), 0.36
(d, J=8.14 Hz, 2H), 0.03-0.10 (m, 2H). MS (ESI+) m/z 426
(M+H).sup.+.
Example 4
10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azul-
en-11(1 OH)-one
Example 4a
4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0943] 2-bromo-4-(methylsulfonyl)aniline (1.0 g, 4.00 mmol),
Example 1f (1.712 g, 4.00 mmol),
tris(dibenzylideneacetone)dipalladium (O) (0.110 g, 0.120 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.117 g, 0.400 mmol) and sodium carbonate (1.483 g, 13.99 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (26 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 3 hours at 60.degree. C.,
cooled, diluted into 100 mL of water and the resulting solid was
collected by filtration, washed with water and dried to constant
mass to afford the title compound (2.05 g, 100%).
Example 4b
4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[0944] Example 4b was prepared according to the procedure used for
the preparation of Example 5e, substituting Example 4a for Example
5d. Purification by trituration in dichloromethane afforded the
title compound (0.55 g, 82%).
Example 4c
10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azul-
en-1(10H)-one
[0945] Example 4c was prepared according to the procedure used for
the preparation of Example 1k, substituting Example 4b for Example
1j, to afford the title compound as the HCl salt (0.046 g, 98%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.53 (s, 1H), 8.14 (d,
J=2.14 Hz, 1H), 7.63 (s, 1H), 7.56 (dd, J=8.39, 2.29 Hz, 1H), 7.23
(d, J=8.54 Hz, 1H), 7.13 (d, J=2.44 Hz, 1H), 4.23 (s, 2H), 3.65 (s,
3H), 3.17 (s, 3H). MS (ESI+) m/z 330 (M+H).sup.+.
Example 5
10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[c-
d,f]azulen-11(10H)-one
Example 5a
1-((methylsulfonyl)methyl)-4-nitrobenzene
[0946] To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol)
in N,N-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 and diluted with water. The resulting suspension was
stirred 10 minutes and filtered through a medium frit to provide
the title compound.
Example 5b
4-((methylsulfonyl)methyl)aniline
[0947] Example 5a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL)
were added to 5% Pd/C, wet (1.6 g, 0.376 mmol) in a 50 mL pressure
bottle and stirred for 2 hours at 30 psi and 50.degree. C. The
mixture was filtered through a nylon membrane and washed with a
small amount of tetrahydrofuran and methanol. The solvent was
removed to provide the title compound.
Example 5c
2-iodo-4-((methylsulfonyl)methyl)aniline
[0948] To a solution of Example 5b (3.80 g, 20.51 mmol) in
N,N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g,
22.56 mmol). The reaction mixture was stirred at ambient
temperature for 1 hour. The reaction mixture was quenched with 150
mL 10% sodium thiosulfate and 100 mL saturated sodium bicarbonate.
The reaction mixture was extracted 3.times. with ethyl acetate. The
combined organic layers were washed with saturated aqueous sodium
chloride and concentrated. Water was added, and the resulting
suspension was stirred at ambient temperature for 10 minutes. The
suspension was filtered and dried overnight to provide the title
compound.
Example 5d
4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2-
,3-c]pyridin-7(6H)-one
[0949] A 100 mL round-bottomed flask was charged with Example 5c
(0.160 g, 0.514 mmol), Example 1f (0.200 g, 0.467 mmol), potassium
phosphate (0.446 g, 2.101 mmol),
tris(dibenzylideneacetone)dipalladium (II) (0.021 g, 0.023 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.023 g, 0.079 mmol). The solids were flow purged with nitrogen
for 30 minutes. Degassed dioxane (3.74 mL) and water (0.934 mL)
were added. The reaction mixture was heated at 60.degree. C. for 3
hours. The reaction mixture was cooled to ambient temperature and
diluted with water. The resulting suspension was filtered, and the
brown solid was collected.
Example 5e
4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0950] A 250 mL round-bottomed flask was charged with Example 5d
(0.230 g, 0.474 mmol), potassium hydroxide (0.691 g, 12.32 mmol),
N,N,N-trimethylhexadecan-1-aminium bromide (8.63 mg, 0.024 mmol),
dioxane (3.55 mL) and water (1.18 mL) to give a light yellow
solution. The reaction mixture was heated at 90.degree. C.
overnight. The reaction mixture was cooled to ambient temperature
and treated with 1N hydrochloric acid to achieve a pH of 1. The
reaction mixture was extracted with twice 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
(0%-10% methanol in dichloromethane) to provide the title
compound.
Example 5f
10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[c-
d,f]azulen-11(1H)-one
[0951] A 20 mL microwave tube was charged with Example 5e (0.0397
g, 0.120 mmol), paraformaldehyde (0.018 g, 0.599 mmol) and methanol
(1.198 mL) to give a white suspension. Hydrochloric acid (4N in
dioxane 0.599 mL, 2.396 mmol) was added. The reaction mixture was
heated at 90.degree. C. for 1 hour. The reaction mixture was cooled
to ambient temperature and diluted with ether and ethyl acetate.
The reaction mixture was washed with saturated sodium bicarbonate
and saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography (0%-10% methanol in
dichloromethane) to provide the title compound. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.75 (s, 1H), 7.68 (d, J=1.8 Hz, 1H),
7.50 (s, 1H), 7.07-7.15 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 4.37 (s,
2H), 4.11 (d, J=3.2 Hz, 2H), 3.61 (s, 3H), 2.90 (s, 3H). MS (ESI+)
m/z 344.4 (M+H).sup.+.
Example 6
4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 6a
N-(cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline
[0952] Example 5c (0.200 g, 0.643 mmol) and
cyclopropanecarbaldehyde (0.062 mL, 0.836 mmol) were suspended in
dichloromethane (3.21 mL) and methanol (3.21 mL). Acetic acid
(0.368 mL, 6.43 mmol) was added. The reaction mixture was heated at
50.degree. C. for 30 minutes, then cooled to ambient temperature.
Polymer supported cyanoborohydride (0.817 g, 1.928 mmol) was added.
The reaction mixture was stirred at ambient temperature overnight.
Cyclopropanecarbaldehyde (0.062 mL, 0.836 mmol) was added, and the
reaction mixture was stirred at ambient temperature for 2 hours.
The reaction mixture was filtered, thoroughly rinsed with
dichloromethane, and concentrated. The residue was purified by
flash chromatography (20-100% ethyl acetate/heptane) to provide the
title compound.
Example 6b
4-(2-((cyclopropylmethyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-
-1-tosyl-H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0953] A 250 mL round-bottomed flask was charged with Example 6a
(0.1546 g, 0.423 mmol), Example if (0.404 g, 1.905 mmol),
tris(dibenzylideneacetone)dipalladium (II) (0.019 g, 0.021 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.021 g, 0.072 mmol). The solids were sparged with nitrogen for 30
minutes. Degassed dioxane (3.40 mL) and water (0.850 mL) were
added. The reaction was heated at 60.degree. C. for 3 hours. The
reaction was cooled to room temperature and partitioned between
ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography (0-5% methanol/dichloromethane) to provide the
title compound (0.211 g, 92% yield).
Example 6c
4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0954] A 250 mL round-bottomed flask was charged with Example 6b
(0.211 g, 0.391 mmol), potassium hydroxide (0.570 g, 10.17 mmol),
and N,N,N-trimethylhexadecan-1-aminium bromide (7.12 mg, 0.020
mmol), dioxane (2.93 mL) and water (0.977 mL). The reaction mixture
was heated at 90.degree. C. for 2.5 hours. The reaction mixture was
cooled to ambient temperature and treated with 1N HCl to achieve a
pH of about 7. The reaction mixture was extracted with ethyl
acetate (2.times.). The combined organic extracts were washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and concentrated to provide the title
compound (0.0886 g, 59% yield).
Example 6d
4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0955] A 5 mL microwave tube was charged with Example 6c (0.027 g,
0.070 mmol), paraformaldehyde (0.032 g, 0.350 mmol) and methanol
(0.700 mL) to give a white suspension. 4N HCl in dioxane (0.350 mL,
1.401 mmol) was added. The tube was closed and the reaction was
heated at 90.degree. C. for 1 hour. The reaction was cooled to room
temperature and diluted with ether. The resulting suspension was
filtered, and the solid was rinsed with ether, collected, and dried
in a 60.degree. C. vacuum oven overnight to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6 90.degree. C.) .delta.
11.64 (m, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.39-7.52 (m, 1H), 7.32
(d, J=7.1 Hz, 1H), 7.19 (s, 1H), 4.44 (s, 2H), 4.40 (s, 2H), 3.55
(s, 1H), 2.84-2.92 (m, 5H), 0.85 (s, 1H), 0.35 (dd, J=7.9, 1.1 Hz,
2H), -0.02-0.04 (m, 2H). MS (ESI+) m/z 398.0 (M+H).sup.+.
Example 7
ethyl
4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,-
4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[0956] A 5 mL microwave tube was charged with Example 6c (0.027 g,
0.070 mmol), ethyl glyoxalate (0.069 mL, 0.350 mmol) and ethanol
(0.700 mL) to give a white suspension. Hydrochloric acid (4N in
dioxane, 0.350 mL, 1.401 mmol) was added. The suspension became a
colorless solution. The vial was closed and the reaction mixture
was heated at 90.degree. C. for 1 hour. The reaction mixture was
cooled to ambient temperature and diluted with ether. A white
precipitate formed. The resulting suspension was filtered, and the
solid was rinsed with ether, collected, and dried in a 60.degree.
C. vacuum oven overnight. The residue was purified by reverse phase
HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford
the title compound (0.0090 g, 27%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.91 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H),
7.21 (dd, J=13.0, 5.3 Hz, 4H), 5.39 (s, 1H), 4.42 (m, 2H), 3.83 (s,
2H), 3.83 (s, 2H), 3.63 (s, 3H), 2.86 (s, 3H), 0.93 (t, J=7.2 Hz,
3H), 0.83 (m, 1H), 0.29-0.46 (m, 2H), 0.07 (m, 2H). MS (ESI+) m/z
470.0 (M+H).sup.+.
Example 8
4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one
Example 8a
4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0957] Example 1f (1.71 g, 4.00 mmol),
2-bromo-4-(methylsulfonyl)aniline (1.00 g, 4.00 mmol),
tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.117
g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) were
combined and purged with argon for 15 minutes. A mixture of dioxane
(21.3 mL) and water (5.3 mL) was purged with nitrogen for 15
minutes and transferred to the reaction vessel. The reaction
mixture was heated at 60.degree. C. for 3 hours, cooled to ambient
temperature and diluted with water. The resulting solid was
filtered, washed with water and dried to afford the title compound
(2.06 g, quantitative yield).
Example 8b
4-(2-((4-fluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-
-pyrrolo[2,3-c]pyridin-7(6H)-one
[0958] Example 8a (47.2 mg, 0.100 mmol), 1-bromo-4-fluorobenzene
(17.5 mg, 0.100 mmol), diacetoxypalladium (0.9 mg, 4 .mu.mol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(3.8 mg, 8.0 .mu.mol) and cesium carbonate (45.6 mg, 0.140 mmol)
were combined in a mixture of toluene (1.6 mL) and tert-butanol
(0.4 mL). The reaction mixture was heated in a microwave reactor at
150.degree. C. for 15 minutes. The reaction mixture was partitioned
with 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
provide the title compound (30 mg, 53%).
Example 8c
4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydr-
o-7H-pyrrolo[2,3-c]pyridin-7-one
[0959] Example 8b (28 mg, 0.050 mmol), potassium hydroxide (41.7
mg, 0.743 mmol) and cetyltrimethylammonium bromide (0.90 mg, 2.5
.mu.mol) were combined in a mixture of tetrahydrofuran (2 mL) and
water (1 mL). The reaction mixture was heated at 100.degree. C. for
20 hours and then cooled to ambient temperature. To this mixture
was added water, and the pH was adjusted to pH 7 by the addition of
1M HCl. The mixture was extracted with ethyl acetate and the
organic layer was washed with saturated aqueous sodium chloride
twice, dried with anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 2-4% methanol in dichloromethane) to provide the title
compound (13 mg, 64%).
Example 8d
4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one
[0960] A 2 mL vial was charged with Example 8c (8.0 mg, 0.019
mmol), paraformaldehyde (5.8 mg, 0.19 mmol) and methanol (0.5 mL).
To this suspension was added 4M HCl in dioxane (0.097 mL, 0.39
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 this residue was added water, and the pH was
adjusted to pH 7 by addition of saturated aqueous sodium
bicarbonate. The residue was sonicated for 5 minutes and filtered
to afford the title compound (7.0 mg, 85%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.88 (d, J=1.70 Hz, 1H) 8.37 (d, J=2.37 Hz,
1H) 7.88 (dd, J=8.14, 2.37 Hz, 1H) 7.85 (s, 1H) 7.53 (d, J=8.14 Hz,
1H) 7.35 (d, J=2.37 Hz, 1H) 6.75-6.91 (m, 2H) 6.43-6.51 (m, 2H)
4.80 (s, 2H) 3.59 (s, 3H) 3.36 (s, 3H). MS (ESI+) m/z 424
(M+H).sup.+.
Example 9
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 9a
1-bromo-4-((methylsulfonyl)methyl)benzene
[0961] A 250 mL round-bottomed flask was charged with 4-bromobenzyl
bromide (5.000 g, 20.01 mmol) and N,N-dimethylformamide (10.81 mL)
to give a colorless solution. Sodium methanesulfinate (3.06 g, 30.0
mmol) was added. The reaction mixture was stirred at 65.degree. C.
for 1 hour. The reaction mixture was cooled to room 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 the title compound
(4.75 g, 95% yield).
Example 9b
4-fluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline
[0962] A 100 mL microwave tube was charged with 4-fluoroaniline
(0.388 mL, 4.04 mmol),
[0963] Example 9a (1.0065 g, 4.04 mmol), diacetoxypalladium (0.036
g, 0.162 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.154 g, 0.323 mmol), cesium carbonate (1.843 g, 5.66 mmol),
toluene (20.20 mL) and t-butanol (4.04 mL) to give a yellow
suspension. The tube was sealed, and the reaction mixture was
heated in a Milestone Ethos microwave reactor to 150.degree. C. for
15 minutes fixed hold time. The reaction mixture was filtered
through a 10 g Celite SPE column and rinsed with ethyl acetate. The
filtrate was washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered and concentrated onto
silica gel. The crude product was purified by flash chromatography
(20-100% ethyl acetate in heptanes) to provide the title compound
as an off white solid.
Example 9c
2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline
[0964] A 250 mL round-bottomed flask was charged with Example 9b
(1.32 g, 4.73 mmol) and acetic acid (47.3 mL) to give a white
suspension. The reaction mixture was cooled in a water bath.
N-bromosuccinimide (0.807 g, 4.54 mmol) was added in two portions
10 minutes apart. The reaction mixture was stirred at ambient
temperature for 1.5 hours. The reaction mixture was quenched with
10% sodium thiosulfate (40 mL) and diluted with 2N sodium hydroxide
and ethyl acetate. The layers were separated, and the organic layer
was washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered and concentrated onto silica
gel. The crude product was purified by flash chromatography (20-70%
ethyl acetate in heptanes) to provide the title compound as a white
solid.
Example 9d
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1--
tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0965] A 250 mL round-bottomed flask was charged with Example 9c
(1.9175 g, 5.35 mmol), Example if (2.084 g, 4.87 mmol), sodium
carbonate (1.805 g, 17.03 mmol),
tris(dibenzylideneacetone)dipalladium (II) (0.223 g, 0.243 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.242 g, 0.827 mmol). The solids were sparged with nitrogen for 30
minutes. Degassed dioxane (38.9 mL) and water (9.73 mL) were added.
The reaction mixture was heated at 60.degree. C. for 3 hours. The
reaction mixture was cooled to room temperature and partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate and mercaptopropyl silica gel, filtered and
concentrated. The residue was taken up into dichloromethane,
triturated with ether, and filtered to provide the title compound
(2.13 g, 75% yield).
Example 9e
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-
-pyrrolo[2,3-c]pyridin-7(6H)-one
[0966] A 250 mL round-bottomed flask was charged with Example 9d
(2.1251 g, 3.67 mmol), potassium hydroxide (5.35 g, 95 mmol), and
N,N,N-trimethylhexadecan-1-aminium bromide (0.067 g, 0.183 mmol),
dioxane (55.0 mL) and water (18.33 mL). The reaction mixture was
heated at 90.degree. C. for 2.5 hours. The reaction mixture was
cooled to room temperature and diluted to 500 mL (total volume)
with water. The resulting suspension was filtered, and the solid
was rinsed with water and allowed to dry on the frit for 1.5 hours.
The solid was collected and dried in a 60.degree. C. vacuum oven
overnight to provide the title compound (1.24 g, 80% yield).
Example 9f
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0967] A 20 mL microwave tube was charged with Example 9e (0.5195
g, 1.221 mmol), paraformaldehyde (0.550 g, 6.10 mmol) and methanol
(12.21 mL) to give a white suspension. Hydrochloric acid (4N in
dioxane, 6.10 mL, 24.42 mmol) was added. The vial was closed and
the reaction mixture was heated at 90.degree. C. for 1 hour. The
reaction mixture was cooled to ambient temperature. The reaction
mixture was partitioned between dichloromethane and saturated
sodium bicarbonate. The aqueous layer was extracted 3.times. with
dichloromethane. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue was taken up into
dichloromethane and triturated with ether. The resulting slurry was
stirred for 10 minutes, and filtered. The white solid was rinsed
with ether, collected, and dried in a 60.degree. C. vacuum oven
overnight to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.90-11.84 (m, 1H), 7.91 (d, J=1.9 Hz, 1H),
7.61 (s, 1H), 7.44 (dd, J=8.0, 1.9 Hz, 1H), 7.33 (d, J=4.9 Hz, 2H),
6.80 (t, J=8.8 Hz, 2H), 6.35-6.46 (m, 2H), 4.56 (m, 2H), 3.55 (s,
3H), 3.00 (s, 3H). MS (ESI+) m/z 438.2 (M+H).sup.+.
Example 10
4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-te-
traazadibenzo[cd,f]azulene-7-sulfonamide
Example 10a
5-bromo-6-((cyclopropylmethyl)amino)pyridine-3-sulfonamide
[0968] A mixture of 5-bromo-6-chloropyridine-3-sulfonamide (0.272
g, 1 mmol) and cyclopropylmethanamine (0.213 g, 3.00 mmol) in
dioxane (5 mL) was heated at 100.degree. C. overnight. 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 under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with 60% ethyl acetate in
hexanes to give 0.298 g (97%) of the title compound.
Example 10b
6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)pyridine-3-sulfonamide
[0969] Example 10b was prepared according to the procedure used for
the preparation of Example 1j, substituting Example 10a for Example
1i, to provide the title compound.
Example 10c
4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-te-
traazadibenzo[cd,f]azulene-7-sulfonamide
[0970] Example 10c was prepared according to the procedure used for
the preparation of Example 1k, substituting Example 10b for Example
1j, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.90 (s, 1H), 8.46 (d, J=2.44 Hz, 1H), 8.31
(d, J=2.44 Hz, 1H), 7.51 (s, 1H), 7.31 (s, 2H), 7.22 (d, J=2.44 Hz,
1H), 4.39 (s, 2H), 3.63 (s, 3H), 3.48 (d, J=6.41 Hz, 2H), 0.45 (dd,
J=8.09, 1.68 Hz, 2H), 0.25 (dd, J=4.88 Hz, 2H). MS (ESI+) m/z 386.1
(M+H).sup.+.
Example 11
4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[c-
d,f]azulen-11(1H)-one
Example 11a
3-bromo-N-(4-fluorophenyl)-5-methylpyridin-2-amine
[0971] 2-Amino-3-bromo-5-methylpyridine (0.468 g, 2.5 mmol),
4-fluoroiodobenzene (0.555 g, 2.500 mmol), diacetoxypalladium
(0.017 g, 0.075 mmol),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.043 g,
0.075 mmol) and sodium 2-methylpropan-2-olate (0.336 g, 3.50 mmol)
were combined in t-butanol (10.00 mL) and sparged with argon for 10
minutes. The mixture was heated for 60 minutes at 85.degree. C.,
cooled, diluted with 50 mL ethanol and filtered through Celite to
remove solids. The filtrate was concentrated and diluted with ethyl
acetate. The organic layer was washed with water, saturated aqueous
sodium chloride, dried (anhydrous sodium sulfate), treated with
3-mercaptopropyl functionalized silica, filtered and concentrated.
Purification by chromatography (silica gel, 0-25% ethyl acetate in
heptanes) afforded the title compound (0.317 g, 45%).
Example 11b
4-(2-((4-fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1-tosyl-1H-pyr-
rolo[2,3-c]pyridin-7(6H)-one
[0972] Example 11a (0.3 g, 1.067 mmol), Example if (0.457 g, 1.067
mmol), tris(dibenzylideneacetone)dipalladium (O) (0.029 g, 0.032
mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.031 g, 0.107 mmol) and sodium carbonate (0.396 g, 3.74 mmol)
were combined and sparged with argon for 15 minutes. 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 1 hour at 60.degree. C., cooled and
partitioned into 100 mL of water and 120 mL of dichloromethane. The
organic layer was washed with water, saturated aqueous sodium
chloride, dried (anhydrous sodium sulfate), treated with
3-mercaptopropyl functionalized silica, filtered and concentrated.
Purification by trituration in 9:1 heptane/ethyl acetate afforded
the title compound (0.46 g, 86%).
Example 11c
4-(2-((4-fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-
-c]pyridin-7(6H)-one
[0973] Example 11c was prepared according to the procedure used for
the preparation of Example 5e, substituting Example 11b for Example
5d. Purification by trituration in dichloromethane afforded the
title compound (0.20 g, 63%).
Example 11d
4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[c-
d,f]azulen-11(10H)-one
[0974] A mixture of Example 11c (0.05 g, 0.144 mmol),
paraformaldehyde (0.043 g, 1.435 mmol) and 4M hydrogen chloride
(1.076 mL, 4.31 mmol) in methanol (1.435 mL) in a sealed microwave
tube was heated by microwave at 130.degree. C. for 2 hours. The
mixture was concentrated and the residue was partitioned between
ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer
was washed with saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered and concentrated. Purification by
chromatography (silica gel, 1-4% methanol in dichloromethane)
afforded the title compound (0.008 g, 14%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.48 (s, 1H), 8.23 (s, 1H), 8.08 (s, 1H),
7.63 (s, 1H), 7.27 (s, 1H), 6.78 (t, J=9.00 Hz, 2H), 6.49-6.55 (m,
2H), 4.74 (s, 2H), 3.57 (s, 3H), 2.39 (s, 3H). MS (ESI+) m/z 361
(M+H).sup.+.
Example 12
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 12a
2,4-difluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline
[0975] A 100 mL microwave tube was charged with 2,4-difluoroaniline
(1.235 mL, 12.26 mmol), Example 9a (3.0539 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, 0.490 mmol), cesium carbonate (5.59 g, 17.16 mmol),
toluene (40.9 mL) and tert-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, and
the residue was purified by flash chromatography (20-100% ethyl
acetate/heptanes) to provide the title compound (3.44 g, 94%
yield).
Example 12b
2-bromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline
[0976] A 500 mL round-bottomed flask was charged with Example 12a
(3.4409 g, 11.57 mmol) and acetic acid (116 mL). The reaction
mixture was placed into a water bath. N-bromosuccinimide (2.060 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% sodium thiosulfate
and diluted with water. The reaction mixture was extracted 2.times.
with ethyl acetate. The combined organic layers were washed
2.times. with 2N NaOH (until the pH of the aqueous was >7) and
1.times. 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 the title compound 3.82 g, 88% yield).
Example 12c
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methy-
l-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0977] A 250 mL round-bottomed flask was charged with Example 12b
(1.9813 g, 5.27 mmol), Example 1f (2.051 g, 4.79 mmol), sodium
carbonate (1.776 g, 16.76 mmol),
tris(dibenzylideneacetone)dipalladium (II) (0.219 g, 0.239 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.238 g, 0.814 mmol). The solids were sparged with nitrogen for 30
minutes. Degassed dioxane (38.3 mL) and water (9.58 mL) were added.
The reaction was heated at 60.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature and partitioned between
ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered, and concentrated. The residue was taken up into
dichloromethane, triturated with ether, and filtered to provide the
title compound (2.30 g, 80% yield).
Example 12d
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0978] A 20 mL microwave tube was charged with Example 12c (1.9830
g, 3.32 mmol), lithium hydroxide monohydrate (1.392 g, 33.2 mmol),
dioxane (16 mL) and water (5.33 mL) to give a white suspension. The
reaction mixture was heated at 50.degree. C. for 72 hours. The
reaction mixture was cooled to ambient temperature and diluted with
water. The resulting suspension was filtered, and the solid was
rinsed with water and dried under vacuum overnight (1.25 g, 85%
yield).
Example 12e
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0979] A 5 mL microwave tube was charged with Example 12d (0.0504
g, 0.114 mmol), paraformaldehyde (0.051 g, 0.568 mmol) and methanol
(1.137 mL). 4N HCl in dioxane (0.568 mL, 2.273 mmol) was added. The
tube was closed and the reaction mixture was heated at 90.degree.
C. for 1 hour. The reaction mixture was cooled to room temperature
and diluted with ether. The resulting suspension was filtered, and
the solid was rinsed with ether and collected. The solid and the
filtrate were combined and purified by flash chromatography (0-5%
methanol/dichloromethane) to provide the title compound (0.0234 g,
45% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.83 (s,
1H), 7.85 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 7.26 (d, J=10.2 Hz, 1H),
6.99-7.19 (m, 3H), 6.81 (s, 1H), 4.72-4.78 (m, 2H), 4.49 (d, J=1.1
Hz, 3H), 4.01 (m, 1H), 3.62 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z
456.3 (M+H).sup.+.
Example 13
4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulen-11(1 OH)-one
Example 13a
2-bromo-N-(cyclopropylmethyl)aniline
[0980] A 100 mL flask was charged with 2-bromoaniline (1.72 g, 10.0
mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), acetic acid
(2.86 mL, 50.0 mmol) and dichloromethane (50 mL). The resulting
solution was heated at 50.degree. C. for 1 hour. The solution was
cooled in an ice bath and the sodium triacetoxyborohydride (2.119
g, 10.0 mmol) was added portionwise over a few minutes. After 15
minutes, the ice bath was removed and the solution was stirred for
2 hours while warming to ambient temperature. The reaction mixture
was quenched with 2.5 M sodium hydroxide (about 15 mL) and
partitioned between saturated aqueous 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 13b
4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]p-
yridin-7(6H)-one
[0981] A 25 mL vial was charged with Example 1f (244 mg, 0.570
mmol), tris(dibenzylideneacetone)dipalladium (O) (15.66 mg, 0.017
mmol), Example 13a (132.1 mg, 0.584 mmol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(18.33 mg, 0.063 mmol) and potassium phosphate (363 mg, 1.710
mmol). This mixture was sparged with argon for 30 minutes. To this
vial was added a mixture of dioxane (4 mL) and water (1 mL) [that
had been degassed with argon for 30 minutes]. The mixture was
heated at 75.degree. C. for 2.5 hours. Upon cooling the reaction
mixture was partitioned between ethyl acetate (75 mL) and 50%
saturated aqueous sodium chloride (100 mL). The layers were
separated and the organic layer was treated with 3-mercaptopropyl
functionalized silica gel (Aldrich), dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography (silica gel, 0-3% methanol in dichloromethane)
to provide the title compound (266 mg, 100%).
Example 13c
4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7-
(6H)-one
[0982] A 25 mL flask was charged with Example 13b (255 mg, 0.570
mmol), cetyltrimethylammonium bromide (10.38 mg, 0.028 mmol),
potassium hydroxide (615 mg, 10.96 mmol), dioxane (9 mL) and water
(3 mL). The mixture was heated at 90.degree. C. for 2.5 hours. Upon
cooling, the mixture was neutralized with 1M aqueous hydrogen
chloride solution and partitioned between ethyl acetate (80 mL) and
50% saturated aqueous sodium chloride (75 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2.times.40 mL). The combined organics were dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by flash chromatography (silica gel, 0-5% methanol in
dichloromethane) to provide the title compound (120 mg, 72%).
Example 13d
4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulen-1 (10H)-one
[0983] A 5 mL microwave vial was charged with Example 13c (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
vial was sealed and the reaction mixture was heated at 90.degree.
C. for 1 hour. Upon cooling, the reaction mixture was partitioned
between 50% saturated bicarbonate solution (100 mL) and ethyl
acetate (75 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (50 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-5% methanol in dichloromethane) to provide the title
compound (52 mg, 83%). 1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.74
(s, 1H), 7.63-7.67 (m, 1H), 7.59 (s, 1H), 7.10-7.25 (m, 4H), 4.19
(s, 2H), 3.60 (s, 3H), 2.68 (d, J=6.41 Hz, 2H), 0.74-0.87 (m, 1H),
0.45-0.36 (m, 2H), -0.07 (q, J=4.78 Hz, 2H). MS (ESI+) m/z 306.0
(M+H).sup.+.
Example 14
methyl
3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate
[0984] A stock solution of Example 6c (0.086 M in methanol, 455
.mu.L, 0.040 mmol, 1.0 equivalent), HCl (4.0 M in dioxane, 195
.mu.L, 0.78 mmol, 20 eq), and methyl 4-oxobutanoate (0.40 M in
methanol, 243 .mu.L, 0.19 mmol, 5 equivalents) were combined and
heated under microwave conditions at 90.degree. C. for 99 minutes.
The reaction mixture was concentrated and purified by reverse phase
HPLC (C8 column, CH.sub.3CN/water (0.1% ammonium acetate), 5-100%
gradient) to afford the title compound (5.1 mg, 27% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.70 (s, 1H), 7.52 (s,
1H), 7.22-7.33 (m, 2H), 7.12 (s, 1H), 4.43 (bs, 1H), 3.63 (s, 2H),
3.55 (m, 4H), 2.89 (s, 3H), 1.71 (m, 2H), 0.74 (s, 1H), 0.02-0.37
(m, 2H), -0.13 (s, 2H). MS (APCI) m/z 484.1 (M+H).sup.+.
Example 15
4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)meth-
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0985] A stock solution of Example 6c (0.086 M in methanol, 455
.mu.L, 0.040 mmol, 1.0 equivalent), HCl (4.0 M in dioxane, 195
.mu.L, 0.78 mmol, 20 eq), and 3-methoxypropanal (0.40 M in
methanol, 243 .mu.L, 0.19 mmol, 5 equivalents) were combined and
heated under microwave conditions at 90.degree. C. for 99 minutes.
The reaction mixture was concentrated and purified by reverse phase
HPLC (C8 column, CH.sub.3CN/water (0.1% ammonium acetate), 5-100%
gradient) to afford the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6-D.sub.2O) .delta. 7.69 (bs, 1H), 7.51 (s, 1H),
7.19-7.32 (m, 2H), 7.10 (s, 1H), 4.42 (bs, 2H), 3.63 (s, 3H),
2.74-2.93 (m, 5H), 1.77 (s, 2H), 1.08-1.43 (m, 1H), 0.70-0.83 (m,
1H), 0.02-0.40 (m, 2H), -0.11 (s, 2H). MS (APCI) m/z 456.1
(M+H).sup.+.
Example 16
3-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulen-11(10H)-one
[0986] A stock solution of Example 5e (0.11 M in methanol, 417
.mu.L, 0.045 mmol, 1.0 equivalent), HCl (4.0 M in dioxane, 226
.mu.L, 0.90 mmol, 20 equivalents), and 2-phenylacetaldehyde (0.40 M
in methanol, 189 .mu.L, 0.225 mmol, 5 equivalents) 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 a 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, CH.sub.3CN/water (0.1% ammonium
acetate), 5-100% gradient) to afford the title compound. (3.4 mg,
17% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.70 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.21
(dd, J=8.3, 6.1 Hz, 1H), 7.10 (dd, J=10.1, 4.3 Hz, 3H), 6.78 (d,
J=0.4 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 4.54 (t, J=7.2 Hz, 1H), 4.36
(bs, 2H), 3.64 (s, 3H), 2.91-3.01 (m, 2H), 2.88 (s, 3H). MS (APCI)
m/z 434.0 (M+H).sup.+.
Example 17
methyl
3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate
[0987] Example 17 was prepared according to the procedure used for
the preparation of Example 16, substituting methyl 4-oxobutanoate
for 2-phenylacetaldehyde to provide the title compound (8.7 mg, 45%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.68
(d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.14 (dd, J=8.2, 1.8 Hz, 1H), 7.11
(s, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.36 (bs, 2H), 4.27 (t, J=6.8 Hz,
1H), 3.63 (s, 3H), 3.55 (s, 3H), 2.87 (s, 3H), 2.26-2.46 (m, 2H),
1.75-1.97 (m, 2H). MS (APCI) m/z 430.0 (M+H).sup.+.
Example 18
10-methyl-7-((methylsulfonyl)methyl)-3-phenethyl-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one
[0988] Example 18 was prepared according to the procedure used for
the preparation of Example 16, substituting 3-phenylpropanal for
2-phenylacetaldehyde to provide the title compound (5.1 mg, 25%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.67
(d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.21 (t, J=7.4 Hz, 2H), 7.01-7.19
(m, 6H), 4.36 (bs, 2H), 4.23-4.30 (m, 1H), 3.63 (s, 3H), 2.86 (s,
3H), 2.72-2.84 (m, 1H), 2.58-2.71 (m, 1H), 1.65-1.98 (m, 2H). MS
(APCI) m/z 448.1 (M+H).sup.+.
Example 19
3-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one
[0989] Example 19 was prepared according to the procedure used for
the preparation of Example 16, substituting 3-methylbutanal for
2-phenylacetaldehyde to provide the title compound (4.4 mg, 24%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.67
(d, J=2.0 Hz, 1H), 7.48 (s, 1H), 7.13 (dd, J=8.1, 2.0 Hz, 1H), 7.09
(s, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.35 (bs, 2H), 4.27 (t, J=7.0 Hz,
1H), 3.63 (s, 3H), 2.87 (s, 3H), 1.63-1.79 (m, 1H), 1.54 (ddd,
J=13.6, 7.7, 6.0 Hz, 1H), 1.33-1.48 (m, 1H), 0.89 (t, J=6.6 Hz,
6H). MS (APCI) m/z 400.0 (M+H).sup.+.
Example 20
(E)-3-(4-fluorostyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[0990] Example 20 was prepared according to the procedure used for
the preparation of Example 16, substituting
(E)-3-(4-fluorophenyl)acrylaldehyde for 2-phenylacetaldehyde to
provide the title compound (4.8 mg, 23% yield). .sup.1H NMR (400
MHz, DMSO_D.sub.2O) .delta. 7.67 (s, 1H), 7.52 (s, 1H), 7.31 (dd,
J=8.7, 5.6 Hz, 2H), 7.11-7.17 (m, 1H), 7.01-7.11 (m, 4H), 6.45 (d,
J=15.8 Hz, 1H), 6.29 (dd, J=15.9, 6.9 Hz, 1H), 5.00 (d, J=6.7 Hz,
1H), 4.35 (s, 2H), 3.65 (s, 3H), 2.82 (s, 3H). MS (APCI) m/z 464.0
(M+H).sup.+.
Example 21
7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadiben-
zo[cd,f]azulen-11(1H)-one
Example 21a
[0991] 3-Bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol),
4-fluoroaniline (5.53 g, 49.7 mmol) and dimethyl sulfoxide (DMSO)
(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 with
15% ethyl acetate in heptanes to provide 4.2 g (81%) of the title
compound.
Example 21b
4-(2-((4-fluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0992] Example 21b was prepared according to the procedure used for
the preparation of Example 1j, substituting Example 21a for Example
1i, to provide the title compound.
Example 21c
4-(4-fluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazadiben-
zo[cd,f]azulen-11(10H)-one
[0993] Example 21c was prepared according to the procedure used for
the preparation of Example 1k, substituting Example 21b for Example
1j, to provide the title compound.
Example 21d
7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadiben-
zo[cd,f]azulen-11(10H)-one
[0994] A mixture of Example 21c (0.06 g, 0.153 mmol), and Pd/C
(0.033 g, 0.031 mmol) in ethyl acetate (10 mL) was treated with a
balloon of hydrogen. The reaction mixture was stirred overnight.
The solvent was removed, and residue was purified by reverse phase
HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford
the title compound (0.0351 g, 63%) as the bis TFA salt. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.92 (s, 1H), 7.85 (d, J=2.44 Hz,
1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.36 (d, J=2.44 Hz, 1H), 6.84 (t,
J=8.85 Hz, 1H), 6.44-6.47 (m, 2H), 4.81 (s, 2H), 3.56 (s, 3H). MS
(ESI+) m/z 362.1 (M+H).sup.+.
Example 22
N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-te-
traazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide
[0995] A mixture of Example 21d (0.025 g, 0.069 mmol),
ethanesulfonyl chloride (0.027 g, 0.208 mmol), and triethylamine
(0.042 g, 0.415 mmol) in dichloromethane (2 mL) was stirred at
ambient temperature for 2 hours. The solvent was removed, and
residue was treated with dioxane (2 mL) and 2.0 N NaOH (1 mL). The
reaction mixture was heated at 85.degree. C. for 2 hours. The
reaction mixture was partitioned between water and ethyl acetate.
The organic layer was separated. The aqueous layer was neutralized
to pH=7, 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%
gradient) to afford the title compound (0.022 g, 0.049 mmol, 70.1%
yield) as mono TFA salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.89 (s, 1H), 10.12 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H),
7.59 (s, 1H), 7.35 (s, 1H), 6.83 (t, J=8.39 Hz, 1H), 6.49-6.50 (m,
2H), 4.76 (s, 2H), 3.57 (s, 3H), 3.27 (q, J=7.17 Hz, 2H), 1.29 (t,
J=7.17 Hz, 3H). MS (ESI+) m/z 451.1 (M+H).sup.+.
Example 23
N-(4-(2,4-difluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-
-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide
Example 23a
3-bromo-N-(2,4-difluorophenyl)-5-nitropyridin-2-amine
[0996] A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10
mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in DMSO (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 solution, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel, eluting
with 1:20 ethyl acetate/heptans to give the title compound (1.75 g,
5.30 mmol, 53.0% yield) as yellow crystals.
Example 23b
4-(2-((2,4-difluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[-
2,3-c]pyridin-7(6H)-one
[0997] A mixture of 3Example 23a (0.330 g, 1 mmol), Example if
(0.471 g, 1.100 mmol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(0.034 g, 0.117 mmol), tris(dibenzylideneacetone)dipalladium(O)
(0.027 g, 0.030 mmol), and potassium phosphate (0.531 g, 2.500
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. overnight. To this reaction mixture were
added dioxane (5 mL) and 2.0 N NaOH (5 mL). The reaction was heated
at 90.degree. C. for 2 hours. After cooling, the reaction mixture
was partitioned between 0.1 N HCl and ethyl acetate. The aqueous pH
appeared around 5. 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 solution, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was triturated with 3:7
ethyl acetate/heptanes to give the title compound (0.365 g, 0.919
mmol, 92% yield).
Example 23c
4-(2,4-difluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazad-
ibenzo[cd,f]azulen-11(10H)-one
[0998] A mixture of Example 23b (0.17 g, 0.428 mmol), 4 N hydrogen
chloride in dioxane (3.21 mL, 12.84 mmol) and formaldehyde (0.128
g, 4.28 mmol) in methanol (2) was heated at 130.degree. C. under
microwave conditions 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 three times. The combined organic
layers were washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was used for the next reaction without additional
purification.
Example 23d
7-amino-4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazad-
ibenzo[cd,f]azulen-11(10H)-one
[0999] A mixture of 23c (0.18 g, 0.440 mmol), iron (0.123 g, 2.199
mmol), and ammonium hydrochloride (0.047 g, 0.879 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. It was then poured into
water. 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% gradient) to give 0.05 g (23.1%) of the title
compound as a bis TFA salt.
Example 23e
N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,1-
0-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide
[1000] A mixture of Example 23d (0.05 g, 0.132 mmol),
ethanesulfonyl chloride (0.017 g, 0.132 mmol), and triethylamine
(0.013 g, 0.132 mmol) in dichloromethane (5 mL) was stirred at
ambient temperature for 2 hours. The solvent was removed, and
residue was treated with dioxane (2 mL) and 2.0 N NaOH (1 mL). The
reaction mixture was heated at 85.degree. C. for 2 hours. The
reaction mixture was partitioned between water and ethyl acetate.
The organic layer was separated. The aqueous layer was neutralized
to pH=7, 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%
gradient) to afford the title compound (0.048 g, 0.77 mmol, 58.3%
yield) as mono TFA salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.92 (s, 1H), 9.76 (s, 1H), 7.91-7.93 (m, 2H), 7.62 (s,
1H), 7.29-7.35 (m, 1H), 7.20 (d, J=2.75 Hz, 1H), 7.07-7.13 (m, 1H),
7.00-7.06 (m, 1H), 4.76 (s, 2H), 3.65 (s, 3H), 3.14 (q, J=7.32 Hz,
2H), 1.25 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 472.2 (M+H).sup.+.
Example 24
4-butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazad-
ibenzo[cd,f]azulen-11(10H)-one
[1001] A 5 mL vial was charged with Example 5f (75 mg, 0.218 mmol),
butyraldehyde (0.039 mL, 0.437 mmol), acetic acid (0.125 mL, 2.184
mmol) and dichloromethane (2.5 mL). The vial was sealed and the
mixture was heated at 60.degree. C. for 1 hour. The reaction
mixture was cooled in an ice bath and sodium triacetoxyborohydride
(93 mg, 0.437 mmol) was added portionwise over a few minutes.
Stirring was continued overnight while warming to ambient
temperature. The reaction mixture was quenched with 1 M sodium
hydroxide (2 mL) and partitioned between saturated sodium
bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers
were separated and the aqueous layer was extracted with ethyl
acetate (2.times.25 mL). The combined organic layers were dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by flash chromatography (silica gel, 0-10%
methanol in dichloromethane) to provide the title compound (74 mg,
85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.76 (s, 1H),
7.68 (d, J=1.83 Hz, 1H), 7.50 (s, 1H), 7.23-7.29 (m, 1H), 7.17-7.21
(m, 1H), 7.14 (d, J=2.14 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.62
(s, 3H), 2.90-2.98 (m, 5H), 1.32-1.43 (m, 2H), 1.14-1.25 (m, 2H),
0.77 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 400.1 (M+H).sup.+.
Example 25
tert-butyl
3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxyla-
te
[1002] Example 25 was prepared according to the procedure used for
the preparation of Example 24, substituting tert-butyl
3-formylpyrrolidine-1-carboxylate for butyraldehyde to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.79
(d, J=2.14 Hz, 1H), 7.70 (d, J=1.83 Hz, 1H), 7.53 (s, 1H),
7.24-7.29 (m, 1H), 7.18-7.24 (m, 1H), 7.14 (d, J=2.44 Hz, 1H), 4.44
(s, 2H), 4.12 (s, 2H), 3.62 (s, 3H), 3.13-3.24 (m, 2H), 3.03-3.12
(m, 1H), 2.75-2.97 (m, 6H), 2.18-2.30 (m, 1H), 1.73 (d, J=6.71 Hz,
1H), 1.26-1.49 (m, 10H). MS (ESI+) m/z 526.9 (M+H).sup.+.
Example 26
10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1003] A 5 mL vial was charged with Example 5f (75 mg, 0.218 mmol),
tetrahydrofuran-3-carbaldehyde (50% weight in water, 131 mg, 0.655
mmol), acetic acid (0.125 mL, 2.184 mmol) and dichloromethane (2.5
mL). The vial was sealed and the mixture was heated at 60.degree.
C. for 1 hour. The reaction mixture was cooled in an ice bath and
sodium triacetoxyborohydride (93 mg, 0.437 mmol) was added
portionwise over several minutes. Stirring was continued overnight
while warming to ambient temperature. The reaction mixture was
quenched with 1 M sodium hydroxide (2 mL) and partitioned between
saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50
mL). The layers were separated and the aqueous layer was extracted
with ethyl acetate (2.times.25 mL). The combined organic layers
were dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-10% methanol in dichloromethane) to provide the
title compound (79.6 mg, 85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.79 (s, 1H), 7.70 (d, J=1.83 Hz, 1H), 7.54 (s, 1H),
7.24-7.30 (m, 1H), 7.18-7.23 (m, 1H), 7.15 (d, J=2.44 Hz, 1H), 4.45
(s, 2H), 4.13 (s, 2H), 3.45-3.66 (m, H), 3.25-3.30 (m, 1H), 2.94
(s, 3H), 2.84-2.92 (m, 1H), 2.77 (dd, J=12.36, 8.70 Hz, 1H),
2.20-2.35 (m, 1H), 1.65-1.85 (m, 1H), 1.33-1.46 (m, 1H). MS (ESI+)
m/z 428.1 (M+H).sup.+.
Example 27
4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,-
4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1004] Example 27 was prepared according to the procedure used for
the preparation of Example 24, substituting
4,4-difluorocyclohexanecarbaldehyde for butyraldehyde, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.77 (d, J=1.83 Hz, 1H), 7.69 (d, J=1.83 Hz, 1H), 7.51 (s, 1H),
7.24-7.29 (m, 1H), 7.19-7.23 (m, 1H), 7.13 (d, J=2.44 Hz, 1H), 4.44
(s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H), 2.82 (d, J=7.02
Hz, 2H), 1.82-1.96 (m, 2H), 1.48-1.76 (m, 5H), 0.94-1.10 (m, 2H).
MS (ESI+) m/z 428.1 (M+H).sup.+.
Example 28
tert-butyl
4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylat-
e
[1005] Example 28 was prepared according to the procedure used for
the preparation of Example 24, substituting tert-butyl
4-formylpiperidine-1-carboxylate for butyraldehyde, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.77
(d, J=2.44 Hz, 1H), 7.68 (d, J=1.83 Hz, 1H), 7.51 (s, 1H),
7.23-7.28 (m, 1H), 7.18-7.23 (m, 1H), 7.13 (d, J=2.44 Hz, 1H), 4.44
(s, 2H), 4.08 (s, 2H), 3.81 (d, J=11.90 Hz, 2H), 3.62 (s, 3H), 2.94
(s, 3H), 2.80 (d, J=6.10 Hz, 2H), 2.51 (s, 2H), 1.56 (d, J=10.68
Hz, 3H), 1.34 (s, 9H), 0.76-0.92 (m, 2H). MS (ESI+) m/z 540.9
(M+H).sup.+.
Example 29
10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1006] Example 29 was prepared according to the procedure used for
the preparation of Example 24, substituting
tetrahydro-2H-pyran-3-carbaldehyde for butyraldehyde, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.77 (d, J=1.83 Hz, 1H), 7.68 (d, J=2.14 Hz, 1H), 7.51 (s, 1H),
7.23-7.29 (m, 1H), 7.18-7.23 (m, 1H), 7.15 (d, J=2.75 Hz, 1H), 4.44
(s, 2H), 4.00-4.13 (m, 2H), 3.56-3.70 (m, 5H), 3.16-3.25 (m, 1H),
2.91-3.00 (m, 4H), 2.83-2.91 (m, 1H), 2.73-2.81 (m, 1H), 1.57-1.72
(m, 2H), 1.28-1.50 (m, 2H), 1.07 (t, J=9.61 Hz, 1H). MS (ESI+) m/z
540.9 (M+H).sup.+.
Example 30
4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1007] Example 30 was prepared according to the procedure used for
the preparation of Example 24, substituting
4,4-difluorocyclohexanone for butyraldehyde, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.84 (d,
J=1.70 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.25 (s, 2H), 7.19 (d,
J=2.71 Hz, 1H), 4.46 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.94 (s,
3H), 2.88 (s, 1H), 1.96 (d, J=12.55 Hz, 2H), 1.19-1.86 (m, 6H). MS
(ESI+) m/z 462.1 (M+H).sup.+.
Example 31
4-(4-fluorophenyl)-(3,3-.sup.2H.sub.2)-10-methyl-7-((methylsulfonyl)methyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1008] A 20 mL microwave tube was charged Example 9e (0.0506 g,
0.119 mmol), formaldehyde-d.sub.2 (0.095 mL, 0.595 mmol) and
methanol (1.189 mL). 4N HCl in dioxane (0.595 mL, 2.379 mmol) was
added. The tube was closed and the reaction was heated to
90.degree. C. for 2 hours. The reaction was cooled to room
temperature. The reaction was partitioned between dichloromethane
and saturated aqueous sodium bicarbonate. The aqueous layer was
extracted with dichloromethane. The combined organic layers were
washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was taken up into dichloromethane and triturated with
ether. The resulting slurry was stirred for 10 minutes and
filtered. The white solid was rinsed with ether, collected, and
dried in a 60.degree. C. vacuum oven to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.80-11.85 (m, 1H),
7.91 (d, J=2.0 Hz, 1H), 7.60 (s, 1H), 7.40-7.51 (m, 1H), 7.33 (d,
J=4.5 Hz, 2H), 6.72-6.85 (m, 2H), 6.36-6.46 (m, 2H), 4.53-4.59 (m,
2H), 3.56 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 440.1
(M+H).sup.+.
Example 32
7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibe-
nzo[cd,f]azulen-11(1H)-one
Example 32a
4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-H-pyrrolo[2,3-c]pyridin--
7(6H)-one
[1009] 3-Bromo-5-fluoropyridin-2-amine (0.3 g, 1.571 mmol), Example
if (0.673 g, 1.571 mmol), tris(dibenzylideneacetone)dipalladium (O)
(0.043 g, 0.047 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.046 g, 0.157 mmol) and potassium phosphate (1.167 g, 5.50 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (8 mL) was sparged with nitrogen for
15 minutes and then transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 2 hours at 60.degree. C.,
cooled, diluted with 50 mL of water and the crude solid was
collected by filtration, washed with additional water and dried to
afford the title compound (0.648 g, 100%).
Example 32b
4-(5-fluoro-2-((4-fluorophenyl)amino)pyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-
-c]pyridin-7(6H)-one
[1010] 1-Bromo-4-fluorobenzene (0.424 g, 2.425 mmol), Example 32a
(0.5 g, 1.212 mmol), diacetoxypalladium (10.89 mg, 0.048 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.046 g, 0.097 mmol) and cesium carbonate (0.790 g, 2.425 mmol)
were combined in a mixture of t-butanol (2.021 mL) and toluene
(10.10 mL) and heated by microwave at 150.degree. C. for 2 hours.
The mixture was cooled and partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride, dried (anhydrous sodium sulfate), treated with
3-mercaptopropyl functionalized silica, filtered and concentrated.
Purification by chromatography (silica gel, 1-5% methanol in
dichloromethane) afforded the title compound (0.065 g, 15%).
Example 32c
7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibe-
nzo[cd,f]azulen-11(1H)-one
[1011] Example 32b (0.055 g, 0.156 mmol), paraformaldehyde (0.141
g, 4.68 mmol) and hydrogen chloride (4M in 1,4-dioxane, 1 mL, 4.00
mmol) were combined in methanol (1 mL) in a sealed tube and heated
by microwave at 130.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 as the TFA salt (0.009 g, 12%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.91 (s, 1H), 8.43 (d, J=2.75 Hz, 1H), 8.27
(dd, J=9.92, 2.90 Hz, 1H), 7.85 (s, 1H), 7.36 (d, J=2.44 Hz, 1H),
6.78-6.92 (m, 2H), 6.43-6.53 (m, 2H), 4.78 (s, 2H), 3.56 (s, 3H).
MS (ESI+) m/z 365 (M+H).sup.+.
Example 33
4-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraaza-
dibenzo[cd,f]azulen-11(10H)-one
[1012] A mixture of Example 11c and benzaldehyde (0.116 mL, 1.148
mmol) in acetic acid (1 mL) was heated in a sealed tube at
110.degree. C. for 15 hours, cooled and concentrated. Purification
by reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%
gradient) afforded the title compound (0.016 g, 25%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.75 (s, 1H), 8.02 (s, 1H), 7.99
(s, 1H), 7.68 (s, 1H), 7.38 (d, J=2.75 Hz, 1H), 6.98-7.12 (m, 5H),
6.81-6.88 (m, 2H), 6.71-6.78 (m, 2H), 6.68 (s, 1H), 3.60 (s, 3H),
2.25 (s, 3H). MS (ESI+) m/z 437 (M+H).sup.+.
Example 34
ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,1-
0,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[1013] Example 34 was prepared according to the procedure used for
the preparation of Example 7, substituting Example 9e for Example
6c to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.95-12.00 (m, 1H), 7.85 (d, J=2.0 Hz, 1H),
7.62 (s, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.87
(t, J=8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62
(m, 2H), 3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03
(m, 3H). MS (ESI+) m/z 510.1 (M+H).sup.+.
Example 35
tert-butyl
4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)pi-
perazine-1-carboxylate
Example 35a
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-t-
etrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic
Acid
[1014] A 100 mL round-bottomed flask was charged with Example 34
(0.453 g, 0.888 mmol), dioxane (6.66 mL) and water (2.22 mL) to
give a yellow solution. Lithium hydroxide hydrate (0.186 g, 4.44
mmol) was added. The reaction mixture was stirred at ambient
temperature for 5 hours. The reaction mixture was quenched with 1N
hydrochloric acid. The resulting slurry was stirred for 10 minutes
and filtered. The solid was rinsed with water, dried on the frit
overnight and collected to provide the title compound (0.3664 g,
86% yield).
Example 35b
tert-butyl
4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)pi-
perazine-1-carboxylate
[1015] A 2 mL microwave tube was charged with Example 35a (0.0498
g, 0.103 mmol), tert-butyl piperazine-1-carboxylate (0.019 g, 0.103
mmol), polymer supported-carbodiimide (0.248 g, 0.310 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (0.014 g, 0.103 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.036 mL, 0.207 mmol) and
dimethylacetamide (1.034 mL). The tube was sealed, and the reaction
mixture was heated in a Biotage Creator at 110.degree. C. for 10
minutes fixed hold time. The reaction mixture was filtered, and the
resin was rinsed thoroughly with ethyl acetate. The filtrate was
washed twice with saturated aqueous sodium chloride. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-10% methanol in dichloromethane) to provide the
title compound (0.0133 g, 20% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.78-11.89 (m, 1H), 7.77-7.89 (m, 1H),
7.50-7.61 (m, 1H), 7.35-7.45 (m, 1H), 7.20-7.34 (m, 2H), 6.76-6.90
(m, 2H), 6.43-6.57 (m, 2H), 6.33-6.43 (m, 1H), 4.42-4.66 (m, 2H),
3.66-3.81 (m, 2H), 3.40-3.61 (m, 5H), 2.98-3.22 (m, 2H), 2.92 (s,
3H), 2.66-2.85 (m, 2H), 1.47-1.29 (m, 9H). MS (ESI+) m/z 549.8
(M+H).sup.+.
Example 36
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1016] A 4 mL vial was charged with Example 25 (98 mg, 0.186 mmol)
and dichloromethane (2 mL). The mixture was cooled in an ice bath
and 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) was added.
Stirring was continued for 2 hours as the reaction mixture warmed
to ambient temperature. The reaction mixture was concentrated under
a heated stream of nitrogen and the residue was partitioned between
saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50
mL). The layers were separated and the aqueous layer was extracted
with 10% methanol in dichloromethane (16.times.100 mL). The
combined organics were also dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by reverse
phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to
afford the title compound (56.6 mg, 56%) as the trifluoroacetic
acid salt. .sup.1H NMR (400 MHz, PYRIDINE-d.sub.6) .delta. 13.48
(s, 1H), 11.08-11.34 (m, 1H), 8.06 (d, J=1.83 Hz, 1H), 7.56 (s,
2H), 7.38-7.42 (m, 1H), 7.36 (d, J=8.24 Hz, 1H), 4.76 (s, 2H),
4.25-4.40 (m, 2H), 3.63 (s, 3H), 3.58 (dd, J=11.29, 7.63 Hz, 1H),
3.42-3.52 (m, 1H), 3.30-3.42 (m, 2H), 3.14-3.21 (m, 1H), 3.14 (s,
3H), 3.02 (dd, J=12.51, 9.16 Hz, 1H), 2.59-2.72 (m, 1H), 1.90-2.04
(m, 1H), 1.59-1.73 (m, 1H). MS (ESI+) m/z 427.1 (M+H).sup.+.
Example 37
10-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1017] A 4 mL vial was charged with Example 28 (81.5 mg, 0.151
mmol) and dichloromethane (2 mL). The mixture was cooled in an ice
bath and 2,2,2-trifluoroacetic acid (1 mL, 13 mmol) was added.
Stirring was continued for 2 hours while warming to ambient
temperature. The reaction mixture was concentrated under a heated
stream of nitrogen and the residue was purified by reverse phase
HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford
the title compound (76.9 mg, 92%) as the trifluoroacetic acid salt.
.sup.1H NMR (400 MHz, PYRIDINE-d.sub.6) .delta. 13.45 (d, J=1.53
Hz, 1H), 10.89 (d, 1H), 8.08 (d, J=2.14 Hz, 1H), 7.61 (dd, J=8.24,
1.83 Hz, 2H), 7.41 (d, J=2.44 Hz, 1H), 7.37 (d, J=7.93 Hz, 1H),
4.77 (s, 2H), 4.27 (s, 2H), 3.64 (s, 3H), 3.52 (d, J=12.51 Hz, 2H),
3.13 (s, 3H), 3.00 (d, J=6.41 Hz, 2H), 2.88-2.98 (m, 2H), 1.80-1.99
(m, 3H), 1.55 (d, J=12.82 Hz, 2H). MS (ESI+) m/z 441.1
(M+H).sup.+.
Example 38
7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(-
10H)-one
Example 38a
4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-H-pyrrolo[2,3-c]pyridin--
7(6H)-one
[1018] Example 38a was prepared according to the procedure used for
the preparation of Example 8a, substituting
3-bromo-5-fluoropyridin-2-amine for
2-bromo-4-(methylsulfonyl)aniline and the reaction time was 4 hours
instead of 3 hours, to provide the title compound in quantitative
yield.
Example 38b
4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-o-
ne
[1019] Example 38a (825 mg, 2.00 mmol), potassium hydroxide (1.68
g, 30.0 mmol) and cetyltrimethylammonium bromide (36.4 mg, 0.100
mmol) were combined in a mixture of dioxane (20 mL) and water (10
mL). The reaction mixture was heated at 100.degree. C. for 3 hours
and then cooled to ambient temperature. To this mixture was added
water, and the pH was adjusted to pH 7 by the addition of 1M HCl.
The mixture was extracted with ethyl acetate and the organic layer
was washed with saturated aqueous sodium chloride twice, dried with
anhydrous sodium sulfate, treated with 3-mercaptopropyl
functionalized silica gel, filtered, and concentrated. The residue
was triturated with dichloromethane to afford the title compound
(460 mg, 89%).
Example 38c
7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(-
10H)-one
[1020] A 5 mL vial was charged with Example 38b (25.8 mg, 0.100
mmol), paraformaldehyde (30 mg, 1.0 mmol) and methanol (2 mL). To
this suspension was added 4M HCl in dioxane (0.50 mL, 2.0 mmol).
The vial was closed and heated in a microwave reactor at
120.degree. C. for 2 hours. The reaction mixture was cooled to
ambient temperature and concentrated. To this residue was added
water, and the pH was adjusted to pH 7 by addition of saturated
aqueous sodium bicarbonate. The residue was sonicated for 5 minutes
and filtered to afford the title compound (23 mg, 85%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.84 (s, 1H) 7.96-8.06 (m, 2H)
7.79 (s, 1H) 7.18 (d, J=2.71 Hz, 1H) 6.16 (t, J=3.05 Hz, 1H) 4.15
(d, J=3.05 Hz, 2H) 3.61 (s, 3H). MS (ESI+) m/z 271 (M+H).sup.+.
Example 39
ethyl
7-fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazad-
ibenzo[cd,f]azulene-3-carboxylate
[1021] A 5 mL vial was charged with Example 38b (25.8 mg, 0.100
mmol), 50% ethyl 2-oxoacetate in toluene (0.198 mL, 1.00 mmol) and
ethanol (2 mL). To this suspension was added 4M HCl in dioxane
(0.50 mL, 2.0 mmol). The vial was closed and heated in a microwave
reactor at 120.degree. C. for 2 hours. The reaction mixture was
cooled to ambient temperature and concentrated. The residue was
purified by flash chromatography (silica gel, 2-4% methanol in
dichloromethane) to afford the title compound (17 mg, 50%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 12.10 (s, 1H) 7.96-8.06 (m, 2H)
7.87 (s, 1H) 7.34 (d, J=2.71 Hz, 1H) 6.50 (d, J=5.43 Hz, 1H) 5.11
(d, J=5.43 Hz, 1H) 3.91 (q, J=7.12 Hz, 2H) 3.61 (s, 3H) 0.98 (t,
J=7.12 Hz, 3H). MS (ESI+) m/z 343 (M+H).sup.+.
Example 40
4-(4-fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methyl-
sulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-o-
ne
[1022] Example 40 was prepared according to the procedure used for
the preparation of Example 35b, substituting 4-methoxypiperidine
for tert-butyl piperazine-1-carboxylate to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.78-11.83
(m, 1H), 7.81-7.86 (m, 1H), 7.55 (s, 1H), 7.33-7.43 (m, 1H),
7.24-7.33 (m, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.79-6.89 (m, 2H),
6.43-6.53 (m, 2H), 6.28-6.40 (m, 1H), 4.46-4.61 (m, 2H), 4.01 (d,
J=1.1 Hz, 1H), 3.53-3.41 (m, 1H), 3.56 (s, 3H), 3.41-3.53 (m, 1H),
3.25-3.29 (m, 5H), 2.92 (s, 3H), 1.89-2.14 (m, 1H), 1.69-1.89 (m,
1H), 1.32-1.69 (m, 2H). MS (ESI+) m/z 579.0 (M+H).sup.+
Example 41
4-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methyls-
ulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-on-
e
[1023] Example 41 was prepared according to the procedure used for
the preparation of Example 35b, substituting 1-methylpiperazine for
tert-butyl piperazine-1-carboxylate to provide the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.79-11.85 (m, 1H),
7.84 (d, J=1.7 Hz, 1H), 7.55 (s, 1H), 7.40 (dd, J=8.0, 1.9 Hz, 1H),
7.18-7.32 (m, 2H), 6.78-6.89 (m, 2H), 6.45-6.54 (m, 2H), 6.32-6.40
(m, 1H), 4.47-4.61 (m, 2H), 3.44-3.61 (m, 5H), 2.74-3.04 (m, 5H),
2.15-2.38 (m, 5H). MS (ESI+) m/z 564.1 (M+H).sup.+.
Example 42
5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 42a
4-(2-amino-3,5-difluorophenyl)-6-methyl-1-tosyl-H-pyrrolo[2,3-c]pyridin-7(-
6H)-one
[1024] 2-Bromo-4,6-difluoroaniline (1.0 g, 4.81 mmol), Example 1f
(2.059 g, 4.81 mmol), tris(dibenzylideneacetone)dipalladium (O),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.141 g, 0.481 mmol) and potassium phosphate (3.57 g, 16.83 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (8 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 2 hours at 60.degree. C.,
cooled to ambient temperature, and diluted with 100 mL of water.
The resulting solid was collected by filtration, washed with
additional water and dried to afford the title compound (1.6 g,
77%).
Example 42b
4-(2-amino-3,5-difluorophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1025] Example 42a (1.6 g, 3.73 mmol), potassium hydroxide (6.27 g,
112 mmol) and N,N,N-trimethylhexadecan-1-aminium bromide (0.068 g,
0.186 mmol) were combined in dioxane (33.1 mL)/water (16.6 mL) and
heated at 100.degree. C. for 3 hours, cooled, diluted with ethyl
acetate and water and the pH was adjusted to pH 8 by careful
addition of 12 M HCl. The organic layer was washed with saturated
aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered
and concentrated. Purification by chromatography (silica gel,
0.5-4% methanol in dichloromethane) afforded the title compound
(0.80 g, 78%).
Example 42c
5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(-
10H)-one
[1026] A mixture of Example 42b (0.25 g, 0.908 mmol) and
paraformaldehyde (0.273 g, 9.08 mmol) in methanol (9.08 mL) was
treated with hydrogen chloride (4M in 1,4-dioxane, 6.81 mL, 27.2
mmol). The mixture was heated at 90.degree. C. for 3 hours in a
sealed tube, cooled and filtered to collect a solid that was rinsed
repeatedly with diethyl ether. The solid was sonicated in 2 mL
methanol and 20 mL 5% aqueous sodium bicarbonate for 5 minutes and
collected by filtration to afford the title compound (0.2 g,
77%).
Example 42d
5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1027] A mixture of tetrahydrofuran-3-carboxaldehyde (0.131 g,
0.654 mmol) and Example 42c (0.063 g, 0.218 mmol) in
dichloromethane (2.5 mL) in a sealed tube was treated with acetic
acid (0.125 mL, 2.180 mmol) and heated for 1 hour at 60 Co, cooled
to 0.degree. C. and treated portionwise with sodium
triacetoxyhydroborate (0.092 g, 0.436 mmol). The reaction mixture
was stirred for 18 hours allowing the mixture to warm to ambient
temperature. The mixture was partitioned between dichloromethane
and 5% aqueous sodium bicarbonate. The organic layer was washed
with saturated aqueous sodium chloride, dried (anhydrous sodium
sulfate) filtered 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 (0.04 g, 38%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.91 (s, 1H), 7.83 (d, J=2.03 Hz, 1H),
7.41-7.46 (m, 1H), 7.06-7.22 (m, 2H), 4.19-4.30 (m, 1H), 4.00-4.10
(m, 1H), 3.61 (s, 3H), 3.25-3.63 (m, 5H), 1.66-2.70 (m, 4H). MS
(ESI+) m/z 372 (M+H).sup.+.
Example 43
ethyl
4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,-
5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate
[1028] A mixture of ethyl glyoxalate (0.586 g, 2.87 mmol) and
Example 1c (0.1 g, 0.287 mmol) in ethanol (2 mL) was treated with
hydrogen chloride (4M in 1,4-dioxane, 2.153 mL, 8.61 mmol). The
mixture was heated at 120.degree. C. for 18 hours in a sealed tube,
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, 6%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.06 (d, J=1.70 Hz, 1H), 8.16 (s, 2H), 7.83
(s, 1H), 7.39 (d, J=2.71 Hz, 1H), 6.92-7.00 (m, 2H), 6.74-6.81 (m,
2H), 6.18 (s, 1H), 3.91 (d, J=7.12 Hz, 2H), 3.61 (s, 3H), 2.36 (s,
3H), 0.92 (t, J=7.12 Hz, 3H). MS (ESI+) m/z 433 (M+H).sup.+.
Example 44
N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1029] A 5 mL vial was charged with Example 5f (72.5 mg, 0.211
mmol), isocyanatocyclopentane (0.036 mL, 0.317 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.110 mL, 0.633 mmol),
dichloromethane (2 mL) and N,N-dimethylformamide (2 mL). The
reaction mixture was stirred for 18 hours at ambient temperature
and then heated at 90.degree. C. for 72 hours. Upon cooling, the
reaction mixture was partitioned between 50% saturated aqueous
sodium chloride (60 mL) and dichloromethane (60 mL). The layers
were separated and the aqueous layer was extracted with
dichloromethane (2.times.50 mL). The combined extracts were dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by flash chromatography (silica gel, 0-10%
methanol in dichloromethane) to provide the title compound (59.1
mg, 62%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (d,
J=2.37 Hz, 1H), 7.83 (d, J=2.03 Hz, 1H), 7.63 (s, 1H), 7.33-7.40
(m, 1H), 7.25-7.31 (m, 1H), 7.20 (d, J=2.03 Hz, 1H), 5.36 (d,
J=15.94 Hz, 1H), 5.24 (d, J=6.78 Hz, 1H), 4.52-4.62 (m, 1H),
4.40-4.51 (m, 1H), 3.96 (d, J=15.60 Hz, 1H), 3.69-3.83 (m, 1H),
3.62 (s, 3H), 2.96 (s, 3H), 1.54-1.72 (m, 2H), 1.31-1.52 (m, 4H),
1.09-1.27 (m, 2H). MS (ESI+) m/z 455.1 (M+H).sup.+.
Example 45
N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1030] Example 45 was prepared according to the procedure used for
the preparation of Example 44, substituting isocyanatoethane for
isocyanatocyclopentane to provide the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.85 (d, J=1.36 Hz, 1H), 7.83 (d,
J=1.70 Hz, 1H), 7.62 (s, 1H), 7.34-7.40 (m, 1H), 7.26-7.32 (m, 1H),
7.19 (d, J=2.37 Hz, 1H), 5.59 (s, 1H), 5.35 (d, J=15.94 Hz, 1H),
4.42-4.62 (m, 2H), 3.94 (d, J=15.60 Hz, 1H), 3.59-3.66 (m, 3H),
2.97 (s, 3H), 2.75-2.96 (m, 2H), 0.85 (t, J=7.12 Hz, 3H). MS (ESI+)
m/z 415.1 (M+H).sup.+.
Example 46
N-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1031] Example 46 was prepared according to the procedure used for
the preparation of Example 44, substituting
1-fluoro-4-isocyanatobenzene for isocyanatocyclopentane to provide
the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.91 (d, J=2.37 Hz, 1H), 7.87 (s, 2H), 7.66 (s, 1H), 7.38 (s, 2H),
7.28-7.34 (m, 2H), 7.25 (d, J=2.37 Hz, 1H), 6.95-7.02 (m, 2H), 5.52
(d, J=15.60 Hz, 1H), 4.45-4.63 (m, 2H), 4.07 (d, J=16.62 Hz, 1H),
3.63 (s, 3H), 2.98 (s, 3H). MS (ESI+) m/z 481.1 (M+H).sup.+.
Example 47
4-butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]az-
ulen-11(10H)-one
[1032] A mixture of butyraldehyde (0.079 g, 1.097 mmol) and Example
42c (0.063 g, 0.219 mmol) in dichloroethane (1.0 mL) in a sealed
tube was treated with acetic acid (0.126 mL, 2.193 mmol) and heated
for 2 hours at 60 Co, cooled to 0.degree. C. and treated
portionwise with sodium triacetoxyhydroborate (0.139 g, 0.658
mmol). The reaction mixture was stirred for 18 hours allowing the
mixture to warm to ambient temperature. The mixture was partitioned
between ethyl acetate and 5% aqueous sodium bicarbonate. The
organic layer was washed with saturated aqueous sodium chloride,
dried (anhydrous sodium sulfate) filtered and concentrated.
Purification by chromatography (silica gel, 0.5-3% methanol in
dichloromethane) gave a solid that was then triturated in 9:1
hexane/ethyl acetate to afford the title compound (0.057 g, 76%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H), 7.81 (s,
1H), 7.40-7.45 (m, 1H), 7.19 (d, J=2.14 Hz, 1H), 7.05-7.14 (m, 1H),
4.19-4.24 (m, 2H), 4.01-4.06 (m, 2H), 3.61 (s, 3H), 1.13-1.33 (m,
4H), 0.76 (t, J=7.02 Hz, 3H). MS (ESI+) m/z 344 (M+H).sup.+.
Example 48
5,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulen-11(1 OH)-one
[1033] A mixture of propionaldehyde (0.064 g, 1.097 mmol) and
Example 42c (0.063 g, 0.219 mmol) in 1,2-dichloroethane (1.0 mL) in
a sealed tube was treated with acetic acid (0.126 mL, 2.193 mmol)
and stirred for 2 hours at 60.degree. C., cooled to 0.degree. C.
and treated portion-wise with sodium triacetoxyhydroborate (0.139
g, 0.658 mmol). The reaction mixture was stirred for 18 hours
allowing the mixture to warm to ambient temperature. The mixture
was partitioned between ethyl acetate and 5% aqueous sodium
bicarbonate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried (anhydrous Na.sub.2SO.sub.4)
filtered and concentrated. Purification by flash chromatography
(silica gel, 0.5-3% methanol in dichloromethane) gave a solid that
was triturated in 9:1 hexane/ethyl acetate to afford the title
compound (0.044 g, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.89 (s, 1H), 7.81 (s, 1H), 7.43 (d, J=10.68 Hz, 1H), 7.18
(s, 1H), 7.05-7.13 (m, 1H), 4.17-4.25 (m, 1H), 3.99-4.08 (m, 1H),
3.61 (s, 3H), 2.39-2.64 (m, 2H), 1.07-1.43 (m, 2H), 0.74 (t, J=7.32
Hz, 3H). MS (ESI+) m/z 330 (M+H).sup.+.
Example 49
4-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazad-
ibenzo[cd,f]azulen-11(10H)-one
[1034] Example 49 was prepared according to the procedure used for
the preparation of Example 47, substituting
cyclopropanecarboxaldehyde for butyraldehyde, to afford the title
compound (0.054 g, 72%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.90 (s, 1H), 7.80 (s, 1H), 7.38-7.45 (m, 1H), 7.18 (d,
J=1.83 Hz, 1H), 7.08-7.13 (m, 1H), 4.35 (d, J=15.87 Hz, 1H), 4.08
(d, J=15.87 Hz, 1H), 3.60 (s, 3H), 2.61 (dd, J=12.51, 6.41 Hz, 1H),
2.25 (dd, J=12.51, 7.02 Hz, 1H), 0.73-0.82 (m, 1H), 0.23-0.36 (m,
1H), 0.10-0.20 (m, 1H), -0.18--0.08 (m, 1H), -0.42--0.30 (m, 1H).
MS (ESI+) m/z 342 (M+H).sup.+.
Example 50
methyl
4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibe-
nzo[cd,f]azulen-4(3H)-yl)butanoate
[1035] Example 50 was prepared according to the procedure used for
the preparation of Example 47, substituting 4-oxobutanoic acid
methyl ester for butyraldehyde, to afford the title compound (0.064
g, 74%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.90 (s, 1H),
7.82 (s, 1H), 7.43 (d, J=9.77 Hz, 1H), 7.19 (s, 1H), 7.07-7.14 (m,
1H), 4.17-4.23 (m, 1H), 4.01-4.07 (m, 1H), 3.61 (s, 3H), 3.52 (s,
3H), 2.59-2.68 (m, 2H), 2.30 (t, J=7.32 Hz, 2H), 1.46-1.56 (m, 2H).
MS (ESI+) m/z 388 (M+H).sup.+.
Example 51
5,7-difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibe-
nzo[cd,f]azulen-11(1H)-one
[1036] Example 51 was prepared according to the procedure used for
the preparation of Example 47, substituting 3-phenylpropionaldehyde
for butyraldehyde, to afford the title compound (0.062 g, 69%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H), 7.81 (s,
1H), 7.43 (dd, J=10.83, 1.37 Hz, 1H), 7.01-7.24 (m, 7H), 4.22-4.27
(m, 1H), 4.04-4.10 (m, 1H), 3.61 (s, 3H), 2.49-2.69 (m, 4H),
1.44-1.67 (m, 2H). MS (ESI+) m/z 406 (M+H).sup.+.
Example 52
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1037] A 4 mL vial was charged with Example 5f (25 mg, 0.073 mmol),
1-isocyanato-2-methylbenzene (13.39 mg, 0.091 mmol),
diisopropylethylamine (38.4 .mu.L, 0.220 mmol) and
N,N-dimethylformamide (1 mL). The reaction mixture was heated at
80.degree. C. for 18 hours. The reaction mixture was concentrated
and the residue was purified by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford the title
compound (5.6 mg, 16%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.90 (d, J=1.8 Hz, 1H), 7.67 (s,
1H), 7.45-7.53 (m, 2H), 7.31-7.39 (m, 1H), 7.26 (s, 1H), 7.02 (t,
J=7.2 Hz, 2H), 6.86-6.94 (m, 1H), 5.40-5.48 (m, 1H), 4.51-4.56 (m,
2H), 4.10-4.19 (m, 1H), 3.64 (s, 3H), 2.96 (s, 3H), 1.76 (s, 3H).
MS (ESI+) m/z 477.1 (M+H).sup.+.
Example 53
2-ethylhexyl
10-methyl-7-((methylsulfonyl)methyl)-1-oxo-10,11-dihydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulene-4(3H)-carboxylate
[1038] A 4 mL vial was charged with Example 5f (15 mg, 0.044 mmol),
2-ethylhexyl carbonochloridate (10.10 mg, 0.05 mmol),
diisopropylethylamine (50 .mu.L, 0.287 mmol) and
N,N-dimethylacetamide (2 mL). The reaction mixture was heated at
80.degree. C. for 18 hours. To this mixture was added
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (19.93 mg, 0.05 mmol) and heating was continued
for 18 hours. The reaction mixture was concentrated and the residue
was purified by reverse phase HPLC (C18, CH.sub.3CN/water (0.1%
TFA), 0-100% gradient) to afford the title compound (4.4 mg,
20.2%). .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta.
7.78-7.81 (m, 1H), 7.59-7.60 (m, 1H), 7.35-7.39 (m, 1H), 7.27-7.31
(m, 1H), 7.20-7.22 (m, 1H), 5.17-5.23 (m, 1H), 4.44-4.54 (m, 1H),
4.12-4.19 (m, 1H), 3.77 (bs, 2H), 3.61-3.64 (m, 3H), 2.90-2.94 (m,
3H), 1.21-1.35 (m, 1H), 0.95-1.18 (m, 9H), 0.65-0.79 (m, 6H). MS
(ESI+) m/z 500.1 (M+H).sup.+.
Example 54
4-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
[1039] A 4 mL vial was charged with Example 5f (15 mg, 0.044 mmol),
isobutyryl chloride (4.65 mg, 0.044 mmol), diisopropylethylamine
(50 .mu.L, 0.287 mmol) and N,N-dimethylacetamide (2 mL). The
reaction mixture was heated at 80.degree. C. for 18 hours. To this
mixture was added
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (19.93 mg, 0.05 mmol) and heating was continued
for 18 hours. The reaction mixture was concentrated and the residue
was purified by reverse phase HPLC (C18, CH.sub.3CN/water (0.1%
TFA), 0-100% gradient) to afford the title compound (1.3 mg, 7.2%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83-7.87 (m,
1H), 7.65-7.69 (m, 1H), 7.42-7.45 (m, 1H), 7.33-7.41 (m, 1H),
7.20-7.26 (m, 1H), 5.45-5.60 (m, 1H), 4.47-4.58 (m, 2H), 3.89-4.01
(m, 1H), 3.63 (s, 3H), 2.95 (s, 4H), 1.96 (s, 1H), 0.91-1.01 (m,
3H), 0.44-0.55 (m, 2H). MS (ESI+) m/z 414.1 (M+H).sup.+.
Example 55
5,7-difluoro-10-methyl-4-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,-
f]azulen-11(1H)-one
[1040] Example 55 was prepared according to the procedure used for
the preparation of Example 47, substituting 2-phenylacetaldehyde
for butyraldehyde. Purification by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 0-100% gradient) afforded the title
compound (0.034 g, 40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.91 (d, J=1.22 Hz, 1H), 7.82 (s, 1H), 7.44 (dd, J=10.38,
2.14 Hz, 1H), 7.08-7.21 (m, 5H), 7.02 (d, J=6.71 Hz, 2H), 4.28-4.33
(m, 1H), 4.05-4.10 (m, 1H), 3.60 (s, 3H), 2.67-2.78 (m, 2H),
2.45-2.53 (m, 2H). MS (ESI+) m/z 392 (M+H).sup.+.
Example 56
4-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1041] Example 56 was prepared according to the procedure used for
the preparation of Example 47, substituting
2-(benzo[d][1,3]dioxol-5-yl)acetaldehyde for butyraldehyde.
Purification by reverse phase HPLC (C18, CH.sub.3CN/water (0.1%
TFA), 0-100% gradient) afforded an impure product that was purified
a second time (silica gel, 0.5-3% methanol in dichloromethane) to
give the title compound (0.033 g, 32%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.90 (s, 1H), 7.80 (s, 1H), 7.43 (dd,
J=8.70, 2.59 Hz, 1H), 7.19 (d, J=2.14 Hz, 1H), 7.08-7.16 (m, 1H),
6.68 (d, J=7.93 Hz, 1H), 6.60 (s, 1H), 6.39-6.49 (m, 1H), 5.89 (s,
2H), 4.28 (d, J=15.87 Hz, 1H), 4.05 (d, J=15.87 Hz, 1H), 3.60 (s,
3H), 2.33-2.88 (m, 4H). MS (ESI+) m/z 436 (M+H).sup.+.
Example 57
4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1042] Example 57 was prepared according to the procedure used for
the preparation of Example 47, substituting 2-phenylacetaldehyde
for butyraldehyde. The crude material was triturated in 1 mL of
50/50 DMSO/methanol and filtered to collect a yellow solid (0.013
g, 12%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.62 (s, 1H),
7.60 (s, 1H), 6.95-7.16 (m, 10H), 6.87 (d, J=15.87 Hz, 1H), 6.67
(dd, J=6.56, 2.59 Hz, 2H), 6.59 (s, 1H), 6.50-6.56 (m, 1H), 5.42
(d, J=15.56 Hz, 1H), 4.68 (d, J=15.56 Hz, 1H), 4.26 (d, J=14.95 Hz,
1H), 3.66 (s, 3H). MS (ESI+) m/z 492 (M+H).sup.+.
Example 58
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-t-
etrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
Example 58a
(Z)-ethyl
3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyacrylate
[1043] To a solution of ethanol (15 mL) and ether (150 mL) was
added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60
mmol), diethyl oxalate (13.15 g, 90 mmol), and potassium ethoxide
(6.06 g, 72 mmol). The reaction mixture was heated at 45.degree. C.
for 24 hours. During the reaction, the flask was shaken by hand
several times. After cooling, 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 chromatography on silica gel eluting
with 10-20% ethyl acetate in hexanes to 9.5 g of the title compound
(yield 46%).
Example 58b
ethyl 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1044] A mixture of Example 58a (9.5 g, 27.4 mmol) and iron powder
(7.64 g, 137 mmol) in ethanol (60 mL) and acetic acid (60 mL) was
heated at 100.degree. C. for 1 hour. The solid was filtered off,
and then washed with additional ethyl acetate. The solvents were
removed under reduced pressure to 20% of original volume, and the
mixture was partitioned between water and ethyl acetate. The
aqueous layer was extracted with additional 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 20-40% ethyl acetate in
hexanes to give 6.05 g of the title compound.
Example 58c
ethyl
1-benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1045] Example 58b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL)
was treated with 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of
a 60% in oil dispersion). The solution was stirred at ambient
temperature for 10 minutes. To this solution was added benzyl
bromide (0.59 g, 3.45 mmol). The reaction mixture was stirred for
another 2 hours and was then partitioned between water and ethyl
acetate. 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 by
flash chromatography on silica gel eluting with 20-40% ethyl
acetate in hexanes to give 1.07 g of the title compound.
Example 58d
ethyl
1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbo-
xylate
[1046] The mixture of Example 58c (2, 5.14 mmol) in dioxane (20 mL)
was treated with 4.0 M HCl in dioxane (20 mL, 80 mmol). The
reaction mixture was stirred at 45.degree. C. for 18 hours. The
mixture was concentrated to remove dioxane. The residue was slurry
in petroleum ether to obtain the title compound (1.8 g, 4.80 mmol,
93% yield) as gray solid.
Example 58e
ethyl
1-benzyl-4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
e-2-carboxylat
[1047] To a suspension of Example 58d (5.16 g, 13.75 mmol) in
dimethylformamide (100 mL) at ambient temperature was added NaH
(0.660 g, 16.50 mmol) and the mixture was stirred at ambient
temperature for 30 minutes. Iodomethane (1.032 mL, 16.50 mmol) was
added into the reaction mixture. The reaction mixture was stirred
at ambient temperature for 2 hours, and was then partitioned
between water and ethyl acetate. 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 by chromatography on silica gel eluting with
20-40% ethyl acetate in hexanes to give the title compound (4.23 g,
8.91 mmol, 64.8% yield).
Example 58f
ethyl
1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1048] A mixture of Example 58e (2 g, 5.14 mmol),
bis(pinacolato)diboron (2.61 g, 10.3 mmol), potassium acetate (1.11
g, 11.3 mmol tris(dibenzylideneacetone)dipalladium(O) (0.235 g,
0.257 mmol) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.245 g,
0.514 mmol) in dioxane (50 mL) was stirred at 90.degree. C. for 16
hour under an argon atmosphere. The mixture was filtered through
Celite, washed with ethyl acetate several times and concentrated.
The residue was purified by flash chromatography (silica gel,
50-75% ethyl acetate/petroleum ether gradient) to afford the title
compound (1.15 g, 40% yield).
Example 58g
2-bromo-4-((methylsulfonyl)methyl)aniline
[1049] To a solution of Example 5b (2 g, 10.80 mmol) in DMF (60 mL)
was added 1-bromopyrrolidine-2,5-dione (1.922 g, 10.80 mmol) and
the reaction mixture was stirred at 15.degree. C. for 1 hour. The
reaction mixture was quenched with 150 mL 10% sodium thiosulfate
and 100 mL saturated sodium bicarbonate. The reaction mixture was
extracted with ethyl acetate three times. The combined organic
layers were washed with saturated aqueous sodium chloride and
concentrated to a semi-solid. Water was added, and the resulting
suspension was stirred at ambient temperature for 10 minutes. The
solid was collected by filtration and dried on the frit overnight
to give the title compound (2.1 g, 7.85 mmol, 72.7% yield) as a tan
solid.
Example 58h
2-bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline
[1050] To a 500 mL flask were added Example 58g (10 g, 37.9 mmol),
1-chloro-4-iodobenzene (18.06 g, 76 mmol), PdOAc.sub.2 (0.425 g,
1.893 mmol), xantphos (1.75 g, 3.03 mmol), Cs.sub.2CO.sub.3 (24.67
g, 76 mmol) and anhydrous dioxane (350 mL) under argon at ambient
temperature. The mixture was heated at 110.degree. C. for 18 hours.
The reaction mixture was filtered through Celite and washed with
ethyl acetate (100 mL). The filtrate was concentrated to remove the
solvent and the residue was treated with ethyl acetate (50 mL) and
petroleum ether (20 mL) and the mixture was stirred at ambient
temperature for 15 min. The resulting solid was collected by
filtration, washed with a little petroleum ether and dried under
reduced pressure to give the title compound (9.6 g, 24.85 mmol,
65.6% yield) as yellow solid.
Example 58i
ethyl
1-benzyl-4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phen-
yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1051] Example 58i was prepared according to the procedure used for
the preparation of Example 5d, substituting Example 58h for Example
5c, and Example 58f for Example if, respectively, to provide the
title compound.
Example 58j
ethyl
4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-met-
hyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1052] A mixture of Example 58i (0.5 g, 0.828 mmol), anisole (0.181
mL, 1.655 mmol) and H.sub.2SO.sub.4 (0.5 mL, 9.38 mmol) in TFA (20
mL, 260 mmol) was heated at 90.degree. C. for 10 hours. Excess TFA
was removed under reduced pressure, and the residue was partitioned
between water (10 mL) and ethyl acetate (20 mL). The organic layer
was separated, and the aqueous layer was extracted with additional
ethyl acetate twice (20 mL). The combined organic layers were
washed with saturated aqueous sodium bicarbonate (10 mL), followed
by saturated aqueous sodium chloride (10 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated to give the title
compound (0.38 g, 0.355 mmol, 42.9% yield) as pale solid.
Example 58k
ethyl
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,1-
0,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate
[1053] A mixture of Example 58j (0.200 g, 0.389 mmol), HCl (4 M in
dioxane) (4 mL, 16.00 mmol) and paraformaldehyde (0.234 g, 7.78
mmol) in methanol (2 mL) was heated at 130.degree. C. for 1.5 hours
under microwave. The solvent was removed and the residue was
partitioned between water and ethyl acetate. 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 to
give the title compound (0.14 g, 0.130 mmol, 33.5% yield).
Example 581
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-t-
etrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic
Acid
[1054] A mixture of Example 58k and LiOH (0.646 mL, 1.293 mmol) in
dioxane (3 mL) was heated at 65.degree. C. for 18 hours. The
solvent was removed and water (20 mL) was added. The aqueous layer
was adjusted pH to 3 with 1N HCl. The solid was filtered and dried
to give the title compound (0.25 g, 0.487 mmol, 75% yield) as pale
solid.
Example 58m
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-t-
etrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1055] To a solution of Example 581 (0.1 g, 0.201 mmol) in
anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.035
mL, 0.402 mmol) and DMF (0.777 .mu.L, 10.04 .mu.mol) and the
reaction mixture was stirred at ambient temperature for 2 hours.
The reaction mixture was concentrated to dryness. The residue was
redissolved in dichloromethane (5 mL) and was treated with ammonium
hydroxide (25% wt/wt in water) (2 mL, 92 mmol) and the reaction
mixture was stirred at ambient temperature overnight. The resulting
solid was filtered and treated with methanol twice and filtered
again to provide the title compound (30 mg, 0.057 mmol, 28.3%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.23 (s, 1H),
7.93 (s, 1H), 7.83 (s, 1H), 7.68 (s, 2H), 7.47 (d, J=7.4 Hz, 1H),
7.38 (d, J=7.8 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.35 (d, J=8.6 Hz,
2H), 5.89 (m, 1H), 4.68-4.35 (m, 3H), 3.59 (s, 3H), 3.01 (s, 3H).
MS (ESI+) m/z 497.1 (M+H).sup.+
Example 59
4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1056] Example 59 was prepared according to the procedure used for
the preparation of Example 58m, substituting ethylamine for
ammonium hydroxide (25% wt/wt in water), to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6-MeOD): .delta. 8.33
(t, J=5.0 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.67 (s, 1H), 7.47 (dd,
J=8.1, 1.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H),
6.36 (d, J=9.1 Hz, 2H), 6.13-5.82 (m, 2H), 4.50 (dd, J=56.8, 24.0
Hz, 3H), 3.58 (s, 3H), 3.01 (s, 3H), 1.25-1.14 (m, 3H). MS (ESI+)
m/z 525.0 (M+H).sup.+
Example 60
4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methyls-
ulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-on-
e
[1057] Example 60 was prepared according to the procedure used for
the preparation of Example 58m, substituting 1-methylpiperazine for
ammonium hydroxide (25% wt/wt in water), to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.34 (s,
1H), 7.91 (d, J=1.7 Hz, 1H), 7.66 (s, 1H), 7.47 (dd, J=8.1, 1.8 Hz,
1H), 7.37 (d, J=8.0 Hz, 1H), 6.97 (d, J=9.1 Hz, 2H), 6.45 (d, J=9.1
Hz, 2H), 5.10 (d, J=16.8 Hz, 1H), 4.68-4.40 (m, 3H), 3.69-3.40 (m,
7H), 3.00 (s, 3H), 2.36 (s, 4H), 2.21 (s, 3H). MS (ESI+) m/z 580.2
(M+H).sup.+
Example 61
N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1058] Example 61 was prepared according to the procedure used for
the preparation of Example 52, substituting
2-isocyanato-1,3-dimethylbenzene for 1-isocyanato-2-methylbenzene
to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.85 (s, 1H), 7.62 (s, 1H), 7.44 (s,
2H), 7.23 (s, 1H), 6.86-6.96 (m, 3H), 5.31-5.40 (m, 1H), 4.48-4.53
(m, 2H), 4.11-4.21 (m, 1H), 3.65 (s, 3H), 2.95 (s, 3H), 1.82 (s,
6H). MS (ESI+) m/z 491.1 (M+H).sup.+.
Example 62
N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1059] Example 62 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-isocyanato-4-methoxybenzene for 1-isocyanato-2-methylbenzene to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.86 (d, J=1.9 Hz, 1H), 7.63 (s,
1H), 7.43 (dd, J=8.0, 1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 (s,
1H), 7.08-7.15 (m, 1H), 6.70-6.76 (m, 1H), 5.43-5.54 (m, 1H), 4.52
(bs, 2H), 4.02-4.16 (m, 1H), 3.65 (d, J=10.2 Hz, 2H), 2.97 (s, 3H).
MS (ESI+) m/z 493.0 (M+H).sup.+.
Example 63
N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1060] Example 63 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-ethyl-4-(2-isocyanatoethyl)benzene for
1-isocyanato-2-methylbenzene to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.81 (d, J=2.0 Hz,
1H), 7.58 (s, 1H), 7.34 (dd, J=8.1, 2.0 Hz, 1H), 7.16-7.20 (m, 2H),
7.00 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 5.27-5.41 (m, 1H),
4.49 (s, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H), 3.02-3.20 (m, 2H),
2.95 (s, 3H), 2.53-2.58 (m, 2H), 1.16 (t, J=7.6 Hz, 3H). MS (ESI+)
m/z 519.1 (M+H).sup.+.
Example 64
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,-
10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1061] Example 64 was prepared according to the procedure used for
the preparation of Example 52, substituting 1-isocyanatopropane for
1-isocyanato-2-methylbenzene to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.82 (d, J=1.9 Hz,
1H), 7.59 (s, 1H), 7.40 (dd, J=8.1, 2.0 Hz, 1H), 7.30 (d, J=8.0 Hz,
1H), 7.19 (s, 1H), 5.33 (s, 1H), 4.50 (s, 2H), 3.94-4.05 (m, 1H),
3.63 (s, 3H), 2.95 (s, 3H), 2.71-2.92 (m, 2H), 1.25 (h, J=7.3 Hz,
2H), 0.66 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 429.1 (M+H).sup.+.
Example 65
N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1062] Example 65 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-(isocyanatomethyl)-3-methoxybenzene for
1-isocyanato-2-methylbenzene to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.82 (d, J=1.9 Hz,
1H), 7.59 (s, 1H), 7.40 (dd, J=8.1, 2.0 Hz, 1H), 7.30 (d, J=8.0 Hz,
1H), 7.19 (s, 1H), 5.33 (s, 1H), 4.50 (s, 2H), 3.94-4.05 (m, 1H),
3.63 (s, 3H), 2.95 (s, 3H), 2.71-2.92 (m, 2H), 1.25 (h, J=7.3 Hz,
2H), 0.66 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 507.0 (M+H).sup.+.
Example 66
N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1063] Example 66 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-chloro-2-isocyanatoethane for 1-isocyanato-2-methylbenzene to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.95 (d, J=0.4 Hz, 1H), 7.80 (s,
1H), 7.71 (d, J=1.6 Hz, 1H), 7.20 (dd, J=8.2, 1.9 Hz, 1H), 7.04 (d,
J=8.1 Hz, 1H), 4.37 (s, 2H), 4.13 (s, 2H), 3.79 (t, J=6.1 Hz, 2H),
3.73 (s, 3H), 3.69 (dt, J=6.4, 3.5 Hz, 2H), 2.89 (s, 3H). MS (ESI+)
m/z 449.2 (M+H).sup.+.
Example 67
N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1064] Example 67 was prepared according to the procedure used for
the preparation of Example 52, substituting
(isocyanatomethyl)cyclohexane for 1-isocyanato-2-methylbenzene to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=2.0 Hz, 1H), 7.59 (s,
1H), 7.40 (dd, J=8.0, 2.0 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.19 (s,
1H), 5.24-5.37 (m, 1H), 4.50 (s, 1H), 3.96-4.08 (m, 1H), 3.63 (s,
3H), 2.95 (s, 3H), 2.65-2.83 (m, 1H), 1.45-1.58 (m, 3H), 1.34 (dd,
J=13.7, 1.1 Hz, 1H), 1.09-1.27 (m, 1H), 0.95-1.10 (m, 3H),
0.56-0.70 (m, 2H). MS (ESI+) m/z 483.1 (M+H).sup.+.
Example 68
N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1065] Example 68 was prepared according to the procedure used for
the preparation of Example 52, substituting
2,4-difluoro-1-isocyanatobenzene for 1-isocyanato-2-methylbenzene
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.90-11.98 (m, 1H), 7.90 (bs, 1H), 7.70 (s, 1H), 7.33-7.52
(m, 4H), 7.26 (d, J=1.0 Hz, 1H), 7.11-7.21 (m, 1H), 6.88-6.97 (m,
1H), 5.46 (d, J=15.6 Hz, 1H), 4.60 (d, J=13.5 Hz, 1H), 4.50 (d,
J=13.5 Hz, 1H), 4.10 (d, J=15.1 Hz, 1H), 3.64 (s, 3H), 2.98 (s,
3H). MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 69
N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1066] Example 69 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-isocyanato-4-isopropylbenzene for 1-isocyanato-2-methylbenzene to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.86 (d, J=1.8 Hz, 1H), 7.63 (s,
1H), 7.43 (dd, J=8.1, 2.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.25 (s,
1H), 7.12 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 5.43-5.57 (m,
1H), 4.52 (s, 2H), 4.04-4.14 (m, 1H), 3.64 (s, 3H), 2.97 (s, 3H),
2.77 (dt, J=14.1, 7.0 Hz, 1H), 1.17-1.20 (m, 1H), 1.13 (d, J=6.9
Hz, 6H). MS (ESI+) m/z 505.2 (M+H).sup.+.
Example 70
N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1067] Example 70 was prepared according to the procedure used for
the preparation of Example 52, substituting
1,3-difluoro-2-isocyanatobenzene for 1-isocyanato-2-methylbenzene
to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.85 (d, J=1.7 Hz, 1H), 7.64 (s,
1H), 7.40-7.45 (m, 2H), 7.15-7.25 (m, 2H), 6.94 (t, J=8.0 Hz, 2H),
5.45 (d, J=15.2 Hz, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.08-4.16 (m, 1H),
3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 71
N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl-
)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxam-
ide
[1068] Example 71 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for
1-isocyanato-2-methylbenzene to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.87 (d, J=1.7 Hz,
1H), 7.73 (dd, J=6.5, 2.7 Hz, 1H), 7.64 (s, 1H), 7.58 (ddd, J=8.9,
5.6, 2.4 Hz, 1H), 7.43 (dd, J=8.1, 1.8 Hz, 1H), 7.39 (d, J=8.1 Hz,
1H), 7.25 (s, 1H), 7.21 (d, J=9.6 Hz, 1H), 5.49-5.56 (m, 1H), 4.53
(d, J=3.5 Hz, 2H), 4.08-4.14 (m, 1H), 3.64 (s, 3H), 2.97 (s, 3H).
MS (ESI+) m/z 549.0 (M+H).sup.+.
Example 72
ethyl
4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-
-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarb-
oxylate
[1069] Example 72 was prepared according to the procedure used for
the preparation of Example 52, substituting ethyl
4-(isocyanatomethyl)cyclohexanecarboxylate for
1-isocyanato-2-methylbenzene to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=1.9 Hz,
1H), 7.59 (s, 1H), 7.41 (dd, J=8.1, 2.0 Hz, 1H), 7.31 (d, J=8.0 Hz,
1H), 7.19 (s, 1H), 5.26-5.36 (m, 1H), 4.50 (d, J=1.2 Hz, 2H),
3.95-4.08 (m, 3H), 3.63 (s, 3H), 2.95 (s, 3H), 2.68-2.83 (m, 2H),
2.03 (tt, J=12.2, 3.7 Hz, 1H), 1.75 (dd, J=12.8, 2.2 Hz, 2H),
1.36-1.46 (m, 2H), 1.06-1.19 (m, 6H), 0.60-0.71 (m, 2H). MS (ESI+)
m/z 555.1 (M+H).sup.+.
Example 73
N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide
[1070] Example 73 was prepared according to the procedure used for
the preparation of Example 52, substituting
1-isocyanato-3-methoxypropane for 1-isocyanato-2-methylbenzene to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=1.9 Hz, 1H), 7.60 (s,
1H), 7.41 (dd, J=8.1, 2.0 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.19 (s,
1H), 5.29-5.38 (m, 1H), 4.50 (d, J=2.0 Hz, 2H), 3.94-4.04 (m, 1H),
3.63 (s, 3H), 3.15 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.98-3.04 (m,
1H), 2.95 (s, 3H), 2.86-2.93 (m, 1H), 1.47 (p, J=6.4 Hz, 2H). MS
(ESI+) m/z 555.1 (M+H).sup.+.
Example 74
10-methyl-7-((methylsulfonyl)methyl)-4-tosyl-3,4-dihydro-1H-1,4,10-triazad-
ibenzo[cd,f]azulen-11(10H)-one
[1071] A 4 mL vial was charged with Example 5f (15 mg, 0.04 mmol),
4-methylbenzene-1-sulfonyl chloride (19 mg, 0.1 mmol),
diisopropylethylamine (15 .mu.L, 0.08 mmol) and
N,N-dimethylacetamide (0.75 mL). The reaction mixture was heated at
50.degree. C. for 18 hours. The reaction mixture was concentrated
and the residue was purified by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford the title
compound (1.4 mg, 6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.66 (d, J=1.83 Hz, 1H), 7.47-7.49 (m, 1H), 7.41 (dd,
J=8.24, 1.83 Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.77-6.80 (m,
2H), 6.72-6.75 (m, 2H), 5.21 (d, J=16.48 Hz, 1H), 4.58-4.62 (m,
1H), 4.52 (d, J=4.88 Hz, 1H), 4.49 (s, 1H), 3.51 (s, 3H), 2.98 (s,
3H), 2.15 (s, 3H). MS (APCI+) m/z 498 (M+H).sup.+.
Example 75
4-([1,1'-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4--
dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11 (10H)-one
[1072] Example 75 was prepared according to the procedure used for
the preparation of Example 74, substituting biphenyl-4-sulfonyl
chloride for 4-methylbenzene-1-sulfonyl chloride to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.66 (d, J=2.14 Hz, 1H) 7.52-7.55 (m, 3H) 7.48 (t, J=7.32
Hz, 2H) 7.42-7.45 (m, 2H) 7.29 (s, 1H) 7.20-7.23 (m, 3H) 6.93 (d,
J=8.54 Hz, 2H) 5.29 (d, J=16.48 Hz, 1H) 4.48-4.63 (m, 3H) 3.18 (s,
3H) 2.98 (s, 3H). MS (APCI+) m/z 560 (M+H).sup.+.
Example 76
4-((4-methoxyphenyl)sulfonyl)-10-methylsulfonyl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11 (10H)-one
[1073] Example 76 was prepared according to the procedure used for
the preparation of Example 74, substituting
4-methoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl
chloride to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.65 (d, J=2.14 Hz, 1H) 7.47-7.50
(m, 1H) 7.39-7.43 (m, 1H) 7.24 (s, 2H) 6.78 (d, J=9.16 Hz, 2H) 6.44
(d, J=8.85 Hz, 2H) 5.21 (d, J=16.48 Hz, 1H) 4.57-4.62 (m, 1H) 4.50
(s, 1H) 4.46-4.48 (m, J=2.75 Hz, 1H) 3.69 (s, 3H) 3.49 (s, 3H) 2.97
(s, 3H). MS (APCI+) m/z 514 (M+H).sup.+.
Example 77
10-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(1H)-one
[1074] Example 77 was prepared according to the procedure used for
the preparation of Example 74, substituting benzenesulfonyl
chloride for 4-methylbenzene-1-sulfonyl chloride to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.65 (d, J=1.83 Hz, 1H) 7.47-7.51 (m, 1H) 7.41 (dd, J=8.09,
1.98 Hz, 1H) 7.22-7.26 (m, 2H) 7.21 (s, 1H) 6.93-6.98 (m, 2H)
6.88-6.91 (m, 2H) 5.24 (d, J=16.48 Hz, 1H) 4.58-4.62 (m, 1H)
4.48-4.54 (m, 2H) 3.47 (s, 3H) 2.97 (s, 3H). MS (APCI+) m/z 484
(M+H).sup.+.
Example 78
4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1075] Example 78 was prepared according to the procedure used for
the preparation of Example 74, substituting
2-methoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl
chloride to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.74 (d, J=1.83 Hz, 1H) 7.50 (s, 1H)
7.33-7.39 (m, 1H) 7.26-7.30 (m, 2H) 7.12-7.16 (m, 2H) 6.81 (d,
J=8.24 Hz, 1H) 6.72 (t, J=7.48 Hz, 1H) 5.25 (d, J=16.48 Hz, 1H)
4.54-4.59 (m, 1H) 4.41-4.52 (m, 2H) 3.58 (s, 3H) 3.44 (s, 3H) 2.99
(s, 3H). MS (APCI+) m/z 514 (M+H).sup.+.
Example 79
10-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1076] Example 79 was prepared according to the procedure used for
the preparation of Example 74, substituting
4-phenoxybenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl
chloride to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.70 (d, J=1.83 Hz, 1H) 7.47-7.52
(m, 3H) 7.41 (dd, J=8.24, 1.83 Hz, 1H) 7.38 (s, 1H) 7.28 (t, J=7.48
Hz, 1H) 7.21 (s, 1H) 7.08 (d, J=7.63 Hz, 2H) 6.91-6.94 (m, 2H)
6.39-6.44 (m, 2H) 5.22 (d, J=16.48 Hz, 1H) 4.58-4.63 (m, 1H)
4.47-4.56 (m, 2H) 3.57 (s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 576
(M+H).sup.+.
Example 80
4-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1077] Example 80 was prepared according to the procedure used for
the preparation of Example 74, substituting
4-fluorobenzene-1-sulfonyl chloride for 4-methylbenzene-1-sulfonyl
chloride to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.67 (d, J=1.83 Hz, 1H) 7.48-7.51
(m, 1H) 7.42 (dd, J=8.09, 1.68 Hz, 1H) 7.29 (s, 1H) 7.25 (s, 1H)
6.96 (dd, J=8.85, 5.19 Hz, 2H) 6.76 (t, J=8.85 Hz, 2H) 5.23 (d,
J=16.48 Hz, 1H) 4.57-4.63 (m, 1H) 4.47-4.56 (m, 2H) 3.51 (s, 3H)
2.98 (s, 3H). MS (APCI+) m/z 502 (M+H).sup.+.
Example 81
4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-11(10H)-one
[1078] Example 81 was prepared according to the procedure used for
the preparation of Example 54, substituting 2-naphthoyl chloride
for isobutyryl chloride to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.96-7.99 (m, 1H), 7.93
(s, 1H), 7.86 (s, 1H), 7.80 (d, J=7.02 Hz, 1H), 7.71-7.76 (m, 1H),
7.63-7.67 (m, 2H), 7.57-7.61 (m, 1H), 7.46-7.53 (m, 2H), 7.42 (s,
1H), 7.08 (dd, J=8.39, 1.37 Hz, 1H), 5.93 (d, J=14.95 Hz, 1H),
4.39-4.45 (m, 1H), 4.31-4.38 (m, 1H), 4.20 (d, J=14.65 Hz, 1H),
3.73 (s, 3H), 2.77 (s, 3H). MS (ESI+) m/z 498.1 (M+H).sup.+.
Example 82
methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoat-
e
[1079] Example 12d (44.3 mg, 0.100 mmol) and methyl 4-oxobutanoate
(58.1 mg, 0.500 mmol) were combined in tetrahydrofuran (1 mL). To
this suspension was added 1M titanium(IV) chloride in
dichloromethane (0.200 mL, 0.200 mmol). The reaction mixture was
stirred at ambient temperature for 20 hours, and partitioned with
ethyl acetate and water. 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 (38 mg, 70%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.91 (d, J=2.14 Hz, 1H) 7.85 (d, J=1.83 Hz,
1H) 7.69 (s, 1H) 7.24 (dd, J=8.24, 1.83 Hz, 1H) 7.04-7.13 (m, 2H)
6.81-7.02 (m, 3H) 5.03 (t, J=7.63 Hz, 1H) 4.38-4.63 (m, 2H) 3.64
(s, 3H) 3.55 (s, 3H) 2.93 (s, 3H) 2.35-2.46 (m, 2H) 1.82-2.03 (m,
1H) 1.34-1.61 (m, 1H). MS (ESI+) m/z 542 (M+H).sup.+.
Example 83
4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo-
[cd,f]azulen-11(1H)-one
Example 83a
5-chloro-N-(2,4-difluorophenyl)pyrimidin-4-amine
[1080] A mixture of 2,4-difluoroaniline (0.433 g, 3.36 mmol),
4,5-dichloropyrimidine (0.5 g, 3.36 mmol), cesium carbonate (2.187
g, 6.71 mmol),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.097 g,
0.168 mmol) and diacetoxypalladium (0.038 g, 0.168 mmol) were
combined in toluene (4 mL), sealed, sparged for 15 minutes with
argon and heated at 110.degree. C. for 18 hours. The reaction
mixture was partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride,
dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl
functionalized silica, filtered and concentrated. Purification by
chromatography (silica gel, 10-50% ethyl acetate in heptanes)
afforded the title compound (0.66 g, 81%).
Example 83b
4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1-tosyl-1H-pyrrol-
o[2,3-c]pyridin-7(6H)-one
[1081] Example 83a (0.2 g, 0.828 mmol), Example if (0.355 g, 0.828
mmol), tris(dibenzylideneacetone)dipalladium (O) (0.038 g, 0.041
mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.041 g, 0.141 mmol) and sodium carbonate (0.307 g, 2.90 mmol)
were combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (4 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 18 hour at 80.degree. C.,
cooled, diluted with 100 mL ethyl acetate and 20 mL of water and
filtered through Celite to remove elemental palladium. The filtrate
layers were separated. The organic layer was washed with saturated
aqueous sodium chloride, dried (anhydrous sodium sulfate), treated
with 3-mercaptopropyl functionalized silica gel, filtered and
concentrated. Purification by chromatography (silica gel, 0.5-4%
methanol in dichloromethane) afforded the title compound (0.272 g,
65%).
Example 83c
4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1H-pyrrolo[2,3-c]-
pyridin-7(6H)-one
[1082] Example 83b (0.26 g, 0.512 mmol) and lithium hydroxide
monohydrate (0.215 g, 5.12 mmol) were combined in dioxane (4 mL)
and water (1.333 mL) and heated at 50.degree. C. for 18 hours. The
mixture was cooled, diluted with water and the pH was adjusted to
pH 9 with 1 M HCl. The resulting solid was collected by filtration,
rinsed with water and dried to constant mass affording the title
compound (0.171 g, 94%).
Example 83d
4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo-
[cd,f]azulen-11(1H)-one
[1083] Example 83c (0.03 g, 0.085 mmol) and paraformaldehyde (0.025
g, 0.849 mmol) were combined in methanol (1.0 mL) and treated with
hydrogen chloride (4M in 1,4-dioxane, 1.0 mL, 4.00 mmol). The
mixture was sealed and heated at 130.degree. C. for 2 hours by
microwave. The mixture was cooled, diluted with ether and filtered
to collect the HCl salt of the title compound (0.0025 g, 7%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.75 (d, J=2.44 Hz,
1H), 10.45 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.77 (d, J=2.75 Hz,
1H), 7.40-7.52 (m, 3H), 7.17 (t, J=8.39 Hz, 1H), 5.58 (d, J=14.95
Hz, 1H), 4.81 (d, J=15.26 Hz, 1H), 3.58 (s, 3H). MS (ESI+) m/z 366
(M+H).sup.+.
Example 84
(R)-ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[1084] Example 34 (13.4 mg, 0.026 mmol) was subjected to SFC
purification using a modified Berger Instruments PrepSFC.TM.
system. A manual version of the Berger system was integrated with a
Gilson 232 autosampler for sample injection and a Cavro
MiniPrep.TM. pipettor customized for fraction collection at
atmospheric pressure (Olson, J.; Pan, J.; Hochlowski, J.; Searle,
P.; Blanchard, D. JALA 2002, 7, 69-74). Custom designed collection
shoes allowed collection into 18.times.150 mm tubes and a methanol
wash system allows washing of shoes between fractions to maximize
recovery and avoid cross-contamination of fractions. The system was
controlled using SFC ProNTo.TM. software (version 1.5.305.15) and
an Abbott developed Visual Basic application for autosampler and
fraction collector control. The outlet pressure was 100 bar, oven
temperature at 35.degree. C., and mobile phase flow rate at 40
mL/min on a ChiralPak OD-H column (21.times.250 mm, 5 micron).
Samples were injected as solutions in 1.5 mL methanol. The
preparative SFC system was controlled using SFC ProNTo.TM. software
(version 1.5.305.15) and custom software for autosampler and
fraction collector control. Fractions were collected based upon UV
signal threshold and on-line Thermo MSQ mass spectrometry was used
for molecular mass confirmation, using ESI ionization in positive
mode. Mass spectra were acquired using a Navigator4.0 software and
an Abbott developed Visual Basic interface to communicate with SFC
controlling software to provide two white solids (Example 84, 6.5
mg, 48% yield, and Example 85 (6.0 mg, 44% yield). The first
eluting enantiomer was arbitrarily assigned as the R-isomer
(Example 84), and the second eluting enantiomer as the S-isomer
(Example 85). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.95-12.00 (m, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.37 (d,
J=1.9 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (t, J=8.7 Hz, 2H),
6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03
(m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+)
m/z 510.1 (M+H).sup.+.
Example 85
(S)-ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[1085] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.95-12.00 (m,
1H), 7.85 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.37 (d, J=1.9 Hz, 1H),
7.24 (d, J=8.1 Hz, 1H), 6.87 (t, J=8.7 Hz, 2H), 6.46-6.61 (m, 2H),
6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m, 2H), 3.58 (s,
3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1
(M+H).sup.+.
Example 86
2-methoxyethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1086] Example 86 was prepared according to the procedure used for
the preparation of Example 53, substituting 2-methoxyethyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.78-7.80 (m, 1H), 7.61 (s, 1H), 7.35-7.39 (m, 1H), 7.33
(s, 1H), 7.23 (s, 1H), 5.20-5.30 (m, 1H), 4.49 (d, J=6.8 Hz, 2H),
3.88-4.20 (m, 2H), 3.63 (s, 3H), 3.33-3.39 (m, 1H), 3.12 (s, 2H),
2.94 (s, 3H). MS (ESI+) m/z 446.0 (M+H).sup.+.
Example 87
ethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10--
triazadibenzo[cd,f]azulene-4(3H)-carboxylate
[1087] Example 87 was prepared according to the procedure used for
the preparation of Example 53, substituting ethyl carbonochloridate
for 2-ethylhexyl carbonochloridate to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.78-7.80 (m,
1H), 7.61 (s, 1H), 7.35-7.39 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H),
5.21-5.27 (m, 1H), 4.49 (d, J=6.8 Hz, 2H), 4.12-4.17 (m, 1H),
3.85-3.99 (m, 2H), 3.63 (s, 3H), 2.95 (s, 3H), 1.00-1.08 (m, 3H).
MS (ESI+) m/z 416.1 (M+H).sup.+.
Example 88
pentyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulene-4(3H)-carboxylate
[1088] Example 88 was prepared according to the procedure used for
the preparation of Example 53, substituting pentyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.79 (d, J=1.9 Hz, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.1, 1.9
Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 5.22 (d, J=15.5 Hz,
1H), 4.44-4.54 (m, 2H), 4.14 (d, J=15.6 Hz, 1H), 3.91 (dd, J=11.9,
5.4 Hz, 1H), 3.80-3.87 (m, 1H), 3.63 (s, 3H), 2.94 (s, 3H),
1.33-1.41 (m, 2H), 1.03-1.18 (m, 4H), 0.75 (t, J=7.1 Hz, 3H). MS
(ESI+) m/z 458.1 (M+H).sup.+.
Example 89
4-chlorobutyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1089] Example 89 was prepared according to the procedure used for
the preparation of Example 53, substituting 4-chlorobutyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.80 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 7.36-7.39 (m, 1H),
7.32 (d, J=8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d, J=15.7 Hz, 1H),
4.45-4.54 (m, 2H), 4.15 (d, J=15.8 Hz, 1H), 3.93-3.99 (m, 1H),
3.83-3.92 (m, 1H), 3.63 (s, 3H), 3.40-3.47 (m, 2H), 2.94 (s, 3H),
1.47-1.58 (m, 4H). MS (ESI+) m/z 478.0 (M+H).sup.+.
Example 90
naphthalen-2-yl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1090] Example 90 was prepared according to the procedure used for
the preparation of Example 53, substituting naphthalen-2-yl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.76-7.88 (m, 4H), 7.71 (s, 1H), 7.55-7.63 (m, 1H),
7.39-7.50 (m, 4H), 7.29-7.33 (m, 1H), 7.07 (d, J=8.9 Hz, 1H),
5.33-5.46 (m, 1H), 4.46-4.57 (m, 2H), 4.27-4.38 (m, 1H), 3.67 (s,
3H), 2.96 (s, 3H). MS (ESI+) m/z 513.9 (M+H).sup.+.
Example 91
p-tolyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulene-4(3H)-carboxylate
[1091] Example 91 was prepared according to the procedure used for
the preparation of Example 53, substituting p-tolyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.84 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.47-7.54 (m, 1H),
7.42 (dd, J=8.0, 1.8 Hz, 1H), 7.29 (s, 1H), 7.08 (d, J=8.2 Hz, 2H),
6.77 (d, J=8.5 Hz, 2H), 5.30-5.37 (m, 1H), 4.46-4.56 (m, 2H),
4.22-4.32 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H), 2.23 (s, 3H). MS
(ESI+) m/z 478.2 (M+H).sup.+.
Example 92
neopentyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate
[1092] Example 92 was prepared according to the procedure used for
the preparation of Example 53, substituting neopentyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.81 (d, J=1.8 Hz, 1H), 7.62 (s, 1H), 7.38 (dd, J=8.1, 1.9
Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d, J=15.5 Hz,
1H), 4.44-4.54 (m, 2H), 4.18 (d, J=15.6 Hz, 1H), 3.63 (s, 3H),
3.27-3.29 (m, 2H), 2.91 (s, 3H), 0.62-0.79 (m, 9H). MS (ESI+) m/z
458.1 (M+H).sup.+.
Example 93
phenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulene-4(3H)-carboxylate
[1093] Example 93 was prepared according to the procedure used for
the preparation of Example 53, substituting phenyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.85 (d, J=1.9 Hz, 1H), 7.69 (s, 1H), 7.50-7.55 (m, 1H),
7.42 (dd, J=8.0, 2.0 Hz, 1H), 7.29 (t, J=7.8 Hz, 3H), 7.14 (t,
J=7.3 Hz, 1H), 6.89 (dd, J=8.6, 1.1 Hz, 2H), 5.30-5.39 (m, 1H),
4.46-4.57 (m, 2H), 4.26-4.34 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H).
MS (ESI+) m/z 464.1 (M+H).sup.+.
Example 94
4-fluorophenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1094] Example 94 was prepared according to the procedure used for
the preparation of Example 53, substituting 4-fluorophenyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.85 (d, J=1.7 Hz, 1H), 7.68 (s, 1H), 7.50-7.57 (m, 1H),
7.42 (dd, J=8.2, 2.0 Hz, 1H), 7.29 (s, 1H), 7.07 (t, J=8.8 Hz, 2H),
6.91-6.96 (m, 2H), 5.31-5.38 (m, 1H), 4.46-4.56 (m, 2H), 4.25-4.34
(m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 482.0
(M+H).sup.+.
Example 95
2-methoxyphenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1095] Example 95 was prepared according to the procedure used for
the preparation of Example 53, substituting 2-methoxyphenyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.84 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.49-7.55 (m, 1H),
7.41 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (s, 1H), 7.08-7.14 (m, 1H), 6.97
(d, J=8.2 Hz, 1H), 6.83-6.86 (m, 2H), 5.29-5.36 (m, 1H), 4.45-4.56
(m, 2H), 4.23-4.33 (m, 1H), 3.67 (s, 3H), 3.54 (s, 3H), 2.95 (s,
3H). MS (ESI+) m/z 494.1 (M+H).sup.+.
Example 96
2-fluoroethyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1096] Example 96 was prepared according to the procedure used for
the preparation of Example 53, substituting 2-fluoroethyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.80 (d, J=1.5 Hz, 1H), 7.62 (s, 1H), 7.38 (dd, J=8.3, 1.7
Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.24 (d, J=0.6 Hz, 1H), 5.27 (d,
J=15.6 Hz, 1H), 4.45-4.55 (m, 3H), 4.34-4.39 (m, 1H), 3.99-4.28 (m,
3H), 3.63 (s, 3H), 2.94 (s, 3H). MS (ESI+) m/z 434.0
(M+H).sup.+.
Example 97
4-methoxyphenyl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1097] Example 97 was prepared according to the procedure used for
the preparation of Example 53, substituting 4-methoxyphenyl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.84 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.46-7.56 (m, 1H),
7.39-7.44 (m, 1H), 7.25-7.32 (m, 1H), 6.82 (s, 4H), 5.30-5.39 (m,
1H), 4.45-4.56 (m, 2H), 4.21-4.34 (m, 1H), 3.70 (s, 3H), 3.66 (s,
3H), 2.95 (s, 3H). MS (ESI+) m/z 494.0 (M+H).sup.+.
Example 98
but-2-yn-1-yl
10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulene-4(3H)-carboxylate
[1098] Example 98 was prepared according to the procedure used for
the preparation of Example 53, substituting but-2-yn-1-yl
carbonochloridate for 2-ethylhexyl carbonochloridate to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.80 (d, J=1.9 Hz, 1H), 7.62 (s, 1H), 7.39 (dd, J=8.3, 1.9
Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 5.21-5.27 (m, 1H),
4.44-4.55 (m, 4H), 4.13-4.19 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H),
1.72 (t, J=2.3 Hz, 3H). MS (ESI+) m/z 440.1 (M+H).sup.+.
Example 99
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide
Example 99a
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoic
Acid
[1099] Example 82 (375 mg, 0.692 mmol) and lithium hydroxide (83
mg, 3.5 mmol) were combined in the mixture of dioxane (6 mL) and
water (2 mL). The reaction mixture was stirred at ambient
temperature for 5 hours. The reaction mixture was diluted with
water, the pH adjusted to 4 by addition of 1M HCl, and extracted by
ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride, dried with anhydrous sodium sulfate, filtered and
concentrated to afford the title compound (365 mg, 100%).
Example 99b
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide
[1100] Example 99a (31.7 mg, 0.060 mmol),
2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (49.6 mg, 0.120 mmol) and
diisopropylethylamine (0.042 mL, 0.240 mmol) were combined in
dimethylformamide (1 mL). To this solution was added 0.5M ammonia
in dioxane (0.240 mL, 0.120 mmol). The reaction mixture was stirred
at ambient temperature for 2 hours. The reaction mixture was
partitioned with ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride twice, dried with
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by reverse phase HPLC (C18, CH.sub.3CN/water (10 mM
ammonium acetate), 10-100%) to afford the title compound (18 mg,
57%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.91 (s, 1H)
7.82 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.34 (s, 1H) 7.22 (dd, J=8.24,
1.83 Hz, 1H) 7.01-7.17 (m, 3H) 6.86-6.99 (m, 2H) 6.77 (s, 1H) 5.01
(dd, J=9.00, 5.95 Hz, 1H) 4.38-4.55 (m, 2H) 3.64 (s, 3H) 2.93 (s,
3H) 2.10-2.20 (m, 2H) 1.87-1.98 (m, 1H) 1.31-1.45 (m, 1H). MS
(ESI+) m/z 549 (M+Na).sup.+.
Example 100
4-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1101] Example 100 was prepared according to the procedure used for
the preparation of Example 54, substituting 4-fluorobenzoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=1.9
Hz, 1H), 7.75 (s, 1H), 7.25-7.33 (m, 1H), 7.10 (ddd, J=13.0, 8.5,
5.9 Hz, 3H), 6.90-7.03 (m, 3H), 5.66-5.88 (m, 1H), 4.33-4.50 (m,
2H), 4.16 (d, J=16.2 Hz, 1H), 3.69 (s, 3H), 2.84 (s, 3H). MS (ESI+)
m/z 466.1 (M+H).sup.+.
Example 101
4-(3-methoxypropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1102] Example 101 was prepared according to the procedure used for
the preparation of Example 54, substituting 3-methoxypropanoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.86 (s, 1H),
7.67 (s, 1H), 7.38-7.46 (m, 2H), 7.22-7.25 (m, 1H), 5.48-5.61 (m,
1H), 4.52 (q, J=14.0 Hz, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H),
3.29-3.43 (m, 3H), 3.00 (s, 2H), 2.95 (s, 3H), 2.33-2.43 (m, 1H),
1.93-2.02 (m, 1H). MS (ESI+) m/z 430.2 (M+H).sup.+.
Example 102
4-([1,1'-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-di-
hydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1103] Example 102 was prepared according to the procedure used for
the preparation of Example 54, substituting
[1,1'-biphenyl]-4-carbonyl chloride for isobutyryl chloride to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.85 (d, J=1.8 Hz, 1H), 7.78 (s,
1H), 7.54 (d, J=7.6 Hz, 2H), 7.39-7.46 (m, 4H), 7.29-7.37 (m, 2H),
7.14 (d, J=8.4 Hz, 3H), 6.99-7.06 (m, 1H), 5.70-5.94 (m, 1H), 4.42
(d, J=5.2 Hz, 2H), 4.14-4.22 (m, 1H), 3.70 (s, 3H), 2.81 (s, 3H).
MS (ESI+) m/z 424.0 (M+H).sup.+.
Example 103
4-(3-cyclopentylpropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1104] Example 103 was prepared according to the procedure used for
the preparation of Example 54, substituting 3-cyclopentylpropanoyl
chloride for isobutyryl chloride, to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.86 (s, 1H),
7.65 (s, 1H), 7.41 (dd, J=22.9, 9.0 Hz, 2H), 7.23 (s, 1H),
5.51-5.59 (m, 1H), 4.52 (q, J=13.6 Hz, 2H), 3.89-3.99 (m, 1H), 3.63
(s, 3H), 2.94 (s, 3H), 1.83-2.10 (m, 2H), 1.19-1.40 (m, 9H),
0.66-0.80 (m, 2H). MS (ESI+) m/z 468.2 (M+H).sup.+.
Example 104
4-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1105] Example 104 was prepared according to the procedure used for
the preparation of Example 54, substituting
2-(3-methoxyphenyl)acetyl chloride for isobutyryl chloride to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 7.65-7.74 (m, 1H), 7.39-7.49 (m,
2H), 7.16-7.30 (m, 2H), 6.52-6.94 (m, 2H), 6.04-6.18 (m, 1H),
5.49-5.61 (m, 1H), 4.45-4.56 (m, 2H), 3.58 (s, 3H), 3.47 (s, 2H),
2.95 (s, 4H). MS (ESI+) m/z 492.1 (M+H).sup.+.
Example 105
10-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-11(10H)-one
[1106] Example 105 was prepared according to the procedure used for
the preparation of Example 54, substituting propionyl chloride for
isobutyryl chloride to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.81-7.88 (m, 1H), 7.63-7.69
(m, 1H), 7.37-7.45 (m, 2H), 7.22-7.26 (m, 1H), 5.51-5.61 (m, 1H),
4.52 (q, J=13.8 Hz, 2H), 3.91-3.99 (m, 1H), 3.63 (s, 3H), 2.95 (s,
3H), 2.13 (dq, J=14.8, 7.3 Hz, 1H), 1.64-1.81 (m, 1H), 0.72-0.87
(m, 3H). MS (ESI+) m/z 400.1 (M+H).sup.+.
Example 106
10-methyl-4-(3-methylbutanoyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1107] Example 106 was prepared according to the procedure used for
the preparation of Example 54, substituting 3-methylbutanoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.81-7.88 (m,
1H), 7.63-7.69 (m, 1H), 7.32-7.47 (m, 2H), 7.22-7.25 (m, 1H),
5.49-5.62 (m, 1H), 4.47-4.59 (m, 2H), 3.91-3.99 (m, 1H), 3.63 (s,
3H), 2.95 (s, 3H), 1.90-2.01 (m, 1H), 1.66-1.81 (m, 1H), 0.63-0.69
(m, 3H), 0.43-0.51 (m, 4H). MS (ESI+) m/z 428.1 (M+H).sup.+.
Example 107
4-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1108] Example 107 was prepared according to the procedure used for
the preparation of Example 54, substituting 3,3-dimethylbutanoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.85 (s, 1H),
7.65 (s, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.23
(s, 1H), 5.57-5.64 (m, 1H), 3.87-3.97 (m, 1H), 4.52 (q, J=13.7 Hz,
2H), 3.63 (s, 3H), 2.94 (s, 3H), 1.84-2.01 (m, 2H), 0.69 (s, 9H).
MS (ESI+) m/z 442.2 (M+H).sup.+.
Example 108
10-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1109] Example 108 was prepared according to the procedure used for
the preparation of Example 54, substituting 2-phenylacetyl chloride
for isobutyryl chloride to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.69-7.74 (m, 1H), 7.44
(s, 2H), 7.24-7.28 (m, 2H), 7.19-7.23 (m, 2H), 6.93-7.01 (m, 2H),
6.54-6.62 (m, 1H), 5.49-5.57 (m, 1H), 4.46-4.57 (m, 2H), 3.95-4.01
(m, 1H), 3.58 (s, 3H), 2.96 (s, 5H). MS (ESI+) m/z 462.1
(M+H).sup.+.
Example 109
4-benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulen-11(10H)-one
[1110] Example 109 was prepared according to the procedure used for
the preparation of Example 54, substituting benzoyl chloride for
isobutyryl chloride to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.90-7.96 (m, 1H), 7.82 (d,
J=2.0 Hz, 1H), 7.75 (s, 1H), 7.20-7.34 (m, 2H), 7.09-7.18 (m, 2H),
7.04 (d, J=7.4 Hz, 2H), 6.92-7.01 (m, 1H), 5.65-5.87 (m, 1H), 4.41
(d, J=5.0 Hz, 2H), 4.11-4.21 (m, 1H), 3.69 (s, 3H), 2.82 (s, 3H).
MS (ESI+) m/z 448.0 (M+H).sup.+.
Example 110
4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1-
,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1111] Example 110 was prepared according to the procedure used for
the preparation of Example 54, substituting 4-methoxybenzoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=1.8
Hz, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 7.14 (dd, J=8.0, 2.1 Hz, 1H),
7.01 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.68 (d, J=8.8 Hz,
2H), 5.72-5.92 (m, 1H), 4.36-4.49 (m, 2H), 4.12 (d, J=14.4 Hz, 1H),
3.68 (d, J=5.3 Hz, 6H), 2.85 (s, 3H). MS (ESI+) m/z 478.1
(M+H).sup.+.
Example 111
methyl
4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-4-oxobutanoate
[1112] Example 111 was prepared according to the procedure used for
the preparation of Example 54, substituting methyl
4-chloro-4-oxobutanoate for isobutyryl chloride, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.85-7.89 (m, 1H), 7.66-7.71 (m, 1H), 7.42-7.47 (m, 2H),
7.21-7.25 (m, 1H), 5.49-5.58 (m, 1H), 4.47-4.58 (m, 2H), 3.93-4.01
(m, 1H), 3.64 (s, 3H), 3.40-3.44 (m, 2H), 2.95 (s, 3H), 2.28-2.49
(m, 2H), 1.84-2.00 (m, 1H). MS (ESI+) m/z 458.1 (M+H).sup.+.
Example 112
4-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1113] Example 112 was prepared according to the procedure used for
the preparation of Example 54, substituting 2,4-difluorobenzoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.79 (s, 1H),
7.70 (s, 1H), 7.29-7.38 (m, 1H), 7.00-7.17 (m, 3H), 6.78-6.95 (m,
2H), 5.74-5.85 (m, 1H), 4.33-4.47 (m, 2H), 4.14-4.24 (m, 1H), 3.67
(s, 3H), 2.81 (s, 3H). MS (ESI+) m/z 484.1 (M+H).sup.+.
Example 113
4-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1114] Example 113 was prepared according to the procedure used for
the preparation of Example 54, substituting 2-fluorobenzoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.80-7.86 (m,
1H), 7.70 (s, 1H), 7.58-7.64 (m, 1H), 7.30-7.40 (m, 1H), 7.17-7.28
(m, 1H), 6.99-7.14 (m, 2H), 6.83-6.99 (m, 2H), 5.72-5.88 (m, 1H),
4.26-4.49 (m, 2H), 4.12-4.25 (m, 1H), 3.68 (s, 3H), 2.77 (s, 3H).
MS (ESI+) m/z 466.0 (M+H).sup.+.
Example 114
4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-11(10H)-one
[1115] Example 114 was prepared according to the procedure used for
the preparation of Example 54, substituting 1-naphthoyl chloride
for isobutyryl chloride to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.74-7.81 (m, 1H),
7.66-7.73 (m, 1H), 7.60-7.67 (m, 1H), 7.52-7.60 (m, 2H), 7.38-7.49
(m, 2H), 7.16-7.32 (m, 2H), 6.94-7.07 (m, 2H), 6.84-6.92 (m, 1H),
5.89-6.00 (m, 1H), 4.33-4.61 (m, 1H), 4.20-4.30 (m, 2H), 3.69 (s,
3H), 2.59-2.76 (m, 3H). MS (ESI+) m/z 498.1 (M+H).sup.+.
Example 115
4-(cyclopropanecarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1116] Example 115 was prepared according to the procedure used for
the preparation of Example 54, substituting cyclopropanecarbonyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83-7.91 (m,
1H), 7.63-7.71 (m, 1H), 7.39-7.47 (m, 2H), 7.18-7.27 (m, 1H),
5.53-5.66 (m, 1H), 4.44-4.61 (m, 2H), 3.89-4.05 (m, 1H), 3.64 (s,
3H), 2.96 (s, 3H), 1.91-1.98 (m, 1H), 1.18-1.32 (m, 1H), 1.04-1.15
(m, 2H), 0.55-0.66 (m, 1H). MS (ESI+) m/z 412.1 (M+H).sup.+.
Example 116
10-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropanoyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1117] Example 116 was prepared according to the procedure used for
the preparation of Example 54, substituting 3-phenylpropanoyl
chloride for isobutyryl chloride to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 7.83 (d, J=0.6
Hz, 1H), 7.59 (s, 1H), 7.40 (d, J=9.5 Hz, 1H), 7.31 (d, J=8.3 Hz,
1H), 7.23 (s, 1H), 6.97-7.06 (m, 3H), 6.76-6.84 (m, 2H), 5.51-5.63
(m, 1H), 4.51 (q, J=13.9 Hz, 2H), 3.89-4.01 (m, 1H), 3.63 (s, 3H),
2.93 (s, 3H), 2.61 (t, J=7.8 Hz, 2H), 2.33-2.43 (m, 1H), 2.02-2.14
(m, 1H). MS (ESI+) m/z 476.2 (M+H).sup.+.
Example 117
2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindol-
ine-1,3-dione
[1118] Example 12d (0.4 g, 0.902 mmol) and
2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (0.683 g, 3.61 mmol) were
combined in tetrahydrofuran (9.02 mL) under nitrogen, cooled to
0.degree. C. and treated drop-wise with 1M titanium(IV) chloride in
dichloromethane (3.61 mL, 3.61 mmol) to give an opaque red
solution. The solution was stirred for 72 hours at ambient
temperature and partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous sodium sulfate, filtered and concentrated.
Purification by chromatography (silica gel, 0.5-5% methanol in
dichloromethane) afforded the title compound as a yellow powder
(0.45 g, 81%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.78
(d, J=1.83 Hz, 1H), 7.93 (d, J=1.53 Hz, 1H), 7.81-7.86 (m, 4H),
7.76 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (dd, J=8.24, 1.83 Hz, 1H),
7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96 (d, J=2.44 Hz, 1H), 6.92
(d, J=8.24 Hz, 1H), 5.44 (dd, J=9.92, 5.34 Hz, 1H), 4.51-4.56 (m,
1H), 4.44-4.48 (m, 1H), 3.87 (dd, J=13.28, 5.34 Hz, 1H), 3.66 (s,
3H), 3.52 (dd, J=13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z
615 (M+H).sup.+.
Example 118
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropana-
mide
[1119] Example 118 was prepared according to the procedure used for
the preparation of Example 99b, substituting methanamine for
ammonia. Purification by reverse phase HPLC (C18, CH.sub.3CN/water
(10 mM ammonium acetate), 20-100%) afforded the title compound (22
mg, 68%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.90 (d,
J=1.22 Hz, 1H) 7.82 (d, J=1.83 Hz, 1H) 7.77 (q, J=4.48 Hz, 1H) 7.68
(s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.02-7.12 (m, 3H) 6.87-7.00
(m, 2H) 5.00 (dd, J=9.00, 5.95 Hz, 1H) 4.33-4.58 (m, 2H) 3.64 (s,
3H) 2.93 (s, 3H) 2.55 (d, J=4.58 Hz, 3H) 2.07-2.22 (m, 2H)
1.83-2.00 (m, 1H) 1.31-1.48 (m, 1H). MS (ESI+) m/z 563
(M+Na).sup.+.
Example 119
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpro-
panamide
[1120] Example 119 was prepared according to the procedure used for
the preparation of Example 99b, substituting dimethylamine for
ammonia. Purification by reverse phase HPLC (C18, CH.sub.3CN/water
(10 mM ammonium acetate), 20-100%) afforded the title compound (24
mg, 72%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H)
7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 2.14 Hz, 1H)
7.13-7.20 (m, 1H) 7.11 (s, 1H) 7.02-7.10 (m, 1H) 6.97 (d, J=8.24
Hz, 1H) 6.88-6.96 (m, 1H) 5.03-5.12 (m, 1H) 4.37-4.57 (m, 2H) 3.64
(s, 3H) 2.94 (s, 3H) 2.87 (s, 3H) 2.80 (s, 3H) 2.28-2.46 (m, 2H)
1.85-1.95 (m, 1H) 1.37-1.52 (m, 1H). MS (ESI+) m/z 577
(M+Na).sup.+.
Example 120
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholin-
o-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1121] Example 120 was prepared according to the procedure used for
the preparation of Example 99b, substituting morpholine for
ammonia. Purification by reverse phase HPLC (C18, CH.sub.3CN/water
(10 mM ammonium acetate), 20-100%) afforded the title compound (28
mg, 78%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H)
7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H)
7.03-7.16 (m, 3H) 6.99 (d, J=8.24 Hz, 1H) 6.88-6.94 (m, 1H) 5.08
(t, J=7.63 Hz, 1H) 4.39-4.57 (m, 2H) 3.64 (s, 3H) 3.37-3.55 (m, 8H)
2.94 (s, 3H) 2.40-2.48 (m, 1H) 2.29-2.39 (m, 1H) 1.84-1.94 (m, 1H)
1.38-1.55 (m, 1H). MS (ESI+) m/z 619 (M+Na).sup.+.
Example 121
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2-
H-pyran-4-yl)propanamide
[1122] Example 121 was prepared according to the procedure used for
the preparation of Example 99b, substituting
tetrahydro-2H-pyran-4-amine for ammonia. Purification by reverse
phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate),
20-100%) afforded the title compound (28 mg, 76%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.90 (s, 1H) 7.86 (d, J=7.63 Hz, 1H)
7.82 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H)
7.02-7.13 (m, 3H) 6.87-6.98 (m, 2H) 5.00 (dd, J=9.16, 5.80 Hz, 1H)
4.36-4.57 (m, 2H) 3.70-3.85 (m, 3H) 3.64 (s, 3H) 2.93 (s, 3H) 2.16
(t, J=7.17 Hz, 2H) 1.89-2.00 (m, 1H) 1.58-1.73 (m, 2H) 1.27-1.45
(m, 3H). MS (ESI+) m/z 633 (M+Na).sup.+.
Example 122
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N'-methyl-N'-ph-
enylpropanehydrazide
[1123] Example 122 was prepared according to the procedure used for
the preparation of Example 99b, substituting
1-methyl-1-phenylhydrazine for ammonia. Purification by reverse
phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate),
30-100%) afforded the title compound (20 mg, 53%). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.95 (d, J=1.83 Hz, 1H) 9.95 (s, 1H)
7.85 (d, J=1.83 Hz, 1H) 7.70 (s, 1H) 7.25 (dd, J=8.24, 1.83 Hz, 1H)
7.13-7.19 (m, 3H) 6.97-7.12 (m, 3H) 6.83-6.92 (m, 1H) 6.64-6.75 (m,
3H) 5.05 (dd, J=8.85, 6.10 Hz, 1H) 4.39-4.56 (m, 2H) 3.65 (s, 3H)
3.05 (s, 3H) 2.93 (s, 3H) 2.22-2.32 (m, 2H) 1.92-2.01 (m, 1H)
1.43-1.54 (m, 1H). MS (ESI+) m/z 654 (M+Na).sup.+.
Example 123
N-benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-
-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propana-
mide
[1124] Example 123 was prepared according to the procedure used for
the preparation of Example 99b, substituting phenylmethanamine for
ammonia. Purification by reverse phase HPLC (C18, CH.sub.3CN/water
(10 mM ammonium acetate), 30-100%) afforded the title compound (26
mg, 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.91 (d,
J=2.14 Hz, 1H) 8.39 (t, J=5.95 Hz, 1H) 7.83 (d, J=1.83 Hz, 1H) 7.68
(s, 1H) 7.27-7.33 (m, 2H) 7.19-7.25 (m, 4H) 7.02-7.11 (m, 3H) 6.97
(d, J=7.93 Hz, 1H) 6.81-6.92 (m, 1H) 5.02 (dd, J=9.00, 5.95 Hz, 1H)
4.38-4.57 (m, 2H) 4.25 (d, J=5.80 Hz, 2H) 3.64 (s, 3H) 2.93 (s, 3H)
2.25 (t, J=7.48 Hz, 2H) 1.91-2.02 (m, 1H) 1.35-1.56 (m, 1H). MS
(ESI+) m/z 639 (M+Na).sup.+.
Example 124
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxidot-
etrahydrothiophen-3-yl)propanamide
[1125] Example 124 was prepared according to the procedure used for
the preparation of Example 99b, substituting
3-aminotetrahydrothiophene 1,1-dioxide for ammonia. Purification by
reverse phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate),
20-100%) afforded the title compound (27 mg, 70%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.92 (s, 1H) 8.31 (dd, J=6.71, 3.66 Hz,
1H) 7.83 (s, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H)
7.01-7.13 (m, 3H) 6.88-6.98 (m, 2H) 4.95-5.05 (m, 1H) 4.38-4.55 (m,
3H) 3.64 (s, 3H) 3.36-3.44 (m, 1H) 3.23-3.29 (m, 1H) 3.06-3.18 (m,
1H) 2.93 (s, 3H) 2.78-2.92 (m, 1H) 2.27-2.40 (m, 1H) 2.14-2.24 (m,
2H) 1.87-2.05 (m, 2H) 1.37-1.51 (m, 1H). MS (ESI+) m/z 667
(M+Na).sup.+.
Example 125
tert-butyl
4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methy-
l)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pr-
opanoyl)piperazine-1-carboxylate
[1126] Example 125 was prepared according to the procedure used for
the preparation of Example 99b, substituting tert-butyl
piperazine-1-carboxylate for ammonia. Purification by reverse phase
HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate), 30-100%)
afforded the title compound (46 mg, 74%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.89 (d, J=1.53 Hz, 1H) 7.83 (d, J=1.83 Hz,
1H) 7.68 (s, 1H) 7.23 (dd, J=8.24, 1.53 Hz, 1H) 7.11-7.19 (m, 2H)
7.03-7.11 (m, 1H) 6.98 (d, J=8.24 Hz, 1H) 6.87-6.95 (m, 1H) 5.08
(t, J=7.63 Hz, 1H) 4.39-4.56 (m, 2H) 3.64 (s, 3H) 3.38-3.44 (m, 2H)
3.24-3.30 (m, 6H) 2.93 (s, 3H) 2.32-2.46 (m, 2H) 1.84-1.98 (m, 1H)
1.43-1.52 (m, 1H) 1.40 (s, 9H). MS (ESI+) m/z 696 (M+H).sup.+.
Example 126
tert-butyl
4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methy-
l)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pr-
opanamido)piperidine-1-carboxylate
[1127] Example 126 was prepared according to the procedure used for
the preparation of Example 99b, substituting tert-butyl
4-aminopiperidine-1-carboxylate for ammonia. Purification by
reverse phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate),
30-100%) afforded the title compound (48 mg, 75%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.91 (d, J=2.44 Hz, 1H) 7.80-7.85 (m,
2H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.02-7.13 (m, 3H)
6.88-6.98 (m, 2H) 5.00 (dd, J=9.16, 6.10 Hz, 1H) 4.34-4.55 (m, 2H)
3.76-3.86 (m, 2H) 3.68-3.75 (m, 1H) 3.64 (s, 3H) 2.93 (s, 3H)
2.73-2.88 (m, 2H) 2.15 (t, J=7.02 Hz, 2H) 1.88-1.99 (m, 1H)
1.61-1.73 (m, 2H) 1.34-1.48 (m, 10H) 1.11-1.27 (m, 2H). MS (ESI+)
m/z 732 (M+Na).sup.+.
Example 127
4-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-
-triazadibenzo[cd,f]azulene-2-carboxamide
Example 127a
2-bromo-N-(4-chlorophenyl)aniline
[1128] Example 127a was prepared according to the procedure used
for the preparation of Example 58h, substituting 2-bromoaniline for
Example 58g, to provide the title compound.
Example 127b
ethyl
1-benzyl-4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihy-
dro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1129] Example 127b was prepared according to the procedure used
for the preparation of Example 5d, substituting Example 127a for
Example 5c, and Example 58f for Example if, respectively, to
provide the title compound.
Example 127c
ethyl
4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridine-2-carboxylate
[1130] Example 127c was prepared according to the procedure used
for the preparation of Example 58j, substituting Example 127b for
Example 58i, to provide the title compound.
Example 127d
ethyl
4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-t-
riazadibenzo[cd,f]azulene-2-carboxylate
[1131] Example 127d was prepared according to the procedure used
for the preparation of Example 58k, substituting Example 127c for
Example 58j, to provide the title compound.
Example 127e
4-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-
-triazadibenzo[cd,f]azulene-2-carboxamide
[1132] A mixture of Example 127d (150 mg, 0.346 mmol) and
ethanamine (25% in ethanol wt/wt) (5 mL, 0.832 mmol) was sealed and
heated at 78.degree. C. for 2 days. The reaction mixture was cooled
to ambient temperature and concentrated. The residue was purified
by reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%
gradient) to give the title compound (18 mg, 0.042 mmol, 12.03%
yield) as pale solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
12.37 (s, 1H), 8.50 (s, 1H), 7.69 (d, J=4.2 Hz, 1H), 7.43 (m, 3H),
7.27 (m, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.3 Hz, 2H), 6.13
(d, J=15.3 Hz, 1H), 4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32
(m, 3H). MS (ESI+) m/z 433.0 (M+H).sup.+
Example 128
6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexyl
acetate
[1133] 7-oxoheptyl acetate (0.155 g, 0.902 mmol) and Example 12d
(0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.255 mL)
under nitrogen at 5.degree. C., and treated drop-wise with 1 M
titanium(IV) chloride in dichloromethane (0.676 mL, 0.676 mmol) to
afford a deep red reaction mixture. The reaction mixture was
stirred at ambient temperature for 18 hours and partitioned between
ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate, filtered and concentrated. Purification by chromatography
(silica gel, 0.5-4% methanol in dichloromethane) afforded the title
compound (0.108 g, 80%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.85 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.23 (d, J=7.93
Hz, 1H), 7.13 (s, 1H), 7.04-7.10 (m, 1H), 6.98 (d, J=7.93 Hz, 1H),
6.84 (d, J=5.49 Hz, 2H), 5.00 (t, J=6.56 Hz, 1H), 4.40-4.56 (m,
2H), 3.92 (t, J=6.56 Hz, 2H) 3.64 (s, 3H), 2.92 (s, 3H), 1.96 (s,
3H), 1.09-1.67 (m, 10H). MS (ESI+) m/z 598 (M+H).sup.+.
Example 129
3-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1134] Example 117 (0.45 g, 0.732 mmol) and hydrazine hydrate
(0.733 g, 14.64 mmol) were combined in ethanol (14.64 mL) and
stirred at reflux for 2 hours. The solution was allowed to cool to
ambient temperature and the resulting white solid was removed by
filtration. The filtrate was concentrated to a residue.
Purification of the residue by reverse phase HPLC (C18,
CH.sub.3CN/10 mM ammonium acetate in water, 10-100% gradient)
afforded the title compound (0.280 mg, 80%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.84 (s, 1H), 7.82 (d, J=1.83 Hz, 1H), 7.67
(s, 1H), 7.24-7.30 (m, 1H), 7.22 (dd, J=8.09, 1.98 Hz, 1H), 7.15
(s, 1H), 7.00-7.06 (m, 2H), 6.89-6.95 (m, 1H), 5.02 (dd, J=8.24,
6.41 Hz, 1H), 4.41-4.55 (m, 2H), 3.64 (s, 3H), 3.57 (s, 1H), 2.94
(s, 3H), 2.69 (dd, J=12.97, 8.70 Hz, 1H), 2.45 (dd, J=12.97, 6.26
Hz, 1H). MS (ESI+) m/z 485 (M+H).sup.+.
Example 130
N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-
(dimethylamino)methylene)-N-methylmethanaminium
[1135] Example 129 (0.03 g, 0.062 mmol),
N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino-
)(dimethylamino)methylene)-N-methylmethanaminium (HCTU, 0.033 g,
0.080 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.032 mL, 0.186
mmol) were combined in DMF (0.619 mL). To the mixture was added
acetic acid (10.63 .mu.L, 0.186 mmol) and the mixture was stirred
for 1 hour and partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous sodium sulfate, filtered and concentrated.
Purification by reverse phase HPLC (C18, CH.sub.3CN/0.1% TFA in
water, 10-100% gradient) afforded the title compound as a
trifluoroacetate salt (0.03 g, 78%). .sup.1H NMR (500 MHz,
PYRIDINE-d.sub.6) .delta. 13.11 (s, 1H), 9.84 (s, 1H), 8.08 (d,
J=1.47 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.43-7.49 (m, 2H), 7.20
(d, J=8.07 Hz, 1H), 6.82-6.89 (m, 1H), 6.74-6.79 (m, 1H), 5.95-6.00
(m, 1H), 4.65 (s, 2H), 3.73 (dd, J=13.48, 8.71 Hz, 1H), 3.61 (s,
3H), 3.57 (dd, J=13.48, 6.33 Hz, 1H), 3.08 (s, 3H), 2.77 (s, 12H).
MS (ESI+) m/z 583 (M).sup.+.
Example 131
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(pi-
perazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10-
H)-one
[1136] To a mixture of Example 125 (40 mg, 0.057 mmol) in
dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL,
6.5 mmol). The reaction mixture was stirred at ambient temperature
for 30 minutes and concentrated. To the residue was added water,
the pH was adjusted to 7 by addition of saturated aqueous sodium
bicarbonate, and the mixture was sonicated for 5 minutes, filtered,
washed with water, and dried to provide the title compound (18 mg,
53%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H)
7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H)
7.03-7.18 (m, 3H) 6.97 (d, J=7.93 Hz, 1H) 6.87-6.94 (m, 1H) 5.08
(t, J=7.63 Hz, 1H) 4.39-4.60 (m, 2H) 3.64 (s, 3H) 3.18-3.25 (m, 2H)
2.94 (s, 3H) 2.55-2.61 (m, 4H) 2.27-2.46 (m, 3H) 1.83-1.94 (m, 1H)
1.38-1.57 (m, 1H). MS (ESI+) m/z 596 (M+H).sup.+.
Example 132
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4--
yl)propanamide
[1137] To a mixture of Example 126 (42 mg, 0.059 mmol) in
dichloromethane (1.5 mL) was added trifluoroacetic acid (0.50 mL,
6.5 mmol). The reaction mixture was stirred at ambient temperature
for 30 minutes and concentrated. The residue was purified by
reverse phase HPLC (C18, CH.sub.3CN/water (10 mM ammonium acetate),
20-100% gradient) to provide the title compound (15 mg, 42%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.77-7.86 (m, 2H) 7.68
(s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.01-7.13 (m, 3H) 6.85-6.99
(m, 2H) 5.00 (dd, J=9.16, 6.10 Hz, 1H) 4.38-4.56 (m, 2H) 3.57-3.67
(m, 4H) 3.39-3.52 (m, 1H) 2.90-2.99 (m, 5H) 2.51-2.58 (m, 2H) 2.15
(t, J=7.17 Hz, 2H) 1.89-1.97 (m, 1H) 1.62-1.72 (m, 2H) 1.36-1.46
(m, 1H) 1.20-1.35 (m, 2H). MS (ESI+) m/z 610 (M+H).sup.+.
Example 133
4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyl
diacetate
[1138] 5-Oxopentane-1,2-diyl diacetate (0.182 g, 0.902 mmol) and
Example 12d (0.1 g, 0.225 mmol) were combined in tetrahydrofuran
(2.2 mL) under nitrogen at 5.degree. C., and treated dropwise with
1 M titanium(IV) chloride in toluene (0.676 mL, 0.676 mmol). The
reaction mixture was stirred at ambient temperature for 18 hours
and partitioned between ethyl acetate and water. The organic layer
was washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, filtered and concentrated. Purification
by reverse phase HPLC (C18, CH.sub.3CN/0.1% TFA in water, 10-100%
gradient) afforded the title compound (0.038 g, 26%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.87 (s, 1H), 7.83-7.87 (m, 1H),
7.69 (s, 1H), 7.22-7.28 (m, 1H), 6.96-7.18 (m, 3H), 6.69-6.87 (m,
2H), 5.01 (t, J=6.71 Hz, 1H), 4.78-4.92 (m, 1H), 4.40-4.56 (m, 2H),
3.85-4.08 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 1.95 (s, 3H), 1.88
(s, 3H), 1.30-1.79 (m, 4H). MS (ESI.sup.+) m/z 628 (M+H).sup.+.
Example 134
methyl
5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoat-
e
[1139] Methyl 6-oxohexanoate (0.130 g, 0.902 mmol) and Example 12d
(0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.3 mL) under
nitrogen at 5.degree. C., and treated dropwise with 1 M
titanium(IV) chloride (0.676 mL, 0.676 mmol) in dichloromethane.
The reaction mixture was stirred at ambient temperature for 18
hours and partitioned between ethyl acetate and water. The organic
layer was washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, filtered and concentrated. Purification
by reverse phase HPLC (C18, CH.sub.3CN/0.1% TFA in water, 10-100%
gradient) afforded the title compound (0.069 g, 54%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.84 (d, J=1.83 Hz, 1H), 7.85 (d,
J=1.53 Hz, 1H), 7.68 (s, 1H), 7.24 (dd, J=8.24, 1.83 Hz, 1H), 7.13
(d, J=2.44 Hz, 1H), 7.03-7.11 (m, 1H), 6.98 (d, J=8.24 Hz, 1H),
6.76-6.88 (m, 2H), 4.99 (t, J=7.32 Hz, 1H), 4.42-4.55 (m, 2H), 3.64
(s, 3H), 3.54 (s, 3H), 2.92 (s, 3H), 2.19 (t, J=6.71 Hz, 2H),
1.21-1.66 (m, 6H). MS (ESI.sup.+) m/z 570 (M+H).sup.+.
Example 135
tert-butyl
(2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methy-
l)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)me-
thyl)amino)-2-oxoethyl)carbamate
[1140] 2-((Tert-butoxycarbonyl)amino)acetic acid (0.022 g, 0.124
mmol), N-ethyl-N-isopropylpropan-2-amine (0.032 mL, 0.186 mmol) and
2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (HCTU, 0.028 g, 0.068 mmol) were combined in
N,N-dimethylformamide (0.619 mL) and stirred at ambient temperature
for 15 minutes. To this solution was added dropwise a solution of
Example 129 (0.03 g, 0.062 mmol) dissolved in N,N-dimethylformamide
(0.619 mL). The reaction mixture was stirred for 2 hours at ambient
temperature and partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous sodium sulfate, filtered and concentrated.
Purification by reverse phase HPLC (C18, CH.sub.3CN/10 mM ammonium
acetate in water, 10-100% gradient) afforded the title compound
(0.02 g, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.93
(s, 1H), 7.82 (m, 1H), 7.81 (d, J=1.83 Hz, 1H), 7.69 (s, 1H),
7.33-7.46 (m, 1H), 7.20 (dd, J=8.24, 1.83 Hz, 1H), 7.12 (s, 1H),
6.93-7.09 (m, 4H), 5.20 (dd, J=8.39, 6.26 Hz, 1H), 4.39-4.53 (m,
2H), 3.65 (s, 3H), 3.53 (d, J=6.10 Hz, 2H), 2.92 (s, 3H), 2.82-2.91
(m, 2H), 2.48-2.51 (m, 9H). MS (ESI.sup.+) m/z 640 (M+H).sup.+.
Example 136
4-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)met-
hyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1141] The product from Example 128 (0.08 g, 0.134 mmol) and
lithium hydroxide monohydrate (0.056 g, 1.339 mmol) were combined
in tetrahydrofuran (1.785 mL)/water (0.892 mL) and the reaction
mixture was stirred for 2 hours at 50.degree. C. The reaction
mixture was cooled to ambient temperature and partitioned between
ethyl acetate and water and the pH was adjusted to 7 by careful
addition of aqueous 1 M HCl. The organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate, filtered and concentrated. Purification by reverse phase
HPLC (C18, CH.sub.3CN/0.1% TFA in water, 10-100% gradient) afforded
the title compound (0.05 g, 67%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.83 (s, 1H), 7.84 (d, J=1.83 Hz, 1H), 7.67
(s, 1H), 7.23 (dd, J=8.09, 1.98 Hz, 1H), 7.12 (d, J=2.44 Hz, 1H),
7.03-7.10 (m, 1H), 6.98 (d, J=8.24 Hz, 1H), 6.78-6.89 (m, 2H), 5.00
(t, J=7.17 Hz, 1H), 4.41-4.54 (m, 2H), 4.32 (t, J=6.56 Hz, 1H),
3.64 (s, 3H), 3.31 (t, J=6.56 Hz, 2H), 2.92 (s, 3H), 1.20-1.67 (m,
10H). MS (ESI+) m/z 556 (M+H).sup.+.
Example 137
N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamid-
e
[1142] The product from Example 129 (0.03 g, 0.062 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.216 mL, 1.238 mmol) and
benzoyl chloride (0.036 mL, 0.310 mmol) were combined in
N,N-dimethylformamide (1.238 mL) and heated at 50.degree. C. for 2
hours. 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 over anhydrous
sodium sulfate, filtered and concentrated. Purification by reverse
phase HPLC (C18, CH.sub.3CN/0.1% TFA in water, 10-100% gradient)
afforded the title compound (0.023 g, 63%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.86 (d, J=2.44 Hz, 1H), 8.55 (t, J=5.49 Hz,
1H), 7.84 (d, J=1.83 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J=1.53 Hz,
1H), 7.72 (s, 1H), 7.44-7.56 (m, 4H), 7.21 (dd, J=8.24, 1.83 Hz,
1H), 7.02-7.12 (m, 2H), 6.99 (d, J=2.75 Hz, 1H), 6.94 (d, J=8.24
Hz, 1H), 5.42 (dd, J=9.61, 5.34 Hz, 1H), 4.40-4.55 (m, 2H), 3.66
(s, 3H), 2.96-3.06 (m, 2H), 2.94 (s, 3H). MS (ESI+) m/z 589
(M+H).sup.+.
Example 138
1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-pheny-
lurea
[1143] The product from Example 129 (0.03 g, 0.062 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.054 mL, 0.310 mmol) and phenyl
isocyanate (6.77 .mu.L, 0.062 mmol) were combined in
tetrahydrofuran (1.238 mL) and stirred for 30 minutes at ambient
temperature. The reaction mixture was concentrated and the residue
was purified by reverse phase HPLC (C18, CH.sub.3CN/0.1% TFA in
water, 10-100% gradient) to afford the title compound (0.021 g,
56%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.96 (d, J=2.44
Hz, 1H), 8.71 (s, 1H), 7.85 (d, J=1.83 Hz, 1H), 7.72 (s, 1H), 7.41
(d, J=7.63 Hz, 2H), 7.17-7.28 (m, 4H), 7.15 (d, J=2.75 Hz, 1H),
7.03-7.11 (m, 2H), 6.88-6.98 (m, 2H), 6.12 (t, J=5.65 Hz, 1H), 5.25
(t, J=7.48 Hz, 1H), 4.42-4.56 (m, 2H), 3.65 (s, 3H), 3.22-3.31 (m,
1H), 3.00-3.08 (m, 1H), 2.94 (s, 3H). MS (ESI+) m/z 602
(M+H).sup.+.
Example 139
2-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-
-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-
acetamide
[1144] The product from Example 135 (0.01 g, 0.016 mmol) in a
mixture of dichloromethane (2 mL)/TFA (1.0 mL) was stirred at
ambient temperature for 1 hour, concentrated and azeotroped three
times with toluene to afford the title compound as the TFA salt
(0.01 g, 98%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.03
(d, J=2.44 Hz, 1H), 8.45 (t, J=5.80 Hz, 1H), 8.00 (s, 2H), 8.00 (s,
1H), 7.83 (d, J=1.83 Hz, 1H), 7.72 (s, 1H), 6.92-7.40 (m, 5H) 5.18
(dd, J=9.16, 5.49 Hz, 1H), 4.40-4.55 (m, 2H), 3.65 (s, 3H),
3.43-3.67 (m, 4H), 2.94 (s, 3H). MS (ESI+) m/z 542 (M+H).sup.+.
Example 140
4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl-
)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1145] The product from Example 133 (0.038 g, 0.061 mmol) and
lithium hydroxide (0.029 g, 1.211 mmol) were combined in
tetrahydrofuran (1.614 mL)/water (0.807 mL) and stirred for 2 hours
at 50.degree. C. The reaction mixture was cooled to ambient
temperature and partitioned between ethyl acetate and water and the
pH was adjusted to 7 by careful addition of aqueous 1 M HCl. The
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous sodium sulfate, filtered and concentrated to
afford the title compound (0.028 g, 85%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.85 (s, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.67
(s, 1H), 7.19-7.25 (m, 1H), 7.11 (dd, J=5.04, 2.59 Hz, 1H),
7.03-7.09 (m, 1H), 6.84-6.99 (m, 3H), 4.97-5.04 (m, 1H), 4.43-4.53
(m, 2H), 4.34-4.41 (m, J=13.28, 1.98 Hz, 2H), 3.64 (s, 3H),
3.10-3.30 (m, 3H), 2.92 (s, 3H), 1.19-1.86 (m, 4H). MS (ESI+) m/z
544 (M+H).sup.+.
Example 141
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide
Example 141a
ethyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[1146] Example 141a was prepared according to the procedure used
for the preparation of Example 82, substituting ethyl glyoxalate
for methyl 4-oxobutanoate, to provide the title compound as a white
solid.
Example 141b
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylic
Acid
[1147] A 250 mL round-bottomed flask was charged with Example 141a
(0.6446 g, 1.222 mmol), dioxane (9.16 mL) and water (3.05 mL) to
give a yellow solution. Lithium hydroxide hydrate (0.256 g, 6.11
mmol) was added. The reaction mixture was stirred at ambient
temperature for 72 hours. The reaction mixture was quenched with 1N
HCl. The resulting suspension was stirred for 15 minutes, and
filtered. The solid was rinsed with water, dried overnight at
ambient temperature, and then dried in a 60.degree. C. vacuum oven
for 72 hours to provide the title compounds as a yellow solid
(0.5521 g, 90% yield).
Example 141c
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide
[1148] A 250 mL round-bottomed flask was charged with Example 141b
(0.0473 g, 0.095 mmol) and dichloromethane (1.894 mL) to give a tan
solution. Oxalyl dichloride (0.021 mL, 0.237 mmol) and
N,N-dimethylformamide (0.733 .mu.L, 9.47 .mu.mol) were added. The
reaction mixture was stirred at ambient temperature for 2 hours and
then cooled to 0.degree. C. Ammonium hydroxide (0.186 mL, 4.73
mmol) was added. The reaction mixture was stirred at 0.degree. C.
for 15 minutes, and stirred at ambient temperature overnight. The
reaction mixture was partitioned between water and ethyl acetate.
The organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The reaction mixture was purified by HPLC (Phenomenex
Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (30 mm.times.75 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0
min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min
linear gradient 95-10% A). Samples were injected in 1.5 mL
DMSO:methanol (1:1).)) to provide the title compound as a white
solid (7.0 mg, 15% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.96-12.01 (m, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.66 (s, 1H),
7.49-7.59 (m, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.10-7.16 (m, 2H),
6.93-7.11 (m, 3H), 6.89 (d, J=8.2 Hz, 1H), 6.68 (bs, 1H), 5.75 (s,
1H), 4.36-4.50 (m, 2H), 2.91 (s, 3H). MS (ESI+) m/z 499.1
(M+H).sup.+.
Example 142
4-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1149] To a solution of Example 82 (542 mg, 1.00 mmol) in
tetrahydrofuran (10 mL) was added 1.0 M lithium aluminum hydride in
tetrahydrofuran (1.00 mL, 1.00 mmol) dropwise at 0.degree. C. The
reaction mixture was stirred at ambient temperature for 2 hours,
and quenched by the addition of water (0.04 mL), 15% aqueous sodium
hydroxide (0.04 mL) and water (0.12 mL). The resulting mixture was
stirred for 20 minutes, diluted with ethyl acetate, filtered
through Celite, and concentrated. The residue was triturated with
dichloromethane to provide the title compound (413 mg, 80%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.86 (s, 1H), 7.83 (d,
J=1.9 Hz, 1H), 7.67 (s, 1H), 7.22 (dd, J=8.2, 1.9 Hz, 1H), 7.13 (s,
1H), 7.11-7.05 (m, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.93-6.84 (m, 2H),
5.05-4.98 (m, 1H), 4.53-4.42 (m, 2H), 4.36 (s, br, 1H), 3.64 (s,
3H), 2.93 (s, 3H), 1.71-1.62 (m, 1H), 1.61-1.54 (m, 1H), 1.50-1.42
(m, 1H), 1.34-1.25 (m, 1H). MS (ESI+) m/z 514 (M+H).sup.+.
Example 143
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypr-
opyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1150] Example 142 (31 mg, 0.060 mmol), phenol (8.5 mg, 0.090 mmol)
and triphenylphosphine (23.6 mg, 0.0900 mmol) were combined in
tetrahydrofuran (0.1 mL) and sonicated for 5 minutes. To this
reaction mixture was added diisopropyl azodicarboxylate (0.017 mL,
0.090 mmol) and the mixture was sonicated for 6 hours. The reaction
mixture was partitioned with ethyl acetate and water. 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). The resulting material from flash chromatography
was triturated with 10% dichloromethane in heptanes to provide the
title compound (18 mg, 51%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.89 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.30-7.15 (m,
4H), 7.12-7.04 (m, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.93-6.77 (m, 5H),
5.13-5.05 (m, 1H), 4.54-4.42 (m, 2H), 3.89 (s, br, 2H), 3.64 (s,
3H), 2.92 (s, 3H), 1.95-1.85 (m, 1H), 1.84-1.71 (m, 2H), 1.49-1.40
(m, 1H). MS (ESI+) m/z 590 (M+H).sup.+.
Example 144
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-pheno-
xypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1151] The product from Example 143 was purified by chiral
chromatography on a Chiralpak IB column, eluting with a 4:6 mixture
of methanol/carbon dioxide. The fractions containing the first
eluted enantiomer were collected and concentrated. The compound was
randomly assigned as the (S)-enantiomer. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.88 (s, 1H), 7.86 (d, J=1.7 Hz, 1H), 7.69
(s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04 (m, 1H), 6.99
(d, J=8.1 Hz, 1H), 6.92-6.82 (m, 5H), 5.09 (t, J=7.1 Hz, 1H),
4.55-4.42 (m, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.65 (s, 3H), 2.92 (s,
3H), 1.97-1.85 (m, 1H), 1.83-1.72 (m, 2H), 1.49-1.38 (m, 1H). MS
(ESI+) m/z 590 (M+H).sup.+.
Example 145
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-pheno-
xypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1152] The product from Example 143 was purified by chiral
chromatography on a Chiralpak IB column eluting with a 4:6 mixture
of methanol/carbon dioxide. The fractions containing the second
eluted enantiomer were collected and concentrated. The compound was
randomly assigned as the (R)-enantiomer. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.88 (s, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.69
(s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04 (m, 1H), 6.99
(d, J=8.1 Hz, 1H), 6.92-6.80 (m, 5H), 5.09 (t, J=7.1 Hz, 1H),
4.55-4.42 (m, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.64 (s, 3H), 2.92 (s,
3H), 1.95-1.84 (m, 1H), 1.84-1.72 (m, 2H), 1.49-1.39 (m, 1H). MS
(ESI+) m/z 590 (M+H).sup.+.
Example 146
4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 146a
4-(4-chlorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadi-
benzo[cd,f]azulene-2-carboxylic Acid
[1153] Example 146a was prepared according to the procedure used
for the preparation of Example 581, substituting Example 127d for
Example 58k, to provide the title compound.
Example 146b
4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1154] To the solution of Example 146a (0.12 g, 0.296 mmol) in
anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.052
mL, 0.591 mmol) and dimethylformamide (1.1 .mu.l, 0.015 mmol) and
the reaction mixture was stirred at ambient temperature for 2
hours. The reaction mixture was concentrated to dryness and then
dried under vacuum for 2 hours. The residue was redissolved in
dichloromethane (5 mL) and was treated with 1-methylpiperazine
(0.118 g, 1.183 mmol), and the reaction mixture was stirred at
ambient temperature overnight. The reaction mixture was
concentrated to give the crude title compound, which was taken into
next reaction without further purification.
Example 146c
4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1155] To a solution of Example 146b (100 mg, 0.133 mmol) in
anhydrous tetrahydrofuran (5 mL) were added
BH.sub.3.tetrahydrofuran (1.332 mL, 1.332 mmol) and the reaction
mixture was stirred at 65.degree. C. for 3 hours. After cooling,
the reaction mixture was quenched with ethanol (1 mL) and then
concentrated. 3N HCl (2 mL) was added and the mixture was heated at
78.degree. C. for 4 hours. The reaction mixture was cooled to
ambient temperature and 5 N NaOH (2 mL) was added. The mixture was
then extracted with dichlormethane (20 mL.times.3). The combined
organic layers were dried under anhydrous sodium sulfate, filtered,
and concentrated. The residue was purified by reverse phase HPLC
(C18, CH.sub.3CN/water (0.01N ammonium carbonate), 25-55% gradient)
to give the title compound (22 mg, 0.044 mmol, 33% yield) as white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.37 (s, 1H),
8.50 (s, 1H), 7.69 (d, J=4.2 Hz, 1H), 7.43 (m, 3H), 7.27 (m, 1H),
6.92 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.3 Hz, 2H), 6.13 (d, J=15.3 Hz,
1H), 4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32 (m, 3H). MS
(ESI+) m/z 433.0 (M+H).sup.+.
Example 147
4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 147a
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propyl
methanesulfonate
[1156] Example 142 (103 mg, 0.200 mmol), methanesulfonyl chloride
(0.023 mL, 0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol) were
combined in N,N-dimethylformamide (2 mL). The reaction mixture was
stirred at ambient temperature for 20 hours. To this reaction
mixture was added methanesulfonyl chloride (0.023 mL, 0.30 mmol)
and triethylamine (0.056 mL, 0.40 mmol) and the mixture was stirred
at ambient temperature for another 20 hours. The reaction mixture
was partitioned with ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride, dried with anhydrous
sodium sulfate, filtered, and concentrated to provide the title
compound in quantitative yield.
Example 147b
4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1157] Example 147a (35.5 mg, 0.0600 mmol) and 25% sodium methoxide
in methanol (0.027 mL, 0.12 mmol) were combined in tetrahydrofuran
(1 mL). The reaction mixture was heated at 60.degree. C. for 2
hours, cooled, and concentrated. The residue was purified by flash
chromatography (silica gel, 2-4% methanol in dichloromethane) to
provide the title compound (10 mg, 32%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.91 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.8 Hz,
1H), 7.74 (s, 1H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.20 (d, J=2.6 Hz,
1H), 7.17-7.10 (m, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.97-6.89 (m, 2H),
5.07 (t, J=7.3 Hz, 1H), 4.59-4.48 (m, 2H), 3.70 (s, 3H), 3.29 (t,
J=6.1 Hz, 2H), 3.19 (s, 3H), 2.99 (s, 3H), 1.82-1.67 (m, 2H),
1.65-1.54 (m, 1H), 1.43-1.32 (m, 1H). MS (ESI+) m/z 528
(M+H).sup.+.
Example 148
4-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)met-
hyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1158] Example 148 was prepared according to the procedure used for
the preparation of Example 147b, substituting 21% sodium ethoxide
in ethanol for 25% sodium methoxide in methanol, to provide the
title compound (16 mg, 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.86 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.68 (s,
1H), 7.23 (dd, J=8.2, 2.0 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H),
7.11-7.04 (m, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.90-6.84 (m, 2H),
5.08-4.97 (m, 1H), 4.55-4.43 (m, 2H), 3.64 (s, 3H), 3.34-3.25 (m,
4H), 2.93 (s, 3H), 1.72-1.60 (m, 2H), 1.58-1.48 (m, 1H), 1.38-1.25
(m, 1H), 1.03 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 542 (M+H).sup.+.
Example 149
4-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one
[1159] A 4 mL vial was charged with Example 5f (20 mg, 0.058 mmol),
isobutyraldehyde (8.36 mg, 0.116 mmol), acetic acid (0.100 mL,
1.747 mmol) and dichloroethane (2.0 mL). The vial was sealed and
the mixture was heated at 80.degree. C. for 1 hour. To this mixture
was added silica-supported sodiumcyanoborohydride (200 mg, 0.89
mmol/g, 0.178 mmol) and the mixture was heated at 80.degree. C. for
4 hours. Upon cooling, the reaction mixture was filtered and
concentrated. The residue was purified by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to afford the title
compound (16.4 mg, 71%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.80 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.25 (p, J=8.4
Hz, 2H), 7.18 (s, 1H), 4.43 (s, 2H), 4.15 (s, 2H), 3.59 (s, 3H),
2.91 (s, 3H), 2.76 (d, J=7.1 Hz, 2H), 1.62 (dt, J=13.4, 6.8 Hz,
1H), 0.69 (d, J=6.6 Hz, 6H). MS (ESI+) m/z 400.1 (M+H).sup.+.
Example 150
4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,-
4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1160] Example 150 was prepared according to the procedure used for
the preparation of Example 149, substituting
1-ethylpiperidine-3-carbaldehyde for isobutyraldehyde to provide
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.85 (s, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.53 (s, 1H), 7.24 (dt,
J=17.1, 5.0 Hz, 2H), 7.15 (s, 1H), 4.43 (s, 2H), 4.08 (t, J=15.9
Hz, 2H), 3.59 (s, 3H), 3.19 (d, J=54.0 Hz, 2H), 3.06-2.66 (m, 7H),
2.63 (s, 1H), 2.35 (s, 1H), 1.95-1.35 (m, 4H), 0.93 (s, 4H). MS
(ESI+) m/z 469.1 (M+H).sup.+.
Example 151
10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1161] Example 151 was prepared according to the procedure used for
the preparation of Example 149, substituting
dihydro-2H-pyran-4(3H)-one for isobutyraldehyde to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.88
(s, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.58 (s, 1H), 7.27-7.17 (m, 3H),
4.48-4.39 (s, 2H), 3.75-4.3 (m, 2H) 3.73-3.64 (m, 2H), 3.59 (s,
3H), 3.00 (dd, J=11.7, 2.3 Hz, 2H), 2.90 (s, 3H), 2.85-2.77 (m,
1H), 1.80-1.55 (m, 2H), 1.45-1.25 (m, 2H). MS (ESI+) m/z 469.1
(M+H).sup.+. MS (ESI+) m/z 428.1 (M+H).sup.+.
Example 152
4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfo-
nyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1162] Example 152 was prepared according to the procedure used for
the preparation of Example 149, substituting
2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde for isobutyraldehyde
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.76 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.52 (s, 1H),
7.28-7.13 (m, 3H), 4.41 (s, 2H), 4.07 (s, 2H), 3.57 (d, J=16.4 Hz,
3H), 3.45 (dd, J=11.3, 4.4 Hz, 1H), 3.36 (t, J=11.2 Hz, 1H), 2.90
(s, 3H), 2.83-2.66 (m, 2H), 1.78 (s, 1H), 1.39 (dd, J=26.2, 11.8
Hz, 2H), 0.96 (d, J=6.6 Hz, 6H), 0.91-0.47 (m, 2H). MS (ESI+) m/z
470.1 (M+H).sup.+.
Example 153
4-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1163] Example 153 was prepared according to the procedure used for
the preparation of Example 149, substituting 4-ethoxybutan-2-one
for isobutyraldehyde to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.65 (s, 1H), 7.49 (s, 1H), 7.20
(d, J=18.5 Hz, 3H), 4.41 (s, 2H), 4.37-4.14 (m, 3H), 3.58 (s, 3H),
3.54-2.95 (m, 4H), 2.90 (s, 3H), 1.63 (dd, J=13.6, 6.7 Hz, 1H),
1.51-1.41 (m, 1H), 1.06 (s, 3H), 0.84 (s, 3H). MS (ESI+) m/z 444.1
(M+H).sup.+.
Example 154
N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methy-
l)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carb-
oxamide
[1164] A stock solution of Example 141b and diiospropylethyl amine
(0.13 M and 0.38 M in N,N-dimethylacetamide, respectively, 224
.mu.L, 0.03 mmol 3-aminopropanenitrile (1.0 equivalent) and 0.09
mmol diiospropylethyl amine (3.0 equivalents)), HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate), (0.2 M in N,N-dimethylacetamide, 224
.mu.L, 0.045 mmol, 1.5 equivalents), and 3-aminopropanenitrile
(0.40 M in N,N-dimethylacetamide, 113 .mu.L, 0.045 mmol, 1.5
equivalents) 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 preparative HPLC
(Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (30
mm.times.75 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A,
7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A).
Samples were injected in 1.5 mL DMSO:methanol (1:1)) to provide the
title compound (12.6 mg, 76% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6-D.sub.2O) .delta. 7.72 (d, J=2.0 Hz, 1H), 7.71 (s,
1H), 7.51-7.67 (m, 1H), 7.33 (s, 1H), 7.16 (dd, J=8.2, 2.0 Hz, 1H),
6.98-7.08 (m, 2H), 6.86 (d, J=8.1 Hz, 1H), 5.86 (s, 1H), 4.38-4.51
(m, 2H), 3.67 (s, 3H), 3.14 (ddd, J=13.3, 7.3, 6.0 Hz, 1H),
2.94-3.05 (m, 1H), 2.93 (s, 3H), 1.96-2.16 (m, 2H). MS (ESI+) m/z
551.7 (M+H).sup.+.
Example 155
methyl
2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-o-
xo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido-
)acetate
[1165] Example 155 was prepared according to the procedure used for
the preparation of Example 154, substituting methyl 2-aminoacetate
for 3-aminopropanenitrile, to provide the title compound (12.7 mg,
74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.75 (d, J=2.1 Hz, 1H), 7.71 (s, 1H), 7.51-7.61 (m, 1H), 7.36 (s,
1H), 7.13 (dd, J=8.3, 2.0 Hz, 1H), 6.99-7.09 (m, 2H), 6.83 (d,
J=8.2 Hz, 1H), 5.88 (s, 1H), 4.38-4.49 (m, 1H), 3.67 (s, 3H), 3.60
(s, 1H), 3.48 (s, 2H), 2.90 (s, 2H). MS (ESI+) m/z 571.0
(M+H).sup.+.
Example 156
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phene-
thyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxami-
de
[1166] Example 156 was prepared according to the procedure used for
the preparation of Example 154, substituting 2-phenylethanamine for
3-aminopropanenitrile, to provide the title compound (15.4 mg, 85%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.75
(d, J=2.1 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.29 (s,
1H), 7.09-7.22 (m, 4H), 6.98-7.10 (m, 2H), 6.97 (d, J=1.7 Hz, 2H),
6.93-6.97 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.81 (s, 1H), 4.47 (d,
J=13.7 Hz, 1H), 4.40 (d, J=13.6 Hz, 1H), 3.68 (s, 3H), 3.12 (ddd,
J=12.8, 8.8, 5.8 Hz, 1H), 2.87-2.99 (m, 1H), 2.81 (s, 3H), 2.32
(ddd, J=13.6, 8.2, 5.6 Hz, 1H), 2.15-2.26 (m, 1H). MS (ESI+) m/z
603.0 (M+H).sup.+.
Example 157
N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide
[1167] Example 157 was prepared according to the procedure used for
the preparation of Example 154, substituting butan-1-amine for
3-aminopropanenitrile, to provide the title compound (13.8 mg, 83%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.73
(d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.59-7.68 (m, 1H), 7.32 (s, 1H),
7.18-7.12 (m, 2H), 6.98-7.08 (m, 2H), 6.85 (d, J=8.1 Hz, 1H), 5.79
(s, 1H), 4.36-4.50 (m, 1H), 3.67 (s, 3H), 2.90-3.00 (m, 2H), 2.90
(s, 3H), 2.72 (dd, J=11.6, 4.9 Hz, 1H), 0.81-1.02 (m, 4H), 0.66 (t,
J=7.1 Hz, 3H). MS (ESI+) m/z 555.1 (M+H).sup.+.
Example 158
N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-1-
1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxam-
ide
[1168] Example 158 was prepared according to the procedure used for
the preparation of Example 154, substituting cyclohexanamine for
3-aminopropanenitrile, to provide the title compound (13.1 mg, 75%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.74
(d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.48-7.58 (m, 1H), 7.32 (s, 1H),
7.16 (dd, J=8.2, 2.0 Hz, 1H), 6.97-7.09 (m, 2H), 6.82 (dd, J=25.9,
8.2 Hz, 2H), 5.78 (s, 1H), 4.36-4.51 (m, 2H), 3.67 (s, 3H),
3.24-3.36 (m, 1H), 2.87 (s, 3H), 1.85 (s, 1H), 1.34-1.55 (m, 4H),
0.86-1.19 (m, 5H), 0.70-0.85 (m, 1H). MS (ESI+) m/z 581.0
(M+H).sup.+.
Example 159
N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-ox-
o-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide
[1169] Example 159 was prepared according to the procedure used for
the preparation of Example 154, substituting phenylmethanamine for
3-aminopropanenitrile, to provide the title compound (13.2 mg, 75%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.66-7.80 (m, 3H), 7.36 (s, 1H), 7.13-7.17 (m, 1H), 7.11 (m, 3H),
7.09-6.99 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.67-6.73 (m, 2H), 5.94
(s, 1H), 4.44-4.57 (m, 2H), 4.27 (d, J=15.3 Hz, 1H), 3.90 (d,
J=15.2 Hz, 1H), 3.65 (s, 3H), 2.94 (s, 3H). MS (ESI+) m/z 589.0
(M+H).sup.+.
Example 160
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-ph-
enylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-ca-
rboxamide
[1170] Example 160 was prepared according to the procedure used for
the preparation of Example 154, substituting 3-phenylpropan-1-amine
for 3-aminopropanenitrile, to provide the title compound (10.77 mg,
58% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.61-7.73 (m, 3H), 7.32 (s, 1H), 7.17-7.26 (m, 3H), 7.09-7.17 (m,
2H), 6.97-7.07 (m, 4H), 6.85 (d, J=8.2 Hz, 1H), 5.81 (s, 1H), 4.32
(d, J=13.7 Hz, 1H), 4.18-4.26 (m, 1H), 3.67 (s, 3H), 2.85-3.03 (m,
1H), 2.79 (s, 3H), 2.65-2.76 (m, 1H), 2.20 (t, J=7.6 Hz, 2H),
1.20-1.34 (m, 2H). MS (ESI+) m/z 617.0 (M+H).sup.+.
Example 161
4-(2,4-difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11--
oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamid-
e
[1171] Example 161 was prepared according to the procedure used for
the preparation of Example 154, substituting 2-methylpropan-1-amine
for 3-aminopropanenitrile, to provide the title compound (12.7 mg,
76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.72-7.76 (m, 1H), 7.71 (s, 1H), 7.66 (dd, J=15.1, 9.1 Hz, 1H),
7.33 (s, 1H), 7.14 (dd, J=8.2, 2.3 Hz, 2H), 6.98-7.09 (m, 2H), 6.84
(d, J=8.2 Hz, 1H), 5.82 (s, 1H), 4.34-4.42 (m, 2H), 3.67 (s, 3H),
2.89 (s, 3H), 2.83 (dd, J=12.8, 7.7 Hz, 1H), 1.84 (s, 2H), 1.27
(dt, J=13.4, 6.8 Hz, 1H), 0.47 (dd, J=6.6, 1.8 Hz, 6H). MS (ESI+)
m/z 555.1 (M+H).sup.+.
Example 162
4-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)met-
hyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-ca-
rboxamide
[1172] Example 162 was prepared according to the procedure used for
the preparation of Example 154, substituting 2-aminoethanol for
3-aminopropanenitrile, to provide the title compound (11.7 mg, 72%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta. 7.74
(d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.54-7.65 (m, 1H), 7.34 (s, 1H),
7.16 (dd, J=8.2, 2.0 Hz, 1H), 6.98-7.08 (m, 2H), 6.85 (d, J=8.2 Hz,
1H), 5.84 (s, 1H), 4.37-4.52 (m, 2H), 3.67 (s, 3H), 2.86-3.08 (m,
7H). MS (ESI+) m/z 543.0 (M+H).sup.+.
Example 163
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-yl-
methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-
-carboxamide
[1173] Example 163 was prepared according to the procedure used for
the preparation of Example 154, substituting oxazol-4-ylmethanamine
for 3-aminopropanenitrile, to provide the title compound (7.2 mg,
41% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
8.14 (d, J=0.9 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (s, 1H),
7.57-7.67 (m, 1H), 7.36 (s, 1H), 7.14 (dd, J=8.2, 2.0 Hz, 1H),
6.96-7.10 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 5.90 (s, 1H), 4.38-4.52
(m, 2H), 3.84-4.07 (m, 2H), 3.67 (s, 3H), 2.92 (s, 3H). MS (ESI+)
m/z 580.0 (M+H).sup.+.
Example 164
N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)-
methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-
-carboxamide
[1174] Example 164 was prepared according to the procedure used for
the preparation of Example 154, substituting cyclopropylmethanamine
for 3-aminopropanenitrile, to provide the title compound (13.8 mg,
83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.74 (d, J=2.1 Hz, 1H), 7.71 (s, 1H), 7.54-7.64 (m, 1H), 7.33 (s,
1H), 7.15 (dd, J=8.2, 2.0 Hz, 1H), 6.97-7.08 (m, 2H), 6.87 (d,
J=8.2 Hz, 1H), 5.82 (s, 1H), 4.37-4.50 (m, 2H), 3.67 (s, 3H), 2.89
(s, 3H), 2.78-2.87 (m, 1H), 2.60-2.73 (m, 1H), 0.42-0.52 (m, 1H),
0.05-0.18 (m, 2H), -0.21--0.14 (m, 2H). MS (ESI+) m/z 553.0
(M+H).sup.+.
Example 165
4-(2,4-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsu-
lfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]az-
ulene-3-carboxamide
[1175] Example 165 was prepared according to the procedure used for
the preparation of Example 154, substituting
1-amino-2-methylpropan-2-ol for 3-aminopropanenitrile, to provide
the title compound (12.2 mg, 71% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6-D.sub.2O) .delta. 7.73-7.77 (m, 1H), 7.72 (s, 1H),
7.67 (dd, J=12.7, 6.5 Hz, 1H), 7.38 (s, 1H), 7.13 (dd, J=8.2, 2.0
Hz, 1H), 6.98-7.10 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.90 (s, 1H),
4.35-4.48 (m, 2H), 3.67 (s, 3H), 2.96 (dd, J=13.2, 5.1 Hz, 1H),
2.88 (s, 3H), 2.74 (d, J=13.1 Hz, 1H), 0.79 (s, 3H), 0.60 (s, 3H).
MS (ESI+) m/z 571.0 (M+H).sup.+.
Example 166
4-(2,4-difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((meth-
ylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,-
f]azulene-3-carboxamide
[1176] Example 166 was prepared according to the procedure used for
the preparation of Example 154, substituting
(1-aminocyclopropyl)methanol for 3-aminopropanenitrile, to provide
the title compound (11.5 mg, 68% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6-D.sub.2O) .delta. 7.75 (d, J=2.0 Hz, 1H), 7.70 (s,
1H), 7.43-7.53 (m, 1H), 7.30 (s, 1H), 7.18 (dd, J=8.2, 2.0 Hz, 1H),
6.94-7.08 (m, 2H), 6.87 (d, J=8.1 Hz, 1H), 5.77 (s, 1H), 4.36-4.53
(m, 2H), 3.66 (s, 3H), 3.26 (d, J=11.1 Hz, 1H), 3.08 (d, J=11.1 Hz,
1H), 2.90 (s, 3H), 0.40-0.53 (m, 2H), -0.03-0.13 (m, 2H). MS (ESI+)
m/z 569.0 (M+H).sup.+.
Example 167
4-(2,4-difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfony-
l)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-
-3-carboxamide
[1177] Example 167 was prepared according to the procedure used for
the preparation of Example 154, substituting
1-methylcyclopropanamine for 3-aminopropanenitrile, to provide the
title compound (10.8 mg, 65% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6-D.sub.2O) .delta. 7.75 (d, J=2.1 Hz, 1H), 7.70 (s,
1H), 7.50 (d, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.18 (dd, J=8.2, 2.0 Hz,
1H), 6.94-7.08 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 5.73 (s, 1H),
4.36-4.52 (m, 2H), 3.66 (s, 3H), 2.88 (s, 3H), 0.93 (s, 3H),
0.23-0.34 (m, 2H), 0.13-0.18 (m, 2H). MS (ESI+) m/z 553.0
(M+H).sup.+.
Example 168
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-ph-
enylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-car-
boxamide
[1178] Example 168 was prepared according to the procedure used for
the preparation of Example 154, substituting 4-phenylbutan-1-amine
for 3-aminopropanenitrile, to provide the title compound (14.7 mg,
77% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) .delta.
7.70-7.72 (m, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 1H), 7.32 (s, 1H),
7.20-7.27 (m, 2H), 6.98-7.19 (m, 6H), 6.84 (d, J=8.2 Hz, 1H), 5.80
(s, 1H), 4.32-4.44 (m, 2H), 3.67 (s, 3H), 2.97 (dt, J=13.2, 6.6 Hz,
1H), 2.87 (s, 3H), 2.68-2.81 (m, 1H), 2.37 (t, J=7.5 Hz, 2H),
1.11-1.25 (m, 2H), 0.96-1.11 (m, 2H). MS (ESI+) m/z 630.9
(M+H).sup.+.
Example 169
4-(3,3-dimethylbutanoyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-tria-
zadibenzo[cd,f]azulen-11(10H)-one
[1179] The product from Example 42c (0.0 5 g, 0.174 mmol),
tert-butylacetyl chloride (0.028 g, 0.209 mmol),
N,N-dimethylpyridin-4-amine (2.126 mg, 0.017 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.152 mL, 0.870 mmol) were
combined in dimethylacetamide (0.870 mL) and stirred at 50.degree.
C. for 18 hours. 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 over anhydrous sodium sulfate, filtered and concentrated.
Purification by reverse phase HPLC (C18, CH.sub.3CN/0.1% TFA in
water, 10-100% gradient) afforded the title compound (0.012 g,
18%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.60 (s, 1H),
7.83 (s, 1H), 7.53 (d, J=10.38 Hz, 1H), 7.18-7.26 (m, 2H), 5.59 (d,
J=14.65 Hz, 1H), 3.87 (d, J=14.95 Hz, 1H), 3.60 (s, 3H), 1.79-1.92
(m, 2H), 0.70 (s, 9H). MS (ESI+) m/z 386 (M+H).sup.+.
Example 170
tert-butyl
((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
Example 170a
tert-butyl
(trans-4-((2-bromo-4-(methylsulfonyl)phenyl)amino)cyclohexyl)ca-
rbamate
[1180] A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene
(0.403 g, 1.592 mmol) and tert-butyl
(trans-4-aminocyclohexyl)carbamate (0.352 g, 1.592 mmol) in
dimethylsulfoxide (12 mL) and N,N-diisopropylethylamine (0.32 mL,
1.831 mmol) was heated at 100.degree. C. for 4 hours. The reaction
mixture was cooled to ambient temperature and partitioned between
aqueous ammonium chloride solution and diethyl ether. The organic
layer was 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 25% ethyl acetate in hexanes to afford the title compound
(0.390 g, 0.872 mmol, 55% yield).
Example 170b
tert-butyl
((trans)-4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate
[1181] A mixture of Example 170a (0.380 g, 0.849 mmol), Example 1f
(0.382 g, 0.892 mmol), cesium fluoride (0.387 g, 2.550 mmol) and
tetrakis(triphenylphosphine)palladium (0.098 g, 0.085 mmol) in
dimethoxyethane (20 mL) and methanol (10 mL) was stirred under an
argon atmosphere at 80.degree. C. for 2 hours. The reaction mixture
was cooled to ambient temperature and excess 5N sodium hydroxide
solution (8 mL) was added. The reaction mixture was stirred at
ambient temperature for 2 hours and then partitioned between
aqueous ammonium chloride solution and ethyl acetate. 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 by flash column
chromatography on silica gel, eluting with 2% methanol in
dichloromethane to afford the title compound (0.279 g, 0.543 mmol,
64% yield).
Example 170c
tert-butyl
((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1182] To a stirring mixture of Example 170b (0.048 g, 0.093 mmol)
and paraformaldehyde (0.048 g, 1.599 mmol) in tetrahydrofuran (1.0
mL) at ambient temperature was added 1M solution of titanium
tetrachloride in toluene (0.187 mL, 0.187 mmol). The reaction
mixture suspension was stirred at ambient temperature for 1 hour
and then partitioned between ethyl acetate and saturated sodium
bicarbonate. 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 reverse
phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) to
give the title compound (0.0043 g, 9% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.83 (s, 1H), 8.13 (s, 1H), 7.73-7.62 (m,
2H), 7.36 (d, J=8.5 Hz, 1H), 7.20-7.14 (m, 1H), 6.62 (d, J=7.7 Hz,
1H), 4.18 (s, 2H), 3.64 (s, 3H), 3.26 (s, 3H), 3.22-3.14 (m, 1H),
3.02-2.93 (m, 1H), 1.83-1.55 (m, 4H), 1.52-1.25 (m, 11H), 1.16-0.95
(m, 2H). MS (ESI+) m/z 527.1 (M+H).sup.+.
Example 171
4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1183] Example 170c (0.0114 g, 0.022 mmol) in dichloromethane (1
mL) was treated with trifluoroacetic acid (0.20 mL) and stirred at
ambient temperature for 1 hour. The reaction mixture was
concentrated and dried under vacuum to afford the title compound as
the trifluoracetic acid salt (0.0113 g, 97% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.84 (d, J=2.2 Hz, 1H), 8.14 (d,
J=2.2 Hz, 1H), 7.68 (dd, J=8.5, 2.3 Hz, 4H), 7.37 (d, J=8.5 Hz,
1H), 7.15 (d, J=2.5 Hz, 1H), 4.12 (bs, 2H), 3.64 (s, 3H), 3.26 (s,
3H), 3.09-2.90 (m, 2H), 1.87 (d, J=10.6 Hz, 2H), 1.72 (d, J=12.6
Hz, 2H), 1.47 (dd, J=23.8, 11.1 Hz, 2H), 1.29-1.18 (m, 2H). MS
(ESI+) m/z 427.1 (M+H).sup.+.
Example 172
4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1184] Example 172 was prepared according to the procedure used for
the preparation of Example 74, substituting cyclopropanesulfonyl
chloride for 4-methylbenzene-1-sulfonyl chloride to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. 7.84 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.44 (d, J=8.1 Hz,
1H), 7.40-7.35 (m, 1H), 7.32 (s, 1H), 5.12 (d, J=16.7 Hz, 1H), 4.54
(dt, J=30.5, 15.1 Hz, 3H), 3.64 (s, 3H), 2.99 (s, 3H), 1.76-1.64
(m, 1H), 0.49 (d, J=5.1 Hz, 3H), 0.35-0.24 (m, 1H). MS (APCI+) m/z
448.0 (M+H).sup.+.
Example 173
ethyl
5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[-
cd,f]azulene-4(3H)-carboxylate
Example 173a
tert-butyl
5,7-difluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulene-1-carboxylate
[1185] The product from Example 42c (0.86 g, 2.99 mmol),
di-tert-butyl dicarbonate (0.98 g, 4.49 mmol),
N,N-dimethylpyridin-4-amine (0.018 g, 0.150 mmol) and
N-ethyl-N-isopropylpropan-2-amine (1.569 mL, 8.98 mmol) were
combined in dimethylacetamide (11.98 mL) and stirred at 50.degree.
C. for 1 hour. 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 over anhydrous sodium sulfate, filtered, and concentrated to
afford the title compound (1.0 g, 86%).
Example 173b
1-tert-butyl 4-ethyl
5,7-difluoro-10-methyl-1-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]a-
zulene-1,4(3H)-dicarboxylate
[1186] The product from Example 173a (0.7 g, 1.807 mmol), ethyl
carbonochloridate (0.7 g, 6.45 mmol),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (1.0 g, 2.63 mmol) and
N-ethyl-N-isopropylpropan-2-amine (1.6 mL, 9.16 mmol) were combined
in dimethylacetamide (9 mL) and stirred at 50.degree. C. for 2
hours. 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 over anhydrous
sodium sulfate, filtered, and concentrated. Purification by
chromatography (silica gel, 0-60% ethyl acetate in heptanes)
afforded the title compound (0.57 g, 69%).
Example 173c
ethyl
5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[-
cd,f]azulene-4(3H)-carboxylate
[1187] The product from Example 173b (0.57 g, 1.241 mmol) in
dichloromethane (5 mL)/TFA (5 mL) was stirred at ambient
temperature for 1 hour, concentrated, and azeotroped 3.times. with
dichloromethane. Purification by trituration in a minimal volume of
9:1 dichloromethane/methanol afforded the title compound (0.427 g.
96%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.00 (s, 1H),
7.90 (s, 1H), 7.53 (dd, J=10.68, 1.53 Hz, 1H), 7.25-7.33 (m, 2H),
5.25 (d, J=15.56 Hz, 1H), 4.13 (d, J=15.56 Hz, 1H), 3.99-4.06 (m,
1H), 3.74-3.84 (m, 1H), 3.61 (s, 3H), 0.99 (t, J=7.17 Hz, 3H). MS
(ESI+) m/z 360 (M+H).sup.+.
Example 174
4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfo-
nyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one
[1188] Example 147a (35.5 mg, 0.0600 mmol), 2.0 M methanamine in
tetrahydrofuran (0.150 mL, 0.300 mmol) and potassium carbonate
(24.9 mg, 0.180 mmol) were combined in tetrahydrofuran (1 mL). The
reaction mixture was heated at 60.degree. C. for 2 hours, cooled,
and concentrated. The residue was purified by reverse phase HPLC
(C18, CH.sub.3CN/water (10 mM ammonium acetate), 20-100% gradient)
to provide the title compound (19 mg, 60%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.84 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.23
(dd, J=8.2, 1.8 Hz, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H), 6.97 (d,
J=8.2 Hz, 1H), 6.93-6.82 (m, 2H), 5.05-4.97 (m, 1H), 4.56-4.42 (m,
2H), 3.64 (s, 3H), 2.92 (s, 3H), 2.45 (t, J=6.1 Hz, 2H), 2.22 (s,
3H), 1.72-1.58 (m, 2H), 1.54-1.42 (m, 1H), 1.36-1.24 (m, 1H). MS
(ESI+) m/z 527 (M+H).sup.+.
Example 175
4-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsul-
fonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one
[1189] Example 175 was prepared according to the procedure used for
the preparation of Example 174, substituting 2.0 M dimethylamine in
tetrahydrofuran for 2.0 M methanamine in tetrahydrofuran, to
provide the title compound (20 mg, 62%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.84 (s, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.67
(s, 1H), 7.22 (dd, J=8.2, 1.7 Hz, 1H), 7.14 (s, 1H), 7.10-7.05 (m,
1H), 6.96 (d, J=8.1 Hz, 1H), 6.93-6.83 (m, 2H), 5.01 (t, J=7.4 Hz,
1H), 4.53-4.42 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H), 2.21-2.03 (m,
2H), 2.01 (s, 6H), 1.72-1.60 (m, 1H), 1.59-1.53 (m, 1H), 1.51-1.41
(m, 1H), 1.32-1.22 (m, 1H). MS (ESI+) m/z 541 (M+H).sup.+.
Example 176
4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methyl-
sulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-o-
ne
[1190] To the solution of Example 60 (110 mg, 0.190 mmol) in
anhydrous tetrahydrofuran (5 mL) was added BH.sub.3.THF (1.896 mL,
1.896 mmol) and the reaction mixture was stirred at 65.degree. C.
for 18 hours. The reaction mixture was quenched with ethanol (1
mL), followed by the addition of HCl (3 M, 2 mL). The mixture was
stirred at 70.degree. C. for an additional 4 hours. The solvent was
evaporated and the residue was treated with 5 N NaOH (2 mL) and the
mixture was extracted with dichlorormethane (20 mL.times.3). The
combined organic layers were concentrated and the residue was
purified by HPLC (C18, 30%-40% acetonitrile in 0.1% aqueous
ammonium hydroxide) to provide the title compound (15 mg, 0.026
mmol, 14% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.87
(s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.34
(d, J=8.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.43 (d, J=8.9 Hz, 2H),
5.22-5.18 (m, 1H), 4.66-4.34 (m, 3H), 3.79-3.73 (m, 1H), 3.66-3.60
(m, 1H), 3.54 (s, 3H), 3.00 (s, 3H), 2.47-2.27 (m, 8H), 2.17 (s,
3H). MS (ESI+) m/z 566.2 (M+H).sup.+.
Example 177
2-(4-(4-fluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulen-7-yl)acetonitrile
Example 177a
2-(4-amino-3-bromophenyl)acetonitrile
[1191] To a solution of 2-(4-aminophenyl)acetonitrile (3.0 g, 22.70
mmol) in 40 mL dimethylformamide cooled with ice bath was added
N-bromosuccinimide (4.04 g, 22.70 mmol) in portions. The mixture
was stirred at 0.degree. C. for 30 minutes and then at ambient
temperature for 1 hour. Water was added. The precipitate was
collected by filtration, washed with water, and dried in a vacuum
oven at 40.degree. C. to give the title compound (3.56 g, 16.9
mmol, 74.4% yield).
Example 177b
2-(4-amino-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin--
4-yl)phenyl)acetonitrile
[1192] A mixture of Example 177a (0.739 g, 3.50 mmol), Example 1f
(1.5 g, 3.50 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.080
g, 0.088 mmol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(0.051 g, 0.175 mmol) and potassium phosphate (2.230 g, 10.51 mmol)
in 30 mL dioxane and 10 mL water was heated at 80.degree. C. under
nitrogen for 2 hours. Water was added, and the mixture was
extracted with ethyl acetate (3.times.), washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
and filtered. The filtrate was concentrated and purified by column
chromatography (silica gel, 0-40% ethyl acetate/heptanes gradient)
to give the title compound (0.933 g, 2.157 mmol, 61.6% yield).
Example 177c
{4-[(4-fluorophenyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl}acetonitrile
[1193] A mixture of Example 177b (120 mg, 0.277 mmol),
1-bromo-4-fluorobenzene (48.6 mg, 0.277 mmol), cesium carbonate
(226 mg, 0.694 mmol), and
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-phos)
(13.23 mg, 0.028 mmol) in 4 mL toluene and 1 mL tert-butanol was
heated in a Biotage initiator microwave oven at 150.degree. C. for
40 minutes. The reaction mixture was then concentrated. The residue
was treated with 1 mL 4N aqueous NaOH solution and 3 mL dioxane.
The resulting mixture was heated at 80.degree. C. in the microwave
oven for 20 minutes. Water was added, and the mixture was extracted
with ethyl acetate (3.times.), washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated and the residue was purified by column
chromatography (silica gel, 0-10% methanol/dichloromethane
gradient) to afford the title compound (43 mg, 0.115 mmol, 41.6%
yield).
Example 177d
2-(4-(4-fluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triaz-
adibenzo[cd,f]azulen-7-yl)acetonitrile
[1194] To a mixture of Example 177c (36 mg, 0.097 mmol) and
paraformaldehyde (43.5 mg, 1.450 mmol) in 2 mL tetrahydrofuran was
added titanium(IV) chloride (193 .mu.L, 0.193 mmol, 1.0 M toluene
solution). The dark red mixture was stirred at ambient temperature
for 3 hours. The mixture was cooled with an ice bath and quenched
with water, extracted with ethyl acetate (2.times.), washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated and the
residue was purified by column chromatography (silica gel, 0-10%
methanol/dichloromethane gradient) to give the title compound (12
mg, 0.031 mmol, 32% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.62-11.28 (m, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.58 (s, 1H),
7.36 (dd, J=8.0, 1.9 Hz, 1H), 7.32-7.26 (m, 2H), 6.79-6.71 (m, 2H),
6.47-6.34 (m, 2H), 4.85-4.62 (m, 2H), 4.05 (s, 2H), 3.56 (s, 3H).
MS (ESI+) m/z 385.2 (M+H).sup.+.
Example 178
4-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1195] Example 178 was prepared according to the procedure used for
the preparation of Example 149, substituting
2,2-dimethyl-3-(pyrrolidin-1-yl)propanal for isobutyraldehyde to
provide the title compound as the trifluoroacetic acid salt.
.sup.1H NMR (400 MHz, pyridine-d.sub.6) .delta. 13.69-12.65 (m,
1H), 8.08 (dd, J=10.0, 2.0 Hz, 1H), 7.57 (d, J=3.6 Hz, 2H),
7.42-7.31 (m, 2H), 4.78 (s, 2H), 4.34 (s, 2H), 3.64 (s, 3H), 3.13
(s, 3H), 3.09 (s, 2H), 3.02 (s, 2H), 2.20-2.85 (m, 4H) 1.83-1.68
(m, 4H), 0.99 (s, 6H). MS (ESI+) m/z 483.1 (M+H).sup.+.
Example 179
2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10--
triazadibenzo[cd,f]azulen-4(3H)-yl)pyrrolidin-1-yl)acetic Acid
[1196] Example 179 was prepared according to the procedure used for
the preparation of Example 149, substituting
2-(3-oxopyrrolidin-1-yl)acetic acid for isobutyraldehyde to provide
the title compound as the trifluoroacetic acid salt. .sup.1H NMR
(400 MHz, pyridine-d.sub.6) .delta. 13.47-13.38 (m, 1H), 8.10-8.01
(m, 1H), 7.57-7.48 (m, 2H), 7.47-7.29 (m, 2H), 4.73 (s, 2H),
4.39-3.77 (m, 4H), 3.64 (s, 3H), 3.58-3.16 (m, 4H), 3.12 (d, J=6.6
Hz, 3H), 2.50 (s, 1H), 2.22-2.03 (m, 2H), 1.37-1.22 (m, 1H). MS
(APCI+) m/z 471.1 (M+H).sup.+.
Example 180
10-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1197] Example 180 was prepared according to the procedure used for
the preparation of Example 149, substituting
2-methyldihydrofuran-3(2H)-one for isobutyraldehyde to provide the
title compound. .sup.1H NMR (400 MHz, pyridine-d.sub.6) .delta.
13.49-13.40 (m, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.4, 1.9
Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.45-7.27 (m, 2H), 4.82-4.68 (m,
2H), 4.68-3.92 (m, 5H), 3.86-3.40 (m, 4H), 3.12 (s, 3H), 2.25-1.85
(m, 2H), 1.36-1.14 (m, 3H). MS (APCI+) m/z 428.1 (M+H).sup.+.
Example 181
10-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1198] Example 181 was prepared according to the procedure used for
the preparation of Example 149, substituting
1-methylpiperidin-4-one for isobutyraldehyde to provide the title
compound as the trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
pyridine-d.sub.6) .delta. 14.00-13.44 (m, 1H), 8.17-7.99 (m, 1H),
7.58-7.42 (m, 2H), 7.42-7.28 (m, 2H), 4.89-4.71 (m, 2H), 4.67-4.11
(m, 3H), 3.65 (s, 3H), 3.53-3.30 (m, 2H), 3.18-3.10 (m, 3H),
2.90-2.6 (m, 2H), 2.69 (s, 3H), 2.27-1.52 (m, 4H). MS (APCI+) m/z
441.1 (M+H).sup.+.
Example 182
10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1199] Example 182 was prepared according to the procedure used for
the preparation of Example 149, substituting
dihydro-2H-pyran-3(4H)-one for isobutyraldehyde to provide the
title compound. .sup.1H NMR (400 MHz, pyridine-d.sub.6) .delta.
13.52-13.29 (m, 1H), 8.09-8.01 (m, 1H), 7.55 (d, J=7.6 Hz, 2H),
7.52-7.28 (m, 2H), 4.84-4.69 (m, 2H), 4.60-3.66 (m, 4H), 3.65-3.56
(m, 3H), 3.53-3.16 (m, 2H), 3.16-3.03 (m, 2H), 2.72-2.56 (m, 1H),
2.21-1.19 (m, 5H). MS (APCI+) m/z 428.1 (M+H).sup.+.
Example 183
4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1200] Example 183 was prepared according to the procedure used for
the preparation of Example 149, substituting
1-isopropylpiperidine-4-carbaldehyde for isobutyraldehyde to
provide the title compound as the trifluoroacetic acid salt.
.sup.1H NMR (400 MHz, pyridine-d.sub.6) .delta. 13.69-12.65 (m,
1H), 8.08 (dd, J=10.0, 2.0 Hz, 1H), 7.57 (d, J=3.6 Hz, 2H),
7.42-7.31 (m, 2H), 4.81-4.71 (m, 2H), 4.30-4.19 (m, 2H), 3.64 (d,
J=6.9 Hz, 3H), 3.54-3.19 (m, 4H), 3.21 (s, 3H), 3.06-2.88 (m, 2H),
2.78-2.53 (m, 2H), 1.97 (dddd, J=9.6, 8.6, 5.4, 2.1 Hz, 2H),
1.84-1.75 (m, 2H), 1.18-1.02 (m, 6H). MS (APCI+) m/z 483.1
(M+H).sup.+.
Example 184
10-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1201] Example 184 was prepared according to the procedure used for
the preparation of Example 149, substituting
3-acetyldihydrofuran-2(3H)-one for isobutyraldehyde to provide the
title compound. .sup.1H NMR (400 MHz, pyridine-d.sub.6) .delta.
13.48-13.34 (m, 1H), 8.10-8.01 (m, J=2.1 Hz, 1H), 7.61-7.53 (m,
2H), 7.50-7.31 (m, 2H), 4.80-4.67 (m, 2H), 4.40-3.98 (m, 4H), 3.62
(s, 3H), 3.10 (s, 3H), 2.80-2.60 (m, 1H), 2.46 (s, 3H), 2.18-1.77
(m, 3H). MS (APCI+) m/z 456.1 (M+H).sup.+.
Example 185
4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1202] Example 185 was prepared according to the procedure used for
the preparation of Example 149, substituting 1-methoxypropan-2-one
for isobutyraldehyde to provide the title compound. .sup.1H NMR
(400 MHz, pyridine-d.sub.6) .delta. 13.89-12.95 (m, 1H), 8.05 (d,
J=1.3 Hz, 1H), 7.56-7.44 (m, 3H), 7.44-7.34 (m, 1H), 4.71 (d,
J=12.4 Hz, 2H), 4.63-4.06 (m, 2H), 3.73-3.64 (m, 1H), 3.64-3.56 (m,
3H), 3.56-3.42 (m, 1H), 3.40-3.27 (m, 1H), 3.17 (s, 3H), 3.09 (d,
J=5.1 Hz, 3H), 1.27-1.12 (m, 3H). MS (APCI+) m/z 416.0
(M+H).sup.+.
Example 186
4-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1203] Example 186 was prepared according to the procedure used for
the preparation of Example 149, substituting 4-methoxybutan-2-one
for isobutyraldehyde to provide the title compound. .sup.1H NMR
(400 MHz, pyridine-d.sub.6) .delta. 13.63-13.11 (m, 1H), 8.04 (d,
J=2.0 Hz, 1H), 7.57-7.36 (m, 4H), 4.88-4.51 (m, 2H), 4.51-3.96 (m,
2H), 3.86-3.72 (m, 1H), 3.62 (s, 3H), 3.47-3.34 (m, 1H), 3.33-3.20
(m, 1H), 3.17-2.99 (m, 6H), 2.06-1.87 (m, 1H), 1.80-1.62 (m, 1H),
1.31-1.05 (m, 3H). MS (APCI+) m/z 430.0 (M+H).sup.+.
Example 187
10-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1204] Example 187 was prepared according to the procedure used for
the preparation of Example 149, substituting
1-methylpyrrolidin-3-one for isobutyraldehyde to provide the title
compound as the trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
pyridine-d.sub.6) .delta. 13.57-13.33 (m, 1H), 8.05 (d, J=1.9 Hz,
1H), 7.57-7.52 (m, 2H), 7.51-7.29 (m, 2H), 4.81-4.69 (m, 2H),
4.69-4.06 (m, 3H), 3.67 (s, 3H), 3.62-3.16 (m, 4H), 3.13 (s, 3H),
2.92-2.74 (m, 3H), 2.35-1.91 (m, 2H). MS (APCI+) m/z 427.1
(M+H).sup.+.
Example 188
10-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1205] Example 188 was prepared according to the procedure used for
the preparation of Example 149, substituting
1-(tetrahydro-2H-pyran-4-yl)ethanone for isobutyraldehyde to
provide the title compound. .sup.1H NMR (400 MHz, pyridine-d.sub.6)
.delta. 13.48-13.34 (m, 1H), 8.11-8.02 (m, 1H), 7.67-7.59 (m, 1H),
7.51-7.40 (m, 2H), 7.39-7.29 (m, 1H), 4.90-4.63 (m, 2H), 4.54-3.64
(m, 4H), 3.61 (s, 3H), 3.51-3.15 (m, 3H), 3.11 (s, 3H), 1.83-1.44
(m, 4H), 1.38-1.01 (m, 4H). MS (APCI+) m/z 456.1 (M+H).sup.+.
Example 189
10-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1206] Example 189 was prepared according to the procedure used for
the preparation of Example 149, substituting 1-methylazepan-4-one
for isobutyraldehyde to provide the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (400 MHz, pyridine-d.sub.6)
.delta. 13.83-13.26 (m, 1H), 8.07 (dd, J=18.6, 1.9 Hz, 1H), 7.55
(d, J=2.5 Hz, 1H), 7.50-7.27 (m, 3H), 4.82-4.73 (m, 1H), 4.66 (s,
2H), 4.54-4.45 (m, 2H), 3.62 (s, 3H), 3.59-3.20 (m, 4H), 3.06 (s,
3H), 2.80 (s, 3H), 2.39-1.46 (m, 6H). MS (APCI+) m/z 455.2
(M+H).sup.+.
Example 190
4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1207] Example 190 was prepared according to the procedure used for
the preparation of Example 149, substituting 1-ethylpiperidin-3-one
for isobutyraldehyde to provide the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (400 MHz, pyridine-d.sub.6)
.delta. 13.83-12.95 (m, 1H), 8.08-8.00 (m, 1H), 7.75-7.69 (m, 1H),
7.56 (s, 1H), 7.49-7.35 (m, 2H), 4.84-4.58 (m, 2H), 4.65-3.76 (m,
3H), 3.69 (s, 3H), 3.47-3.19 (s, 2H), 3.20-3.14 (m, 3H), 3.11-2.55
(m, 4H), 2.40-1.58 (m, 4H), 1.16-1.02 (m, 3H). MS (APCI+) m/z 455.0
(M+H).sup.+.
Example 191
10-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1208] Example 191 was prepared according to the procedure used for
the preparation of Example 149, substituting
2-(tetrahydro-2H-pyran-4-yl)acetaldehyde for isobutyraldehyde to
provide the title compound. .sup.1H NMR (400 MHz, pyridine-d.sub.6)
.delta. 13.45-13.38 (m, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.66-7.60 (m,
1H), 7.56 (s, 1H), 7.50-7.37 (m, 2H), 4.74 (s, 2H), 4.33 (s, 2H),
3.91-3.78 (m, 2H), 3.63 (s, 3H), 3.29-3.13 (m, 4H), 3.11 (s, 3H),
1.56-1.28 (m, 5H), 1.26-1.07 (m, 2H). MS (APCI+) m/z 456.1
(M+H).sup.+.
Example 192
4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile
Example 192a
4-((4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile
[1209] A 20 mL microwave vial was charged with 4-aminobenzonitrile
(0.121 g, 1.023 mmol), Example 9a (0.2549 g, 1.023 mmol),
diacetoxypalladium (9.19 mg, 0.041 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.039 g, 0.082 mmol), cesium carbonate (0.467 g, 1.432 mmol),
toluene (8.5 mL) and t-butanol (1.7 mL) to give a yellow
suspension. The tube was sealed, and the reaction mixture was
heated in a Biotage Creator at 150.degree. C. for 15 minutes fixed
hold time. The reaction mixture was filtered through a 2 g Celite
SPE column and rinsed with ethyl acetate. The filtrate was washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (20-100% ethyl acetate/heptanes)
to provide the title compound (0.100 g, 34% yield).
Example 192b
4-((2-bromo-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile
[1210] In a 250 mL round-bottomed flask was placed Example 192a
(0.100 g, 0.349 mmol) in acetic acid (3.49 mL) to give a white
suspension. N-bromosuccinimide (0.062 g, 0.349 mmol) was added in 2
portions 10 minutes apart. After the 1st portion of
N-bromosucinimide was added, 3 mL dimethylformamide were added. The
reaction mixture was stirred at ambient temperature for 4 hours.
The reaction mixture was quenched with 30 mL 10% sodium thiosulfate
and diluted with water. The reaction mixture was extracted 2.times.
with ethyl acetate. The combined organic layers were washed
2.times. with 2N NaOH (until the pH of the aqueous was >7) and
1.times. with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (50-100% ethyl
acetate/heptanes) to provide the title compound as a white solid
(0.1007 g, 79% yield).
Example 192c
4-((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-((methylsulfonyl)methyl)phenyl)amino)benzonitrile
[1211] Example 192c was prepared according to the procedure used
for the preparation of Example 6b, substituting Example 192b for
Example 6a, to provide the title compound as a white solid (0.115
g, 78% yield).
Example 192d
4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methy-
lsulfonyl)methyl)phenyl)amino)benzonitrile
[1212] Example 192d was prepared according to the procedure used
for the preparation of Example 12d, substituting Example 192c for
Example 12c, to provide the title compound (0.0575 g, 68%
yield).
Example 192e
4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile
[1213] Example 192e was prepared according to the procedure used
for the preparation of Example 82, substituting Example 192d for
Example 12d, and paraformaldehyde for methyl 4-oxobutanoate to
provide the title compound (0.0277 g, 47% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.88-11.93 (m, 1H), 7.95 (d, J=1.9 Hz,
1H), 7.64 (s, 1H), 7.48 (dd, J=8.0, 1.9 Hz, 1H), 7.34-7.46 (m, 4H),
6.48-6.58 (m, 2H), 5.28 (d, J=16.3 Hz, 1H), 4.71-4.42 (m, 3H), 3.56
(s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 445.2 (M+H).sup.+.
Example 193
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethy-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 193a
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholine-4-ca-
rbonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1214] Example 193a was prepared according to the procedure used
for the preparation of Example 58m, substituting morpholine for
ammonium hydroxide (25% wt/wt in water), to provide the title
compound.
Example 193b
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethy-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1215] Example 193b was prepared according to the procedure used
for the preparation of Example 146c, substituting Example 193a for
Example 146b, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.90 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H),
7.49-7.41 (m, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H),
6.42 (d, J=9.0 Hz, 2H), 5.24-5.20 (m, 1H), 4.61-4.38 (m, 3H),
3.80-3.71 (m, 1H), 3.69-3.57 (m, 5H), 3.54 (s, 3H), 3.00 (s, 3H),
2.46-2.36 (m, 4H). MS (ESI+) m/z 553.2 (M+H).sup.+.
Example 194
N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
Example 194a
2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline
[1216] A 100 mL flask was charged with Example 58g (2 g, 7.57
mmol), 1-fluoro-4-iodobenzene (3.36 g, 15.14 mmol), palladium(II)
acetate (0.085 g, 0.379 mmol), xantphos (0.219 g, 0.379 mmol),
Cs.sub.2CO.sub.3 (2.52 g, 7.72 mmol) and anhydrous dioxane (40 mL)
under argon at room temperature. The mixture was heated at
110.degree. C. for 18 hours. After cooling, the reaction mixture
was filtered through a pad of Celite and washed with ethyl acetate.
The solvent was removed and the residue was purified by silica gel
chromatography, eluting with a gradient of 10/1 to 2/1 petroleum
ether/ethyl acetate to provide the title compound (1.1 g, 2.9 mmol,
39% yield) as yellow solid.
Example 194b
ethyl
1-benzyl-4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phen-
yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1217] A mixture of Example 58f (0.8 g, 1.192 mmol), Example 194a
(0.498 g, 1.251 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.035 g, 0.119 mmol), tris(dibenzylideneacetone)dipalladium(O)
(0.055 g, 0.060 mmol) and K.sub.3PO.sub.4 (0.632 g, 2.98 mmol) were
combined and sparged with argon for 30 minutes. A solution of
1,4-dioxane (10 mL) and water (2.500 mL) was sparged with nitrogen
for 30 minutes and transferred by syringe into the reaction vessel
under argon. The reaction mixture was stirred at 60.degree. C. for
4 hours. The mixture was treated with ethyl acetate (150 mL) and
water (50 mL) and the undissolved solid was filtered and washed
with ethyl acetate several times. The resulting solid was dried
under vacuum to afford the title compound (0.58 g, 0.711 mmol,
59.6% yield).
Example 194c
ethyl
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-met-
hyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1218] A mixture of Example 194b (0.58 g, 0.987 mmol), anisole
(0.216 mL, 1.974 mmol) and concentrated H.sub.2SO.sub.4 (0.5 mL,
9.38 mmol) in TFA (10 mL, 130 mmol) was heated at 90.degree. C. for
6 hours. Excess TFA was removed under reduced pressure, and the
residue was partitioned between water (10 mL) and ethyl acetate (50
mL). The organic layer was separated, and the aqueous layer was
extracted with additional ethyl acetate twice (20 mL). The combined
organic layers were washed with saturated aqueous sodium
bicarbonate (10 mL), followed by saturated aqueous sodium chloride,
(10 mL), dried over anhydrous magnesium sulfate, filtered, and
concentrated to give the title compound (0.24 g, 0.241 mmol, 24.4%
yield).
Example 194d
ethyl
4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,1-
0,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate
[1219] A mixture of Example 194c (0.31 g, 0.623 mmol), HCl (4 M in
dioxane) (4 mL, 16.00 mmol) and paraformaldehyde (0.374 g, 12.46
mmol) in methanol (2.5 mL) was heated at 130.degree. C. for 1.5
hours under microwave. The solvent was removed under reduced
pressure to provide the title compound.
Example 194e
N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4-
,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1220] A mixture of Example 194f (150 mg, 0.294 mmol) and
ethylamine (25% in ethanol wt/wt) (5 mL, 0.832 mmol) was sealed and
heated at 78.degree. C. for 2 day. The reaction mixture was cooled
to ambient temperature and concentrated. The residue was purified
by reverse phase preparative HPLC (C18, 30-60% acetonitrile in 0.01
N NH.sub.4CO.sub.3/water) to give the title compound (25 mg, 0.049
mmol, 16.7% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.15 (brs, 1H), 8.30 (t, J=5.1 Hz, 1H), 7.94 (t, J=8.2 Hz, 1H),
7.69-7.61 (m, 1H), 7.48-7.46 (m, 1H), 7.38 (d, J=7.9 Hz, 1H),
6.88-6.77 (m, 2H), 6.39-6.29 (m, 2H), 6.33-5.88 (m, 1H), 4.81-4.14
(m, 3H), 3.58 (s, 3H), 3.34-3.32 (m, 2H), 3.01 (s, 3H), 1.24-1.15
(m, 3H). MS (ESI+) m/z 509.2 (M+H).sup.+.
Example 195
5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 195a
2-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline
[1221] A 5 mL microwave vial was charged with Example 12b (0.2287
g, 0.608 mmol), cyclopropylboronic acid (0.209 g, 2.432 mmol),
cesium carbonate (0.990 g, 3.04 mmol) and dichloropalladium
(II)bistriphenylphosphine (0.021 g, 0.030 mmol). The tube was
sealed, and the mixture was sparged with nitrogen for 30 minutes.
Degassed dioxane (2.53 mL) and water (0.507 mL) were added. The
reaction mixture was heated to 100.degree. C. overnight. The
reaction mixture was 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 reaction mixture was purified by flash
chromatography (10-70% ethyl acetate/heptanes) to provide the title
compound (0.143 g, 70% yield).
Example 195b
2-bromo-6-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)ani-
line
[1222] A 250 mL round-bottomed flask was charged with Example 195a
and acetic acid (1.41 mL) to give a tan solution.
N-bromosuccinimide (0.079 g, 0.445 mmol) was added. The reaction
mixture was stirred at room temperature for 1.5 hours. The reaction
was quenched with sodium thiosulfate (10 mL 10%) and neutralized
with saturated aqueous sodium bicarbonate. The reaction mixture was
extracted with ethyl acetate (2.times.). The combined organic
layers were washed with saturated aqueous sodium chloried and
concentrated. The residue was purified by flash chromatography
(silica gel, 10-70% ethyl acetate/heptanes) to provide the title
compound (0.111 g, 63% yield).
Example 195c
4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)p-
henyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1223] A 250 mL round-bottomed flask was charged with Example 195b
(0.111 g, 0.268 mmol), Example if (0.104 g, 0.243 mmol), sodium
carbonate (0.090 g, 0.851 mmol),
tris(dibenzylideneacetone)dipalladium (O) (0.011 g, 0.012 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.012 g, 0.041 mmol). The solids were sparged with nitrogen for 30
minutes. Degassed dioxane (1.946 mL) and water (0.487 mL) were
added. The reaction mixture was heated at 60.degree. C. for 3
hours. The reaction mixture was cooled to room temperature 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 residue was
purified by flash chromatography (silica gel, 0-5%
methanol/dichloromethane) to provide the title compound. (0.155 g,
100% yield).
Example 195d
4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)p-
henyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1224] A 100 mL round-bottomed flask was charged with Example 195c
(0.1553 g, 0.244 mmol), lithium hydroxide hydrate (0.102 g, 2.435
mmol), dioxane (1.826 mL) and water (0.609 mL). The reaction
mixture was heated at 50.degree. C. overnight. The reaction mixture
was cooled to room temperature and partitioned between ethyl
acetate and water. The aqueous layer was extracted 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, 0-5% methanol/dichloromethane) to
provide the title compound. (0.0792 g, 67% yield).
Example 195e
5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1225] A 250 mL round-bottomed flask was charge with Example 195d
(0.0792 g, 0.164 mmol), paraformaldehyde (0.074 g, 0.819 mmol) and
tetrahydrofuran (1.638 mL). Titanium (IV) chloride (0.328 mL, 0.328
mmol) was added. The reaction mixture was stirred at room
temperature for 1 hour. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, and dried over anhydrous
magnesium sulfate and mercaptopropyl silica gel for 1 hour. The
slurry was filtered through a 10 g Celite SPE column and
concentrated. The residue was purified by flash chromatography
(silica gel, 0-5% methanol/dichloromethane) to provide the title
compound. (0.0609 g, 75% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.79-11.84 (m, 1H), 7.67 (d, J=2.0 Hz, 1H),
7.63 (s, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.96-7.05 (m, 1H), 6.95 (d,
J=1.8 Hz, 1H), 6.59-6.68 (m, 1H), 6.24-6.34 (m, 1H), 5.76 (s, 2H),
5.19 (d, J=16.3 Hz, 1H), 4.35-4.56 (m, 3H), 3.59 (s, 3H), 2.95 (s,
3H), 2.07-2.18 (m, 1H), 0.83-0.94 (m, 1H), 0.62-0.72 (m, 2H),
0.28-0.37 (m, 1H). MS (ESI+) m/z 496.1 (M+H).sup.+.
Example 196
tert-butyl
(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1-
H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1226] A mixture of Example 5f (0.262 g, 0.763 mmol) and tert-butyl
(4-oxocyclohexyl)carbamate (0.332 g, 1.526 mmol) in dichloromethane
(17 mL) was treated with acetic acid (0.437 mL, 7.630 mmol). The
reaction mixture was stirred 60.degree. C. for 1.5 hours, and then
cooled to 0.degree. C. and treated with sodium
triacetoxyborohydride (0.340 g, 1.526 mmol). The reaction mixture
was removed from 0.degree. C. ice bath and stirred at ambient
temperature for 18 hours. The reaction mixture was quenched by slow
addition of saturated sodium bicarbonate solution and then
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 column chromatography on silica gel,
eluting with 1% methanol in dichloromethane to afford the title
compound as a mixture of cis and trans isomers (0.304 g, 0.543
mmol, 74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.87-11.77 (m, 2H), 7.73-7.66 (m, 2H), 7.59-7.52 (m, 2H),
7.31-7.12 (m, 6H), 6.81-6.70 (m, 1H), 6.53-6.48 (m, 1H), 4.54-4.30
(m, 6H), 4.10-3.90 (m, 2H), 3.67-3.57 (m, 6H), 3.30-3.23 (m, 1H),
3.16-3.06 (m, 1H), 2.94 (s, 6H), 2.78-2.68 (m, 1H), 2.62-2.55 (m,
1H), 1.96-1.47 (m, 8H), 1.39-1.32 (m, 18H), 1.26-1.13 (m, 6H),
0.95-0.85 (m, 2H). MS (ESI+) m/z 541.2 (M+H).sup.+.
Example 197
tert-butyl
((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1227] Example 196 (0.025 mg, 0.046 mmol), a mixture of cis and
trans isomers, was purified by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 5-70% gradient). Fractions of the
first eluted isomer were collected, concentrated, and held under
vacuum to remove residual trifluoroacetic acid to give the title
compound (0.008 g, 0.015 mmol). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.81 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.24-7.21 (m,
1H), 7.18-7.12 (m, 2H), 6.51 (d, J=8.0 Hz, 1H), 4.45 (bs, 4H), 3.62
(s, 3H), 3.15-3.06 (m, 1H), 2.94 (s, 3H), 2.58 (t, J=10.9 Hz, 1H),
1.81-1.55 (m, 4H), 1.33 (s, 9H), 1.20-1.16 (m, 2H), 0.94-0.87 (m,
2H). MS (ESI+) m/z 541.0 (M+H).sup.+.
Example 198
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 198a
4-chloro-N-(4-((methylsulfonyl)methyl)phenyl)aniline
[1228] A 20 mL microwave vial was charged with 4-chloroaniline
(0.129 g, 1.012 mmol), Example 9a (0.2522 g, 1.012 mmol),
diacetoxypalladium (9.09 mg, 0.040 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.039 g, 0.081 mmol), cesium carbonate (0.462 g, 1.417 mmol),
toluene (8.44 mL) and tert-butanol (1.687 mL). The tube was sealed,
and the reaction mixture was heated in a Biotage Creator microwave
at 150.degree. C. for 15 minutes fixed hold time. The reaction
mixture was filtered through a Celite SPE column (2 g) and rinsed
with ethyl acetate. The reaction mixture was washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 20-100% ethyl acetate/heptanes) to
provide the title compound. (0.255 g, 85% yield).
Example 198b
2-bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline
[1229] A 250 mL round-bottomed flask was charged with Example 198a
(0.2553 g, 0.863 mmol) and acetic acid (8.63 mL).
N-bromosuccinimide (0.154 g, 0.863 mmol) was added in 2 portions 10
minutes apart. The reaction mixture was stirred at room temperature
for 4 hours. The reaction mixture was quenched with sodium
thiosulfate (30 mL, 10%) and diluted with water. The reaction
mixture was extracted with ethyl acetate (2.times.). The combined
organic layers were washed with 2N sodium hydroxide until the pH of
the aqueous was >7, followed by washing with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue was purified by flash chromatography
(silica gel, 50-100% ethyl acetate/heptanes) to provide the title
compound. (0.198 g, 61% yield).
Example 198c
4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1--
tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1230] A 250 mL round-bottomed flask was charged with Example 198b
(0.1981 g, 0.529 mmol), Example if (0.206 g, 0.481 mmol), sodium
carbonate (0.178 g, 1.682 mmol),
tris(dibenzylideneacetone)dipalladium (O) (0.022 g, 0.024 mmol),
and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.024 g, 0.082 mmol). The solids were flow purged with nitrogen
for 1 hour. Degassed dioxane (4.0 mL) and water (1.0 mL) were
added. The reaction mixture was heated at 60.degree. C. for 3
hours. The reaction mixture was cooled to room temperature 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 residue was
purified by flash chromatography (0-5% methanol/dichloromethane) to
provide a tan solid. The solid was triturated with dichloromethane
and heptanes and filtered to provide the title compound. (0.167 g,
58% yield).
Example 198d
4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-
-pyrrolo[2,3-c]pyridin-7(6H)-one
[1231] A 4 mL vial was charged with Example 198c (0.1673 g, 0.281
mmol), lithium hydroxide hydrate (0.118 g, 2.81 mmol), dioxane
(1.40 mL) and water (0.47 mL). The reaction mixture was heated at
50.degree. C. overnight. The reaction mixture was cooled to room
temperature and partitioned between water and 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, 0-5%
methanol/dichloromethane) to provide the title compound. (0.0795 g,
64% yield).
Example 198e
4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1232] A 250 mL round-bottomed flask was charged with Example 198d
(0.0794 g, 0.180 mmol). paraformaldehyde (0.081 g, 0.898 mmol), and
tetrahydrofuran (1.797 mL). Titanium (IV) chloride (0.359 mL, 0.359
mmol) was added. The reaction mixture was stirred at room
temperature for 1 hour. The reaction mixture was 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 residue was purified by
flash chromatography (silica gel, 0-5% methanol/dichloromethane) to
provide the title compound (0.0596 g, 73% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.86 (bs, 1H), 7.92 (d, J=2.0 Hz, 1H),
7.61 (s, 1H), 7.45 (dd, J=7.9, 1.9 Hz, 1H), 7.34 (d, J=5.5 Hz, 2H),
6.98 (d, J=9.1 Hz, 2H), 6.42 (d, J=9.0 Hz, 2H), 5.13 (s, 1H),
4.37-4.66 (m, 3H), 3.56 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 454.1
(M+H).sup.+.
Example 199
4-(4-chlorophenyl)-10-methyl-7-((methyl
sulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f-
]azulene-2-carbonitrile
[1233] To the suspension of Example 58m (50 mg, 0.101 mmol) and
triethylamine (0.028 mL, 0.201 mmol) in tetrahydrofuran (1 mL) at
0.degree. C. was added trifluroracetic anhydride (0.043 mL, 0.302
mmol) dropwise and the reaction mixture was stirred at ambient
temperature for further 60 minutes. The solvent was removed and the
residue was purified by reverse phase HPLC (C8 column,
CH.sub.3CN/water (0.01 N ammonium carbonate, 25%-55%) to give the
title compound (5 mg, 10.44 .mu.mol, 10% yield) as grey solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.36 (s, 1H), 7.94 (s,
1H), 7.76 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H),
7.06 (d, J=9.0 Hz, 2H), 6.35 (d, J=9.0 Hz, 2H), 5.23-5.13 (m, 1H),
4.70-4.47 (m, 3H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 479.0
(M+H).sup.+.
Example 200
4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)meth-
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 200a
ethyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate
[1234] Example 12d (89 mg, 0.20 mmol) and ethyl 2-oxoacetate (0.119
mL, 0.600 mmol) were combined in tetrahydrofuran (2 mL). To this
suspension was added 1M titanium(IV) chloride in dichloromethane
(0.400 mL, 0.400 mmol). The reaction mixture was stirred at ambient
temperature for 20 hours, and partitioned with ethyl acetate and
water. 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 provide the title
compound (78 mg, 74%).
Example 200b
4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)meth-
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1235] To a solution of Example 200a (76.0 mg, 0.144 mmol) in
tetrahydrofuran (2 mL) was added 1.0 M lithium aluminum hydride in
tetrahydrofuran (0.144 mL, 0.144 mmol) dropwise at 0.degree. C. The
reaction mixture was stirred at ambient temperature for 2 hours,
and partitioned with ethyl acetate and water. 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, 2-5% methanol in
dichloromethane) to provide the title compound (45 mg, 64%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.90 (d, J=2.1 Hz,
1H), 7.78 (d, J=1.8 Hz, 1H), 7.66 (s, 1H), 7.60-7.49 (m, 1H),
7.21-7.14 (m, 2H), 7.06-6.96 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 5.18
(dd, J=9.2, 5.4 Hz, 1H), 4.99 (t, J=4.6 Hz, 1H), 4.52-4.39 (m, 2H),
3.64 (s, 3H), 3.48-3.34 (m, 2H), 2.93 (s, 3H). MS (ESI+) m/z 486
(M+H).sup.+.
Example 201
4-(4-chlorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadi-
benzo[cd,f]azulene-2-carbonitrile
Example 201a
4-(4-chlorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadi-
benzo[cd,f]azulene-2-carboxylic Acid
[1236] Example 201a was prepared according to the procedure used
for the preparation of Example 581, substituting Example 127d for
Example 58k, to provide the title compound.
Example 201b
4-(4-chlorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadi-
benzo[cd,f]azulene-2-carboxamide
[1237] Example 201b was prepared according to the procedure used
for the preparation of Example 58m, substituting Example 201a for
Example 581, to provide the title compound.
Example 201c
4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazad-
ibenzo[cd,f]azulene-2-carbonitrile
[1238] Example 201c was prepared according to the procedure used
for the preparation of Example 199, substituting Example 201b for
Example 58m, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.92 (d, J=7.8 Hz, 1H), 7.84 (s, 1H),
7.52-7.47 (m, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.05 (d, J=9.1 Hz, 2H),
6.33 (d, J=9.1 Hz, 2H), 5.20-5.15 (m, 1H), 4.66-4.63 (m, 1H), 3.57
(s, 3H). MS (ESI+) m/z 387.1 (M+H).sup.+.
Example 202
4-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1239] A mixture of Example 208i (250 mg, 0.289 mmol) and
ethylamine (25% in ethanol wt/wt) (5 mL, 1.386 mmol) was sealed and
heated at 78.degree. C. for 2 days. The mixture was cooled to
ambient temperature and the resulting solid was collected by
filtration and washed with methanol several times. The solid was
then purified by reverse phase preparative HPLC (C18, 30-60%
acetonitrile/0.01 N NH.sub.4CO.sub.3 in water) to give the title
compound (30 mg, 0.057 mmol, 19.71% yield) as white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.15 (s, 1H), 8.26 (d, J=4.8
Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.71 (s, 1H), 7.29-7.22 (m, 1H),
7.21-7.07 (m, 1H), 7.02-6.89 (m, 3H), 5.15 (brs, 1H), 4.49 (s, 2H),
3.66 (s, 3H), 3.29-3.26 (m, 3H), 2.96 (s, 3H), 1.14 (t, J=7.3 Hz,
3H). MS (ESI+) m/z 527.2 (M+H).sup.+.
Example 203
4-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1240] A mixture of Example 59 (100 mg, 0.190 mmol), potassium
hexacyanoferrate(II) trihydrate (17.70 mg, 0.042 mmol),
Pd.sub.2(dba).sub.3 (8.72 mg, 9.52 .mu.mol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(X-Phos) (9.08 mg, 0.019 mmol), palladium(II) acetate (4.28 mg,
0.019 mmol) and Cs.sub.2CO.sub.3 (93 mg, 0.286 mmol) in dioxane (6
mL) and water (1.5 mL) was sealed and heated at 130.degree. C.
under microwave for 3 hours. The reaction mixture was filtered
through Celite and washed with ethyl acetate and then concentrated.
The residue was purified by reverse phase HPLC (C18,
CH.sub.3CN/water (0.01N ammonium carbonate), 25-55% gradient) to
give the title compound (8.4 mg, 0.016 mmol, 8.55% yield) as pale
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.28 (s, 1H),
8.35 (t, J=5.0 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 7.71 (s, 1H),
7.52-7.49 (m, 1H), 7.45-7.37 (m, 3H), 6.47 (d, J=7.6 Hz, 2H), 5.98
(d, J=17.0 Hz, 1H), 4.67-4.63 (m, 1H), 4.54 (d, J=2.3 Hz, 1H),
4.51-4.50 (m, 1H), 3.59 (s, 3H), 3.42-3.36 (m, 2H), 3.02 (s, 3H),
1.20 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 516.2 (M+H).sup.+.
Example 204
(S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoi-
ndoline-1,3-dione
[1241] Preparatory chiral SFC separation of the product from
Example 117 (0.019 g) on an (S,S) WHELK-O 1 column (21 mm.times.250
mm, 5 micron) eluting with a 4:6 mixture of 0.1% diethylamine in
methanol/carbon dioxide afforded the title compound. The
stereochemistry was randomly assigned to this first eluted peak
(5.004 minutes, 98% ee, 5.1 mg, 64% recovery). %). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.78 (d, J=1.83 Hz, 1H), 7.93 (d,
J=1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H),
7.21 (dd, J=8.24, 1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m,
1H), 6.96 (d, J=2.44 Hz, 1H), 6.92 (d, J=8.24 Hz, 1H), 5.44 (dd,
J=9.92, 5.34 Hz, 1H), 4.51-4.56 (m, 1H), 4.44-4.48 (m, 1H), 3.87
(dd, J=13.28, 5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J=13.28, 10.22
Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615 (M+H).sup.+.
Example 205
(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-
-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoi-
ndoline-1,3-dione
[1242] Preparatory chiral SFC separation of the product from
Example 117 (0.019 g) on an (S,S) WHELK-O 1 column (21 mm.times.250
mm, 5 micron) eluting with a 4:6 mixture of 0.1% diethylamine in
methanol/carbon dioxide afforded the title compound. The
stereochemistry was randomly assigned to this second eluted peak
(5.732 minutes, >99% ee, 5.6 mg, 70% recovery). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.78 (d, J=1.83 Hz, 1H), 7.93 (d,
J=1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H),
7.21 (dd, J=8.24, 1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m,
1H), 6.96 (d, J=2.44 Hz, 1H), 6.92 (d, J=8.24 Hz, 1H), 5.44 (dd,
J=9.92, 5.34 Hz, 1H), 4.51-4.56 (m, 1H), 4.44-4.48 (m, 1H), 3.87
(dd, J=13.28, 5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J=13.28, 10.22
Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615 (M+H).sup.+.
Example 206
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile
Example 206a
2,6-dibromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline
[1243] A 500 mL round-bottomed flask was charged with Example 12a
(3.000 g, 7.97 mmol) and trifluoroacetic acid (80 mL) to give a
colorless solution. The reaction mixture was cooled to 0.degree. C.
N-bromosuccinimide (1.419 g, 7.97 mmol) was added in two portions
10 minutes apart. The cold bath was removed, and the reaction
mixture was stirred at ambient temperature for 2 hours. The solvent
was removed, and 200 mL 2N sodium hydroxide, 50 mL 10% sodium
thiosulfate, and 200 mL ethyl acetate were added. The reaction
mixture was stirred for 30 minutes. The layers were separated, and
the organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated onto silica gel. The reaction mixture was purified by
flash chromatography (20-100% ethyl acetate:heptanes) to provide a
white solid (2.48 g, 68%).
Example 206b
4-(3-bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-
-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1244] Example 206b was prepared according to the procedure used
for the preparation of Example 6b, substituting Example 206a for
Example 6a, to provide the title compound as a yellow solid (0.0872
g, 50% yield).
Example 206c
4-(3-bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-
-6-methyl-H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1245] Example 206c was prepared according to the procedure used
for the preparation of Example 12d, substituting Example 206b for
Example 12c, to provide the title compound as a red oil (0.0552 g,
44% yield).
Example 206d
5-bromo-4-(2,4-difluorophenyl)-10-methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11 (10H)-one
[1246] Example 206d was prepared according to the procedure used
for the preparation of Example 82, substituting Example 206c for
Example 12d, to provide the title compound as a yellow solid
(0.0352 g, 62% yield).
Example 206e
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile
[1247] A 2 mL microwave tube was charged with zinc (II) cyanide
(0.012 g, 0.099 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (4.62 mg, 6.59
.mu.mol). Example 206d (0.0352 g, 0.066 mmol) and
N,N-dimethylformamide (0.659 mL) were added. The tube was sealed,
and the reaction mixture was heated in a Biotage Creator at
200.degree. C. for 30 minutes fixed hold time. The reaction mixture
was partitioned between ethyl acetate and water. The organic layer
was washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate and mercaptopropyl silica gel, filtered
and concentrated. The reaction mixture was purified by flash
chromatography (0-5% methanol:dichloromethane) to provide a white
solid (0.0209 g, 66% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.95 (bs, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.81 (s, 1H), 7.78
(d, J=1.9 Hz, 1H), 7.24 (s, 1H), 6.99-7.20 (m, 1H), 6.73 (td,
J=8.5, 2.8 Hz, 1H), 6.45 (td, J=9.5, 5.8 Hz, 1H), 5.05-5.14 (m,
1H), 4.43-4.80 (m, 3H), 3.62 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z
481.0 (M+H).sup.+.
Example 207
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
Example 207a
4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2-
,3-c]pyridin-7(6H)-one
[1248] Example 1f (2.0 g, 4.67 mmol), Example 5c (1.6 g, 5.14
mmol), tris(dibenzylideneacetone)dipalladium(O) (0.128 g, 0.14
mmol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(0.136 g, 0.467 mmol) and sodium carbonate (2.13 g, 20.1 mmol) were
combined and sparged with nitrogen for 30 minutes. To this mixture
were added nitrogen-sparged 1,4-dioxane (24 mL) and water (6 mL)
via syringe. The reaction mixture was stirred at 60.degree. C. for
5 hours, cooled to ambient temperature and 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, 0-100% ethyl acetate in
dichloromethane). The product was further purified by trituration
with diethyl ether and then dried in a vacuum oven at 70.degree. C.
to give 2.06 g (91%) of the title compound.
Example 207b
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1249] Example 207a (0.4 g, 0.824 mmol), 2-bromopyridine (0.325 g,
2.06 mmol), diacetoxypalladium (0.046 g, 0.206 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.196 g, 0.412 mmol) and cesium carbonate (0.537 g, 1.65 mmol)
were combined in a 20-mL microwave vial equipped with a magnetic
stirbar. Toluene (6.6 mL) and tert-butanol (1.65 mL) were added and
the mixture was reacted in a Biotage microwave reactor at
160.degree. C. for 1 hour. The reaction sequence was repeated and
then the two reaction mixtures were combined and filtered through a
fritted funnel to remove the Pd solids. The filtrate 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, 0-50% ethyl acetate in dichloromethane
and then 5-7% methanol in dichloromethane) to give 0.211 g (23%) of
the title compound.
Example 207c
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyr-
rolo[2,3-c]pyridin-7(6H)-one
[1250] A mixture of Example 207b (0.21 g, 0.373 mmol) in
1,4-dioxane (5 mL) and water (1.7 mL) was treated with lithium
hydroxide*H.sub.2O (0.157 g, 3.73 mmol) and
N,N,N-trimethylhexadecan-1-aminium bromide (0.0041 g, 0.011 mmol)
and heated at 63.degree. C. for 3.5 hours, stirred at ambient
temperature overnight and then heated at 75.degree. C. for another
1.5 hours. The reaction mixture was cooled to ambient temperature
and neutralized with hydrochloric acid solution (2 N aqueous). The
resulting mixture was then 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, 0-25% methanol in
dichloromethane) to give 0.15 g (99%) of the title compound.
Example 207d
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
[1251] To a 5-mL microwave vial equipped with a magnetic stirbar
was added Example 207c (0.15 g, 0.367 mmol), paraformaldehyde
(0.033 g, 1.1 mmol), and acetic acid (7.3 mL). The vial was capped
and heated at 75.degree. C. for 55 minutes. A second reaction
mixture was run as follows. To a 5-mL microwave vial equipped with
a magnetic stirbar was added Example 207c (0.082 g, 0.2 mmol),
paraformaldehyde (0.018 g, 0.6 mmol), and acetic acid (4 mL). The
vial was capped and heated at 75.degree. C. for 45 minutes. The
reaction mixtures were combined and concentrated. To the residue
was added 1,4-dioxane (5.7 mL) and sodium hydroxide solution (4 N
aqueous) (1.4 mL, 5.67 mmol). The reaction mixture heated at
60.degree. C. for 1 hour, cooled to ambient temperature and
neutralized with hydrochloric acid solution (2 N aqueous). The
resulting mixture was then partitioned between ethyl acetate and
water and washed with saturated aqueous sodium chloride. The
combined aqueous layers were extracted with ethyl acetate until no
product was detected. 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 0.271 g (89%) of the title compound as the
TFA salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.84 (d,
J=1.53 Hz, 1H), 7.98 (dd, J=4.88, 1.22 Hz, 1H), 7.91 (d, J=1.83 Hz,
1H), 7.63 (s, 1H), 7.43 (m, 1H), 7.36 (d, J=7.93 Hz, 1H), 7.29 (m,
2H), 6.51 (ddd, J=7.02, 4.88, 0.61 Hz, 1H), 6.16 (d, J=8.24 Hz,
1H), 5.79 (d, J=15.56 Hz, 1H), 4.62 (d, 1H), 4.52 (d, 1H), 4.24 (d,
J=15.56 Hz, 1H), 3.57 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 421.1
(M+H).sup.+.
Example 208
ethyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate
Example 208a
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
[1252] To a solution of 5-bromo-2-methoxy-3-nitropyridine (50 g,
215 mmol) in tetrahydrofuran (2000 mL) was added vinyl-magnesium
bromide (800 mL, 644 mmol) dropwise at -70.degree. C., and the
mixture was stirred between -70.degree. C. and -60.degree. C. for 2
hours. The reaction mixture was quenched with 20% aqueous
NH.sub.4Cl, extracted with ethyl acetate, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to get a brown residue. This material was purified by column
chromatography on silica gel (eluted with petroleum ether:ethyl
acetate=10:1) to give a crude product, which was triturated with
dichloromethane and dried under vacuum to give the title compound
(20 g, 41.1% yield) as a light yellow solid.
Example 208b
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[1253] To a solution of Example 208a (44 g, 194 mmol) in
tetrahydrofuran (600 mL) was added sodium hydride (6.98 g, 290
mmol) portion-wise at 0.degree. C. The mixture was stirred for 1
hour. Then 4-methylbenzene-1-sulfonyl chloride (55.4 g, 290 mmol)
was added to the mixture portion-wise at 0.degree. C. After
stirring at ambient temperature for 2 hours, the reaction mixture
was quenched with 20% aqueous ammonium chloride. The mixture was
extracted with ethyl acetate three times and partitioned. The
combined organic layers were dried (anhydrouse sodium sulfate), and
filtered. The filtrate was concentrated in vacuum to afford a
residue which was recrystallized from ethyl acetate and petroleum
ether to give the title compound (52 g, 70.4% yield) as light
yellow solid.
Example 208c
ethyl
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1254] To a solution of Example 208b (10.5 g, 27.5 mmol) in
tetrahydrofuran (170 mL) was added dropwise lithium
diisopropylamide (20.7 mL, 41.40 mmol) at -70.degree. C. and the
reaction mixture was stirred between -70.degree. C. and -50.degree.
C. for 45 minutes. To the stirred resulting mixture at -70.degree.
C. was added ethyl carbonochloridate (4.48 g, 41.3 mmol) dropwise.
The reaction mixture was stirred at -70.degree. C. for 1.5 hours,
quenched with 20% aqueous ammonium chloride, and extracted with
ethyl acetate (150 mL). The combined organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuum to
give the crude product, which was washed with dichloromethane to
give the title compound (10 g, 80%) as a white solid.
Example 208d
ethyl
4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbox-
ylate
[1255] To a mixture of Example 208c (32.5 g, 71.7 mmol) and sodium
iodide (16.12 g, 108 mmol) in acetonitrile (554 mL) was added
chlorotrimethylsilane (11.68 g, 108 mmol) dropwise at ambient
temperature. The resulting mixture was stirred at ambient
temperature for 1 hour. Water (0.685 g, 38.0 mmol) was added
dropwise to the reaction mixture and the mixture was stirred at
65.degree. C. for 3 hours. The reaction mixture was cooled to
ambient temperature and filtered. The precipitate was dissolved in
dichloromethane. The mixture was filtered again and the combined
filtrate was concentrated under reduced pressure to give a brown
solid which was washed with petroleum and dichloromethane to afford
the title compound (23 g, 52.4 mmol, 73.0% yield) as a light yellow
solid.
Example 208e
ethyl
4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-
-2-carboxylate
[1256] To a solution of Example 208d (7.5 g, 17.07 mmol) in
tetrahydrofuran (100 mL) was added sodium hydride (0.520 g, 21.68
mmol) in portions at 0.degree. C., and the reaction mixture was
stirred for 30 minutes. Iodomethane (3.64 g, 25.6 mmol) was added
dropwise to the above mixture at 0.degree. C. The resulting mixture
was stirred at ambient temperature for 3 hours and another portion
of iodomethane (3.64 g, 25.6 mmol) was added at 0.degree. C. The
reaction mixture was stirred at ambient temperature for 12 hours,
quenched with 20% aqueous ammonium chloride and extracted with
ethyl acetate three times. The combined mixtures were dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The resulting residue was purified by column chromatography on
silica gel, eluting with 1:1 ethyl acetate/hexanes to provide a
yellow crude product which was washed with methanol to give the
title compound (15.3 g, 80% yield).
Example 208f
ethyl
6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tos-
yl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1257] Example 208f was prepared according to the procedure used
for the preparation of Example if, substituting Example 208e for
Example 1e, to provide the title compound.
Example 208g
ethyl
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-
-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1258] Example 208g was prepared according to the procedure used
for the preparation of Example 5d, substituting Example 12b for
Example 5c, and Example 208f for Example if, respectively, to
provide the title compound.
Example 208h
ethyl
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-
-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1259] A mixture of ethyl Example 208g (0.2 g, 0.299 mmol) in
dioxane (2 mL) and ethanol (0.5 mL) was treated with sodium
hydroxide (0.747 mL, 1.493 mmol) at ambient temperature. The
reaction mixture was heated to 60.degree. C. over 2 minutes. After
cooling to ambient temperature, the reaction mixture was
partitioned between 1.0 N HCl 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 to give the title compound
(0.15 g, 0.291 mmol, 97% yield).
Example 208i
ethyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate
[1260] Example 208i was prepared according to the procedure used
for the preparation of Example 58k, substituting Example 208h for
Example 58j, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.67 (s, 1H), 7.84 (d, J=2.14 Hz, 1H), 7.72
(s, 1H), 7.29 (dd, J=8.24, 1.83 Hz, 1H), 7.09-7.13 (m, 1H), 7.03
(d, J=7.93 Hz, 1H), 6.84-6.89 (m, 1H), 6.75-6.81 (m, 1H), 5.09 (s,
2H), 4.49 (s, 2H), 4.29 (q, J=7.02 Hz, 1H), 3.64 (s, 3H), 2.96 (s,
3H), 1.34 (t, J=7.02 Hz, 3H). MS (ESI+) m/z 528.1 (M+H).sup.+.
Example 209
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
Example 209a
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic
Acid
[1261] Example 209a was prepared according to the procedure used
for the preparation of Example 581, substituting Example 208i for
Example 58k, to provide the title compound.
Example 209b
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1262] Example 209b was prepared according to the procedure used
for the preparation of Example 58m, substituting Example 209a for
Example 581, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.19 (s, 1H), 7.82 (d, J=2.14 Hz, 1H), 7.72
(s, 2H), 7.70 (s, 1H), 7.53 (s, 1H), 7.26 (dd, J=8.09, 1.98 Hz,
1H), 7.05-7.11 (m, 1H), 6.98 (d, J=7.93 Hz, 1H), 6.90-6.93 (m, 2H),
6.75-6.81 (m, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.66 (s, 3H), 2.95
(s, 3H). MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 210
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile
[1263] Example 210 was prepared according to the procedure used for
the preparation of Example 199, substituting Example 209b for
Example 58m, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 13.32 (s, 1H), 7.89 (d, J=1.83 Hz, 1H), 7.82
(s, 1H), 7.32 (dd, J=8.24, 1.83 Hz, 1H), 7.12-7.15 (m, 1H), 7.08
(d, J=8.24 Hz, 1H), 6.83-6.88 (m, 1H), 6.71-6.77 (m, 1H), 4.86 (s,
2H), 4.51 (s, 2H), 3.65 (s, 3H), 2.97 (s, 3H). MS (ESI+) m/z 481.1
(M+H).sup.+.
Example 211
10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 211a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((3,4,5-trimethoxyphenyl)amino)ph-
enyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1264] A mixture of Example 5d (0.075 g, 0.154 mmol),
5-bromo-1,2,3-trimethoxybenzene (0.114 g, 0.463 mmol), cesium
carbonate (0.101 g, 0.309 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(XPhos) (0.0368 g, 0.077 mmol), and palladium (II) acetate (0.0087
g, 0.039 mmol) in toluene (3 mL) and tert-butanol (0.75 mL) under
argon was heated in a sealed tube in a microwave reactor at
160.degree. C. for 2 hours. The reaction mixture was cooled to
ambient temperature and filtered through filter paper. The
resulting filtrate was concentrated to near dryness and mixed with
ethanol (2 mL), tetrahydrofuran (4 mL), and excess 5N sodium
hydroxide solution (2 mL). The reaction mixture was stirred at
ambient temperature for 1 hour then concentrated to 5 mL and
partitioned between ammonium chloride aqueous solution and ethyl
acetate. The aqueous phase was extracted twice more 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 column
chromatography on silica gel eluting with 3% methanol in
dichloromethane to afford the title compound (0.020 g, 0.040 mmol,
26% yield).
Example 211b
10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1265] A mixture of Example 211a (0.020 g, 0.040 mmol) and
paraformaldehyde (0.006 g, 0.201 mmol) in tetrahydrofuran (2 mL) at
ambient temperature under argon was treated with a 1M solution of
titanium tetrachloride (0.080 mL, 0.080 mmol). The reaction mixture
suspension was stirred at ambient temperature for 1 hour and then
partitioned between ethyl acetate and saturated sodium bicarbonate.
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 triturated with methanol to give the
title compound (0.0026 g, 13% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.83 (s, 1H), 7.92 (s, 1H), 7.64 (s, 1H),
7.46-7.29 (m, 3H), 5.71 (s, 2H), 5.49-4.66 (m, 2H), 4.56 (s, 2H),
3.57 (s, 3H), 3.51 (s, 6H), 3.45 (s, 3H), 2.96 (s, 3H). MS (ESI+)
m/z 510.3 (M+H).sup.+.
Example 212
4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H--
1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1266] A mixture of Example 196 (0.240 g, 0.444 mmol) in
dichloromethane (10 mL) was treated excess with trifluoroacetic
acid (1 mL) and stirred at ambient temperature for 6 hours. The
reaction mixture was concentrated and dried under vacuum to afford
a solid residue which was partitioned between saturated sodium
carbonate solution and ethyl acetate. The aqueous phase was
extracted twice more with ethyl acetate and twice with
dichloromethane. The combined organic extracts were dried with
magnesium sulfate and concentrated. The residue was triturated with
ethyl acetate and filtered to give the title compound (0.0066 g,
0.015 mmol, 45% yield). .sup.1H NMR (501 MHz, DMSO-d.sub.6) .delta.
11.80 (bs, 1H), 7.68 (s, 1H), 7.51-7.45 (m, 1H), 7.27-7.09 (m, 3H),
4.44-4.39 (m, 2H), 4.18 (s, 2H), 3.10 (bs, 2H), 3.61 (s, 3H), 2.90
(s, 3H), 2.82-2.42 (m, 2H), 1.68-1.45 (m, 4H), 1.36-1.17 (m, 3H),
0.88-0.81 (m, 1H). MS (ESI+) m/z 440.8 (M+H).sup.+.
Example 213
4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 213a
4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-
-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1267] Example 207a, 2-bromo-3,5-difluoropyridine (0.245 g, 1.263
mmol), diacetoxypalladium (0.032 g, 0.143 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.137 g, 0.287 mmol) and cesium carbonate (0.374 g, 1.148 mmol)
were combined in a 20-mL microwave vial equipped with a magnetic
stirbar. Toluene (4.4 mL) and tert-butanol (1.1 mL) were added and
the reaction mixture was reacted in a Biotage microwave reactor at
160.degree. C. for 1 hour. The reaction mixture was cooled to
ambient temperature, diluted with ethyl acetate and water and
filtered through a plastic fritted funnel to remove the Pd solids.
The filtrate was poured into a separatory funnel and the layers
were separated. The organic layer was washed with water and
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography (silica gel, 0-70% ethyl acetate in
dichloromethane) to give 0.229 g (71%) of the title compound.
Example 213b
4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-
-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1268] To Example 213a (0.2129 g, 0.356 mmol) in tetrahydrofuran (8
mL) was added tetrabutylammonium fluoride (0.28 g, 1.07 mmol). The
reaction mixture was heated at 60.degree. C. for 45 minutes, 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, 0-8%
methanol in dichloromethane) to give the title compound as a
mixture. It was further purified by flash chromatography (silica
gel, 40-75% ethyl acetate in dichloromethane with 2-4% methanol as
an additive) to give 0.116 g (73%) of the title compound.
Example 213c
4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihy-
dro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1269] To a 5-mL microwave vial equipped with a magnetic stirbar
was added Example 213b (0.116 g, 0.261 mmol), paraformaldehyde
(0.024 g, 0.783 mmol), and acetic acid (4.5 mL). The vial was
capped and heated at 75.degree. C. for 50 minutes. The reaction
mixture was cooled to ambient temperature, concentrated under
vacuum, diluted with 1,4-dioxane (6 mL), treated with sodium
hydroxide solution (4 M aqueous, 1.3 mL, 5.22 mmol) and heated at
75.degree. C. for 1 hour. The reaction mixture was cooled to
ambient temperature, concentrated under vacuum, slurried in water
and neutralized with hydrochloric acid solution (2 N aqueous). The
solid was collected by filtration and rinsed with additional water
(20 mL). The solid was purified by reverse phase HPLC (C18,
acetonitrile/water (0.1% TFA), 10-70%) to provide 0.09 g (61%) of
the title compound as the TFA salt. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.87 (s, 1H), 8.06 (d, J=1.83 Hz, 1H), 7.83
(s, 1H), 7.67 (s, 1H), 7.59 (m, 1H), 7.29 (d, J=7.93 Hz, 1H), 7.25
(d, J=1.53 Hz, 1H), 7.13 (d, J=8.24 Hz, 1H), 5.95 (s, 1H), 4.52 (s,
2H), 4.20 (s, 1H), 3.62 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 457.1
(M+H).sup.+.
Example 214
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-d-
ihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1 OH)-one
[1270] Example 12d (66.5 mg, 0.150 mmol) and benzaldehyde (0.076
mL, 0.75 mmol) were combined in tetrahydrofuran (2 mL). To this
suspension was added 1M titanium(IV) chloride in toluene (0.300 mL,
0.300 mmol). The reaction mixture was stirred at ambient
temperature for 72 hours, and partitioned with ethyl acetate and
water. 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 provide the title
compound (65 mg, 82%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.28
(d, J=2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s,
1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z
532 (M+H).sup.+.
Example 215
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1271] The product from Example 214 was purified by chiral
chromatography on a (S,S) WHELK-O 1 column (21.times.250 mm, 5
micron), eluting with a 4:6 mixture of 0.1% diethylamine in
methanol/carbon dioxide. Fractions of the first eluted enantiomer
was collected and concentrated. The compound isolated was randomly
assigned as (R) enantiomer. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s,
1H), 7.28 (d, J=2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H),
6.47 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS
(ESI+) m/z 532 (M+H).sup.+.
Example 216
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11 (10H)-one
[1272] The product from Example 214 was purified by chiral
chromatography on a (S,S) WHELK-O 1 column (21.times.250 mm, 5
micron), eluting with a 4:6 mixture of 0.1% diethylamine in
methanol/carbon dioxide. Fractions of the second eluted enantiomer
was collected and concentrated. The compound isolated was randomly
assigned as (S) enantiomer. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s,
1H), 7.28 (d, J=2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H),
6.47 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS
(ESI+) m/z 532 (M+H).sup.+.
Example 217
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen--
1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1273] Example 12d (0.06 g, 0.135 mmol) and 1-naphthaldehyde (0.148
mL, 1.082 mmol) were combined in tetrahydrofuran (1.353 mL) under
nitrogen and treated with 1M titanium(IV) chloride in toluene
(1.082 mL, 1.082 mmol). The reaction mixture was heated at
70.degree. C. for 24 hours, cooled to ambient temperature, and
partitioned between ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride, dried over anhydrous
sodium sulfate, filtered, and concentrated. Purification by
chromatography (silica gel, 1-5% methanol in dichloromethane)
afforded the title compound (0.015 g, 19%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.07 (s, 1H), 8.75 (d, J=8.85 Hz, 1H), 7.86
(d, J=7.93 Hz, 1H), 7.69-7.75 (m, 3H), 7.61 (d, J=8.54 Hz, 1H),
7.55 (t, J=7.32 Hz, 1H), 7.38 (d, J=1.53 Hz, 1H), 7.24 (d, J=2.44
Hz, 1H), 7.11-7.19 (m, 1H), 6.98 (t, J=7.63 Hz, 1H), 6.65-6.73 (m,
2H), 6.60 (d, J=7.02 Hz, 1H), 6.37-6.45 (m, 1H), 6.30 (d, J=7.93
Hz, 1H), 4.20-4.34 (m, 2H), 3.66 (s, 3H), 2.59 (s, 3H). MS (ESI+)
m/z 582 (M+H).sup.+.
Example 218
4-(2,4-difluorophenyl)-(3,3-.sup.2H.sub.2)-10-methyl-7-((methylsulfonyl)me-
thyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1274] Example 218 was prepared according to the procedure used for
the preparation of Example 82, substituting formaldehyde-d.sub.2
for methyl 4-oxobutanoate, to provide the title compound as a
yellow solid (0.0352 g, 62% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.85 (s, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.67
(s, 1H), 7.27 (dd, J=8.1, 2.0 Hz, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.08
(ddd, J=12.4, 9.0, 3.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.80-6.88
(m, 1H), 6.76 (td, J=9.4, 5.9 Hz, 1H), 4.50 (bs, 2H), 3.63 (s, 3H),
2.96 (s, 3H). MS (ESI+) m/z 458.1 (M+H).sup.+.
Example 219
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,-
4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1275] Example 12d (0.06 g, 0.135 mmol) and
3,3-dimethylbutyraldehyde (0.081 g, 0.812 mmol) were combined in
tetrahydrofuran (1.353 mL) under nitrogen and treated drop-wise
with 1M titanium(IV) chloride in toluene (0.812 mL, 0.812 mmol).
The reaction mixture was stirred for 2 hours at 60.degree. C.,
cooled to ambient temperature, and partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered and concentrated. Purification by chromatography (silica
gel, 30-60% of 3:1 ethyl acetate/ethanol in heptanes) afforded the
title compound (0.010 g, 14%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.81 (s, 1H), 7.91 (d, J=1.53 Hz, 1H), 7.68 (s, 1H), 7.25
(dd, J=8.09, 1.68 Hz, 1H), 7.16 (d, J=2.44 Hz, 1H), 7.06-7.13 (m,
1H), 6.98 (d, J=7.93 Hz, 1H), 6.73-6.80 (m, 1H), 6.53-6.60 (m, 1H),
5.19 (dd, J=7.32, 4.88 Hz, 1H), 4.45-4.56 (m, 2H), 3.63 (s, 3H),
2.94 (s, 3H), 1.67 (dd, J=13.73, 4.88 Hz, 1H), 1.20 (dd, J=13.73,
7.63 Hz, 1H), 0.89 (s, 9H). MS (ESI+) m/z 526 (M+H).sup.+.
Example 220
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoin-
dolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-
-one
Example 220a
2-(2,2-dimethoxyethyl)isoindolin-1-one
[1276] A 5 mL microwave tube was charged with isoindolin-1-one
(0.2544 g, 1.911 mmol), cesium carbonate (1.245 g, 3.82 mmol) and
N-methyl-2-pyrrolidinone (9.55 mL) to give a colorless solution.
Bromoacetaldehyde dimethyl acetal (1.125 mL, 9.55 mmol) was added.
The tube was sealed, and the reaction mixture was heated in a
Biotage Creator at 160.degree. C. for 60 minutes fixed hold time.
The reaction mixture was 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 reaction mixture was purified by flash
chromatography (20-70% ethyl acetate:heptane) to provide a brown
oil (0.179 g, 42% yield).
Example 220b
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoin-
dolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-
-one
[1277] Example 220b was prepared according to the procedure used
for the preparation of Example 82, substituting Example 220a for
methyl 4-oxobutanoate, to provide the title compound as a white
solid (0.0169 g, 29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.84 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.75 (s, 1H),
7.51-7.66 (m, 3H), 7.47 (t, J=6.7 Hz, 1H), 7.18-7.28 (m, 2H), 7.12
(ddd, J=11.9, 8.9, 3.0 Hz, 1H), 6.96 (ddd, J=17.9, 11.7, 5.4 Hz,
3H), 5.46 (dd, J=9.5, 5.8 Hz, 1H), 4.53 (d, J=15.7 Hz, 2H), 4.46
(d, J=13.7 Hz, 1H), 4.17-4.26 (m, 1H), 3.89 (dd, J=13.4, 5.7 Hz,
1H), 3.66 (s, 3H), 3.34-3.44 (m, 1H), 2.97 (s, 3H). MS (ESI-) m/z
599.2 (M-H).sup.+.
Example 221
4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfony-
l)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1278] Example 12d (53.2 mg, 0.120 mmol) and
2,6-dimethoxybenzaldehyde (100 mg, 0.600 mmol) were combined in
tetrahydrofuran (1 mL). To this suspension was added 1M
titanium(IV) chloride in toluene (0.240 mL, 0.240 mmol). The
reaction mixture was heated at 60.degree. C. for 24 hours, cooled
to ambient temperature, and partitioned with ethyl acetate and
water. 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 provide the title
compound (8 mg, 11% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.62 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.69 (s,
1H), 7.16-6.73 (m, 7H), 6.60-6.34 (m, 3H), 4.52-4.30 (m, 2H), 3.65
(s, 3H), 3.32 (s, 6H), 2.85 (s, 3H). MS (ESI+) m/z 592
(M+H).sup.+.
Example 222
4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfony-
l)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1279] Example 222 was prepared according to the procedure used for
the preparation of Example 221, substituting
3,5-dimethoxybenzaldehyde for 2,6-dimethoxybenzaldehyde, to provide
the title compound (39 mg, 55%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.02 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.69
(s, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.19-7.04 (m, 2H), 6.96-6.81 (m,
3H), 6.34 (s, 1H), 6.27-6.18 (m, 3H), 4.46-4.31 (m, 2H), 3.66 (s,
3H), 3.56 (s, 6H), 2.75 (s, 3H). MS (ESI+) m/z 592 (M+H).sup.+.
Example 223
3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsul-
fonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1280] Example 223 was prepared according to the procedure used for
the preparation of Example 221, substituting
3,5-di-tert-butylbenzaldehyde for 2,6-dimethoxybenzaldehyde, to
provide the title compound (60 mg, 78%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.99 (d, J=1.8 Hz, 1H), 7.70-7.64 (m, 2H),
7.29 (d, J=2.4 Hz, 1H), 7.18-7.09 (m, 1H), 7.07-6.99 (m, 2H), 6.96
(s, 2H), 6.92-6.82 (m, 2H), 6.75 (d, J=8.1 Hz, 1H), 6.44 (s, 1H),
4.41-4.22 (m, 2H), 3.66 (s, 3H), 2.64 (s, 3H), 1.08 (s, 18H). MS
(ESI+) m/z 644 (M+H).sup.+.
Example 224
methyl
(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1281] A mixture of Example 212 (0.065 g, 0.148 mmol) and
N,N-diisopropylethylamine (0.103 mL, 0.590 mmol) in
dimethylformamide (5 mL) under argon at ambient temperature was
treated with dropwise addition of methyl chloroformate (0.012 mL,
0.148 mmol). The reaction mixture was stirred 2 hours at ambient
temperature and then partitioned between aqueous ammonium chloride
solution and ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered and concentrated to afford the title compound
(0.050 g, 0.100 mmol, 68% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.43 (s, 1H), 7.70-7.65 (m, 1H), 7.49-7.43
(m, 1H), 7.28-7.14 (m, 2H), 7.09 (s, 1H), 6.60 (s, 0.5H), 6.37 (d,
J=7.0 Hz, 0.5H), 4.43-4.37 (m, 2H), 4.19 (s, 2H), 3.61 (s, 3H),
3.54-3.44 (m, 3H), 3.42-3.10 (m, 1H), 2.89 (s, 3H), 2.85-2.66 (m,
1H), 1.74-1.45 (m, 4H), 1.39-1.18 (m, 3H), 1.04-0.94 (m, 1H). MS
(ESI+) m/z 499.1 (M+H).sup.+.
Example 225
methyl
((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihyd-
ro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1282] The geometric isomers of Example 224 were separated on
reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 5-40%
gradient). Fractions of the first eluted isomer was collected and
concentrated to provide the title compound (0.008 g, 0.016 mmol,
11% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.49 (s,
1H), 7.71 (d, J=1.7 Hz, 1H), 7.49 (s, 1H), 7.28-7.18 (m, 2H), 7.13
(d, J=2.5 Hz, 1H), 6.38 (s, 1H), 4.41 (s, 2H), 4.25 (s, 2H), 3.61
(s, 3H), 3.47 (s, 3H), 3.21-3.11 (m, 1H), 2.89 (s, 3H), 2.79-2.71
(m, 1H), 1.75-1.58 (m, 4H), 1.39-1.25 (m, 3H), 1.02-0.94 (m, 1H).
MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 226
methyl
((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate
[1283] The geometric isomers of Example 224 were separated on
reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 5-40%
gradient). Fractions of the second eluted isomer was collected and
concentrated to provide the title compound (0.0046 g, 0.009 mmol,
6% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.47 (s,
1H), 7.69 (d, J=1.7 Hz, 1H), 7.49 (s, 1H), 7.30-7.23 (m, 2H), 7.11
(d, J=2.5 Hz, 1H), 6.60 (s, 1H), 4.42 (s, 2H), 4.23 (s, 2H), 3.61
(s, 3H), 3.51 (s, 3H), 2.89 (s, 3H), 2.87-2.79 (m, 2H), 1.72-1.26
(m, 8H). MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 227
2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3-
,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindo-
line-1,3-dione
[1284] Example 12d (0.06 g, 0.135 mmol) and
3-(1,3-dioxoisoindolin-2-yl)propanal (0.082 g, 0.406 mmol) were
combined in tetrahydrofuran (1.353 mL) under nitrogen and treated
drop-wise with 1M titanium(IV) chloride in toluene (0.406 mL, 0.406
mmol). The reaction mixture was stirred for 18 hours at 60.degree.
C., cooled to ambient temperature, and partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered and concentrated. Purification by reverse phase HPLC (C18,
CH.sub.3CN/water (0.1% TFA), 0-100% gradient) provided the title
compound. (0.018 g, 21%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.94 (d, J=2.14 Hz, 1H), 7.88 (d, J=1.53 Hz, 1H),
7.80-7.86 (m, 4H), 7.72 (s, 1H), 7.31 (d, J=2.75 Hz, 1H), 7.28 (dd,
J=8.09, 1.98 Hz, 1H), 7.02-7.10 (m, 2H), 6.77-6.83 (m, 1H),
6.65-6.72 (m, 1H), 5.06-5.11 (m, 1H), 4.40-4.57 (m, 2H), 3.70-3.79
(m, 1H), 3.65 (s, 3H), 3.54-3.63 (m, 1H), 2.95 (s, 3H), 1.97-2.07
(m, 1H), 1.62 (dd, J=13.12, 5.19 Hz, 1H). MS (ESI+) m/z 629
(M+H).sup.+.
Example 228
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro--
2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one
[1285] Example 12d (0.05 g, 0.113 mmol) and
tetrahydropyran-4-carbaldehyde (0.064 g, 0.564 mmol) were combined
in tetrahydrofuran (1.127 mL) under nitrogen and treated drop-wise
with 1M titanium (IV) chloride in toluene (0.248 mL, 0.248 mmol).
The reaction mixture was stirred for 24 hours at 60.degree. C.,
cooled to ambient temperature and partitioned between ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride, dried over anhydrous sodium sulfate, filtered and
concentrated. Purification by chromatography (silica gel, 30-60% of
3:1 ethyl acetate/ethanol in heptanes) afforded the title compound
(0.028 g, 45%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.88
(d, J=1.22 Hz, 1H), 7.89 (d, J=1.83 Hz, 1H), 7.68 (s, 1H), 7.25
(dd, J=8.24, 1.83 Hz, 1H), 7.02-7.12 (m, 3H), 6.72-6.85 (m, 2H),
4.68 (d, J=9.46 Hz, 1H), 4.49 (q, J=13.73 Hz, 2H), 3.83 (d, J=11.60
Hz, 1H), 3.72 (d, J=9.77 Hz, 1H), 3.64 (s, 3H), 2.91 (s, 3H),
2.81-2.98 (m, 2H), 1.97-2.02 (m, 1H), 1.48-1.60 (m, 1H), 1.32 (t,
J=8.70 Hz, 2H), 1.03 (d, J=9.16 Hz, 1H). MS (ESI+) m/z 540
(M+H).sup.+.
Example 229
benzyl
(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11--
oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)ca-
rbamate
[1286] Example 12d (0.05 g, 0.113 mmol) and
3-[(benzyloxycarbonyl)amino]-1-propanal (0.070 g, 0.338 mmol) were
combined in tetrahydrofuran (1.127 mL) under nitrogen and treated
drop-wise with 1M titanium (IV) chloride in toluene (0.248 mL,
0.248 mmol). The reaction mixture was stirred for 24 hours at
60.degree. C., cooled to ambient temperature and partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate, filtered and concentrated. Purification by chromatography
(silica gel, 30-60% of 3:1 ethyl acetate/ethanol in heptanes)
afforded the title compound (0.012 g, 17%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.88 (s, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.68
(s, 1H), 7.28-7.42 (m, 6H), 7.23 (d, J=7.93 Hz, 1H), 7.21 (d,
J=2.44 Hz, 1H), 7.08 (dd, J=12.66, 9.61 Hz, 1H), 6.95 (d, J=7.93
Hz, 1H), 6.81 (d, J=7.02 Hz, 2H), 5.06 (dd, J=9.16, 5.49 Hz, 1H),
5.03 (s, 2H) 4.40-4.54 (m, 2H), 3.64 (s, 3H), 3.03-3.09 (m, 2H),
2.93 (s, 3H), 1.80-1.92 (m, 1H), 1.30-1.39 (m, 1H). MS (ESI+) m/z
633 (M+H).sup.+.
Example 230
3-([1,1'-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfon-
yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one
[1287] Example 230 was prepared according to the procedure used for
the preparation of Example 221, substituting
[1,1'-biphenyl]-2-carbaldehyde for 2,6-dimethoxybenzaldehyde and 48
hours for the reaction time instead of 24 hours, to provide the
title compound (11 mg, 15%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.00 (d, J=2.3 Hz, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.72 (s,
1H), 7.64 (d, J=7.1 Hz, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.46 (d, J=7.3
Hz, 1H), 7.30 (s, 1H), 7.15-7.04 (m, 3H), 6.81-6.58 (m, 5H),
6.53-6.45 (m, 1H), 6.00-5.85 (m, 1H), 4.48-4.34 (m, 2H), 3.64 (s,
3H), 2.73 (s, 3H). MS (ESI+) m/z 608 (M+H).sup.+.
Example 231
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8--
yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1288] Example 12d (53.2 mg, 0.120 mmol) and
quinoline-8-carbaldehyde (94.0 mg, 0.600 mmol) were combined in
tetrahydrofuran (1 mL). To this suspension was added 1M titanium
(IV) chloride in toluene (0.240 mL, 0.240 mmol). The reaction
mixture was heated at 60.degree. for 48 hours, cooled, diluted with
water, the pH adjusted to 7 by the addition of saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. 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 provide the title compound (14 mg, 20%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.02 (s, 1H), 9.14
(dd, J=4.2, 1.7 Hz, 1H), 8.34 (dd, J=8.3, 1.7 Hz, 1H), 8.21 (td,
J=9.6, 6.2 Hz, 1H), 7.77-7.68 (m, 4H), 7.62 (dd, J=8.3, 4.2 Hz,
1H), 7.29 (d, J=2.1 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 7.00 (td,
J=8.1, 2.0 Hz, 1H), 6.93-6.84 (m, 2H), 6.71 (dd, J=8.1, 1.8 Hz,
1H), 6.09 (d, J=8.1 Hz, 1H), 4.37-4.23 (m, 2H), 3.69 (s, 3H), 2.64
(s, 3H). MS (ESI+) m/z 583 (M+H).sup.+.
Example 232
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-y-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1289] Example 12d (53.2 mg, 0.12 mmol) and picolinaldehyde (0.057
mL, 0.60 mmol) were combined in tetrahydrofuran (1 mL). To this
suspension was added 1M titanium(IV) chloride in toluene (0.240 mL,
0.240 mmol). The mixture was heated at 70.degree. C. for 66 hours,
cooled, diluted with water, the pH adjusted to 7 by the addition of
saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate. 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 provide the title
compound (14 mg, 22%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.04 (d, J=1.8 Hz, 1H), 8.54-8.49 (m, 1H), 8.13 (td, J=9.4, 6.1
Hz, 1H), 7.68 (s, 2H), 7.40 (td, J=7.7, 1.8 Hz, 1H), 7.31 (d, J=2.5
Hz, 1H), 7.15-6.99 (m, 3H), 6.91 (dd, J=8.3, 1.9 Hz, 1H), 6.67 (d,
J=7.9 Hz, 1H), 6.61 (s, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.41-4.23 (m,
2H), 3.68 (s, 3H), 2.69 (s, 3H). MS (ESI+) m/z 533 (M+H).sup.+.
Example 233
10-methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methy-
l)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H-
)-one
Example 233a
5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole
[1290] A mixture of 5-iodo-1H-indazole (1.02 g, 4.18 mmol) in
tetrahydrofuran (20 mL) at 0.degree. C. under argon was treated
with sodium hydride (60% oil dispersion, 0.192 g, 4.81 mmol). The
reaction mixture was stirred at 0.degree. C. for 15 minutes.
(2-(chloromethoxy)ethyl)trimethylsilane (0.767 g, 4.60 mmol) was
added dropwise and the reaction mixture was stirred at ambient
temperature for 17 hours. The reaction mixture was partitioned
between water and ethyl acetate. 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 by chromatography on silica gel eluting with
10% ethyl acetate in heptane to give the title compound (0.933 g,
2.49 mmol, 60% yield).
Example 233b
N-(2-bromo-4-((methylsulfonyl)methyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-indazol-5-amine
[1291] A mixture of Example 233a (0.520 g, 1.389 mmol), Example 58g
(0.367 g, 1.389 mmol), cesium carbonate (0.905 g, 2.780 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (0.161
g, 0.278 mmol), and palladium(II)acetate (0.031 g, 0.139 mmol) in
dioxane (20 mL) under argon was heated in a sealed tube in a
microwave reactor at 130.degree. C. for 4 hours. The reaction
mixture was cooled to ambient temperature and partitioned between
saturated sodium chloride solution and ethyl acetate. The aqueous
layer was extracted with additional ethyl acetate. The combined
organic layers were dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by
chromatography on silica gel eluting with 33% ethyl acetate in
heptane to give the title compound (0.170 g, 0.333 mmol, 24%
yield).
Example 233c
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-indazol-5-yl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1292] A mixture of Example 233b (0.320 g, 0.627 mmol) and Example
1f (0.282 g, 0.658 mmol) in dimethoxyethane (20 mL) and methanol
(10 mL) under argon was treated with cesium fluoride (0.286 g,
1.880 mmol) and palladium tetrakis(triphenylphosphine) (0.72 g,
0.063 mmol). The reaction mixture was stirred at 75.degree. C. for
2 hours. The reaction mixture was cooled to ambient temperature and
excess 5N sodium hydroxide solution (8 mL) was added. The reaction
mixture was stirred at ambient temperature for 2 hours and then
partitioned between aqueous ammonium chloride solution and ethyl
acetate. 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 by
flash column chromatography on silica gel eluting with 1% methanol
in dichloromethane to afford the title compound (0.221 g, 0.381
mmol, 61% yield).
Example 233d
10-methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methy-
l)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H-
)-one
[1293] A mixture of Example 233c (0.221 g, 0.383 mmol) and
paraformaldehyde (0.057 g, 1.913 mmol) in tetrahydrofuran (10 mL)
under argon was treated with a 1M toluene solution of titanium
tetrachloride (0.765 mL, 0.765 mmol). The reaction mixture was
stirred at ambient temperature for 3 hours. The reaction mixture
was quenched by the slow addition of excess saturated sodium
bicarbonate solution and partitioned between water and ethyl
acetate. The aqueous layer was extracted with additional ethyl
acetate followed by extraction with dichloromethane. 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 2% methanol in dichloromethane to afford the title
compound (0.120 g, 0.203 mmol, 53% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.79 (d, J=2.4 Hz, 1H), 7.91 (d, J=1.8 Hz,
1H), 7.74 (d, J=0.5 Hz, 1H), 7.58 (s, 1H), 7.44 (dd, J=8.0, 1.9 Hz,
1H), 7.34 (dd, J=8.8, 4.0 Hz, 3H), 6.79 (dd, J=9.2, 2.2 Hz, 1H),
6.57 (d, J=2.0 Hz, 1H), 5.52 (s, 2H), 4.67 (bs, 2H), 4.57 (s, 2H),
3.51 (s, 3H), 3.41-3.36 (m, 2H), 3.00 (s, 3H), 0.74-0.68 (m, 2H),
-0.15--0.21 (m, 9H). MS (ESI-) m/z 588.2 (M-H).sup.-.
Example 234
3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methyl-
sulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-o-
ne
[1294] Example 234 was prepared according to the procedure used for
the preparation of Example 232, substituting
4-(1H-imidazol-1-yl)benzaldehyde for picolinaldehyde and 48 hours
for reaction time instead of 66 hours, to provide the title
compound (8 mg, 11%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.09 (s, 1H), 8.11 (t, J=1.1 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.70
(s, 1H), 7.59 (t, J=1.3 Hz, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.32 (d,
J=1.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.07-7.02 (m, 2H), 6.91-6.80 (m,
3H), 6.50 (s, 1H), 4.44-4.27 (m, 2H), 3.67 (s, 3H), 2.70 (s, 3H).
MS (ESI+) m/z 598 (M+H).sup.+.
Example 235
4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile
[1295] Example 235 was prepared according to the procedure used for
the preparation of Example 232, substituting 4-formylbenzonitrile
for picolinaldehyde and 48 hours for reaction time instead of 66
hours, to provide the title compound (27 mg, 40%). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.13 (s, 1H), 7.71 (d, J=9.8 Hz, 2H),
7.60 (d, J=8.2 Hz, 2H), 7.37-7.26 (m, 3H), 7.23-7.15 (m, 1H), 7.05
(d, J=8.2 Hz, 1H), 6.90-6.78 (m, 3H), 6.54 (s, 1H), 4.45-4.26 (m,
2H), 3.66 (s, 3H), 2.73 (s, 3H). MS (ESI+) m/z 557 (M+H).sup.+.
Example 236
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin--
2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1296] Example 236 was prepared according to the procedure used for
the preparation of Example 232, substituting
3-(pyridin-2-yl)benzaldehyde for picolinaldehyde and 48 hours for
reaction time instead of 66 hours, to provide the title compound
(32 mg, 44%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.07 (d,
J=2.3 Hz, 1H), 8.61-8.56 (m, 1H), 7.85-7.79 (m, 2H), 7.76-7.64 (m,
4H), 7.34 (d, J=2.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.24 (t, J=7.7 Hz,
1H), 7.21-7.13 (m, 2H), 7.03 (dd, J=8.2, 1.9 Hz, 1H), 6.94-6.81 (m,
3H), 6.57 (s, 1H), 4.42-4.25 (m, 2H), 3.67 (s, 3H), 2.64 (s, 3H).
MS (ESI+) m/z 609 (M+H).sup.+.
Example 237
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,-
10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile
[1297] Example 237 was prepared according to the procedure used for
the preparation of Example 232, substituting 3-formylbenzonitrile
for picolinaldehyde and 48 hours for reaction time instead of 66
hours, to provide the title compound (20 mg, 30%). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.13 (s, 1H), 7.73 (d, J=1.8 Hz, 1H),
7.71 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.31
(m, 2H), 7.22-7.13 (m, 1H), 7.06 (dd, J=8.2, 1.9 Hz, 1H), 6.93-6.80
(m, 3H), 6.53 (s, 1H), 4.46-4.27 (m, 2H), 3.66 (s, 3H), 2.72 (s,
3H). MS (ESI+) m/z 557 (M+H).sup.+.
Example 238
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyrid-
in-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H-
)-one
Example 238a
1-(2,2-dimethoxyethyl)pyridin-2(1H)-one
[1298] A 20 mL microwave tube was charged with 2-hydroxypyridine
(0.220 g, 2.313 mmol), cesium carbonate (1.507 g, 4.63 mmol) and
acetonitrile (11.57 mL) to give a white suspension.
Bromoacetaldehyde dimethyl acetal (1.362 mL, 11.57 mmol) was added.
The tube was sealed, and the reaction mixture was heated in a
Biotage Creator at 120.degree. C. for 30 minutes fixed hold time.
The reaction mixture was 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 reaction mixture was purified by flash
chromatography (0-5% methanol:dichloromethane) to provide the title
compound (0.210 g, 50% yield).
Example 238b
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyrid-
in-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1
OH)-one
[1299] Example 238b was prepared according to the procedure used
for the preparation of Example 82, substituting Example 238a for
methyl 4-oxobutanoate, to provide the title compound as a white
solid (0.0884 g, 55% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.88-11.93 (m, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.74 (s, 1H),
7.72-7.63 (m, 1H), 7.43 (ddd, J=8.9, 6.7, 2.1 Hz, 1H), 7.21 (dd,
J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m, 2H), 6.67 (d,
J=2.6 Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 6.00 (td, J=6.6, 1.4 Hz,
1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.54-4.36 (m, 3H), 3.66 (s, 3H),
3.54-3.44 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.0
(M+H).sup.+.
Example 239
ethyl
4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfon-
yl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-
e-3-carboxylate
Example 239a
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methy-
l-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic Acid
[1300] A suspension of Example 208g (450 mg, 0.672 mmol) in 6 mL
tetrahydrofuran was treated with 2N aqueous sodium hydroxide (2016
.mu.L, 4.03 mmol) and heated at 70.degree. C. for 2 hours.
Additional 2N sodium hydroxide (2016 .mu.L, 4.03 mmol) and 3 mL
ethanol were added. The mixture was heated at 70.degree. C. for
another 4 hours. The reaction mixture was concentrated. The residue
was taken into water (10 mL), adjusted to pH 2 and the precipitate
was collected via filtration to give the title compound, which was
used without further purification.
Example 239b
4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-N-ethyl-
-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1301] A solution of Example 239a (270 mg, 0.554 mmol) in 4 mL
dichloromethane was treated at 0.degree. C. with 2 drops of
dimethylformamide and oxalyl dichloride (242 .mu.L, 2.77 mmol). The
mixture was stirred at ambient temperature for 3 hours and then
concentrated. The residue was taken into 2 mL tetrahydrofuran and
treated with ethylamine (2769 .mu.L, 5.54 mmol, 2.0 M solution in
tetrahydrofuran) at 0.degree. C. The mixture was then stirred
overnight. Water was added. The mixture was extracted with ethyl
acetate (3.times.) and partitioned. The combined organic layers
were washed with water (2.times.) and saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by column chromatography
(silica gel, 0-8% methanol/dichloromethane gradient) to give the
title compound (86 mg, 0.167 mmol, 30% yield)
Example 239c
ethyl
4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfon-
yl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-
e-3-carboxylate
[1302] To a suspension of Example 239b (77 mg, 0.150 mmol) and
ethyl 2-oxoacetate (148 .mu.L, 0.748 mmol, 50% solution in toluene)
in tetrahydrofuran (2 mL) at ambient temperature was added
titanium(IV) chloride (1048 .mu.L, 1.048 mmol, 1.0 M solution in
toluene) The mixture was stirred at ambient temperature under
nitrogen for 40 hours. The reaction mixture was partitioned between
water and ethyl acetate. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium bicarbonate and saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, and filtered. The filtrate
was concentrated and the residue was purified by column
chromatography (silica gel, 0-8% methanol/dichloromethane gradient)
to give the title compound (46 mg, 0.077 mmol, 51% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.33 (s, 1H), 8.41-8.21 (m,
1H), 7.76 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.64 (td, J=9.4, 5.9 Hz,
1H), 7.20 (dd, J=8.3, 1.9 Hz, 1H), 7.17-7.04 (m, 2H), 6.84 (d,
J=8.2 Hz, 1H), 6.78 (s, 1H), 4.49 (d, J=13.7 Hz, 1H), 4.39 (d,
J=13.7 Hz, 1H), 3.94 (ddd, J=14.3, 9.0, 5.4 Hz, 1H), 3.85 (dq,
J=10.9, 7.1 Hz, 1H), 3.69 (s, 3H), 3.26 (td, J=7.2, 3.7 Hz, 2H),
2.87 (s, 3H), 1.13 (t, J=7.3 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H). MS
(ESI+) m/z 599.0 (M+H).sup.+.
Example 240
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide
Example 240a
methyl
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo--
3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylate
[1303] Example 206d (20 mg, 0.037 mmol) in methanol (20 mL) was
added to
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.369
mg, 1.871 .mu.mol) and triethylamine (10.43 .mu.L, 0.075 mmol) in a
50 mL pressure bottle. The mixture was pressurized with carbon
monoxide (60 psi), and stirred 32 hours at 100.degree. C. The
solvent was removed. The reaction mixture was purified by flash
chromatography (0-5% methanol:dichloromethane) to provide a white
solid.
Example 240b
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylic
Acid
[1304] A 250 mL round-bottomed flask was charged with Example 240a
(0.108 g, 0.210 mmol), lithium hydroxide (0.050 g, 2.103 mmol),
tetrahydrofuran (3.00 mL), methanol (1.00 mL) and water (1.00 mL)
to give a colorless solution. The reaction mixture was stirred at
ambient temperature for 120 hours. The reaction mixture was
quenched with 1N HCl. The reaction mixture was filtered, and the
solid was rinsed with water and dried in a 60.degree. C. vacuum
oven overnight to provide the title compound as a tan solid (0.0695
g, 66% yield).
Example 240c
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonyl
chloride
[1305] A 25 mL round-bottomed flask was charged with Example 204b
(0.0695 g, 0.139 mmol) and dichloromethane (1.391 mL) to give a tan
suspension. Oxalyl dichloride (0.018 mL, 0.209 mmol) and
N,N-dimethylformamide (1.077 .mu.L, 0.014 mmol) were added. The
reaction mixture was stirred at ambient temperature for 45 minutes.
The solvent was removed, dichloromethane and toluene were added,
and the solvent was evaporated. This was repeated 3.times. to
provide a tan solid.
Example 240d
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide
[1306] A 25 mL round-bottomed flask was charged with Example 240c
(0.024 g, 0.046 mmol) and dichloromethane (0.463 mL) to give a tan
solution. Ammonium hydroxide (0.027 mL, 0.695 mmol) was added, and
the reaction mixture was stirred at ambient temperature for 2
hours. The reaction mixture was partitioned between dichloromethane
and saturated aqueous sodium chloride. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
reaction mixture was purified by reverse phase HPLC (Phenomenex
Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (30 mm.times.75 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0
min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min
linear gradient 95-10% A). Samples were injected in 1.5 mL
DMSO:methanol (1:1)) to provide a white solid (0.0010 g, 4% yield).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.83 (s, 1H), 7.91 (m,
1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.40 (m, 1H), 7.36 (s, 1H), 7.20
(m, 1H), 6.92 (m, 1H), 6.61 (t, J=7.4 Hz, 1H), 6.30 (dd, J=15.9,
9.4 Hz, 1H), 5.09 (d, J=16.7 Hz, 1H), 4.56 (m, 3H), 3.60 (s, 6H),
3.01 (s, 6H). MS (ESI+) m/z 499.1 (M+H).sup.+.
Example 241
4-(2,4-difluorophenyl)-N,
10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4-
,10-triazadibenzo[cd,f]azulene-5-carboxamide
[1307] Example 241 was prepared according to the procedure used for
the preparation of Example 240d, substituting methylamine for
ammonium hydroxide, to provide the title compound as a white solid
(0.0091 g, 38% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.83 (m, 1H), 7.96 (q, J=4.6 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.73
(s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 6.93 (m,
1H), 6.64 (td, J=8.6, 3.0 Hz, 1H), 6.38 (td, J=9.6, 5.8 Hz, 1H),
5.01 (m, 1H), 4.55 (m, 3H), 3.61 (s, 3H), 2.99 (s, 3H), 2.62 (d,
J=4.6 Hz, 3H). MS (ESI+) m/z 513.1 (M+H).sup.+.
Example 242
4-(2,4-difluorophenyl)-N,N,
10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,-
4,10-triazadibenzo[cd,f]azulene-5-carboxamide
[1308] Example 242 was prepared according to the procedure used for
the preparation of Example 240d, substituting N,N-dimethylamine for
ammonium hydroxide, to provide the title compound as a white solid
(0.0076 g, 31% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.82 (s, 1H), 7.93 (d, J=5.9 Hz, 1H), 7.75 (d, J=15.6 Hz, 1H),
7.18 (t, J=3.5 Hz, 1H), 7.21-7.11 (m, 2H), 7.11-6.92 (m, 1H), 6.72
(s, 1H), 6.58 (s, 1H), 6.31 (s, 1H), 4.93 (dd, J=16.1, 10.8 Hz,
1H), 4.66-4.42 (m, 2H), 4.34 (d, J=16.5 Hz, 1H), 3.63 (s, 4H), 2.98
(s, 3H), 2.88 (s, 3H), 2.72 (s, 2H), 2.22 (s, 2H). MS (ESI+) m/z
527.0 (M+H).sup.+.
Example 243
N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10--
triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide
[1309] A mixture of Example 212 (0.062 g, 0.079 mmol) in
dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine
(0.062 mL, 0.356 mmol) and acetyl chloride (0.0062 g, 0.079 mmol)
at ambient temperature under argon. The reaction mixture was
stirred at ambient temperature for 2 hours and then partitioned
between aqueous ammonium chloride solution and ethyl acetate. The
aqueous layer was extracted 4 times with additional ethyl acetate
and then extracted three times with dichloromethane. The combined
organic layers were dried over anhydrous magnesium sulfate,
filtered, and concentrated to afford the title compound (0.017 g,
0.035 mmol, 45% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.48 (s, 1H), 7.70 (s, 1H), 7.52-7.46 (m, 1H), 7.40-7.15 (m, 3H),
7.12 (s, 1H), 4.45-4.38 (m, 2H), 4.22 (s, 2H), 3.68-3.54 (m, 3.5H),
3.44-3.35 (m, 0.5H), 3.17-3.09 (m, 0.5H), 2.90-2.88 (m, 3H),
2.83-2.79 (m, 0.5H), 1.81-1.44 (m, 5H), 1.30 (m, 4H), 1.06-0.86 (m,
2H). MS (ESI+) m/z 483.1 (M+H).sup.+.
Example 244
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
Example 244a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1310] A suspension of Example 5d (200 mg, 0.412 mmol),
3-bromopyridine (65.1 mg, 0.412 mmol), cesium carbonate (335 mg,
1.030 mmol), and
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-phos)
(39.3 mg, 0.082 mmol) in toluene (4 mL) and tert-butanol (1 mL) was
purged with nitrogen and then heated in Biotage Initiator microwave
oven at 150.degree. C. for 45 minutes. Water was added. The mixture
was extracted with ethyl acetate (3.times.). The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, and filtered. The filtrate was
concentrated and the residue was purified by column chromatography
(silica gel, 0-8% methanol/dichloromethane gradient) to give the
title compound (74 mg, 0.132 mmol, 31.9% yield).
Example 244b
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1H-pyr-
rolo[2,3-c]pyridin-7(6H)-one
[1311] Example 244a (55 mg, 0.098 mmol) and lithium hydroxide
monohydrate (20.51 mg, 0.489 mmol) in dioxane (1.5 mL) and water
(0.5 mL) was stirred at 60.degree. C. for 6 hours. The mixture was
partitioned between water and ethyl acetate. The aqueous layer was
extracted with ethyl acetate (3.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 column chromatography (silica gel, 0-8%
methanol/dichloromethane gradient) to give the title compound (33
mg, 0.081 mmol, 83% yield) as an off-white solid.
Example 244c
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,1-
0-triazadibenzo[cd,f]azulen-11(10H)-one
[1312] A suspension of Example 244b (27 mg, 0.066 mmol) and
paraformaldehyde (19.85 mg, 0.661 mmol) in acetic acid (1 mL) was
stirred at 75.degree. C. for 1.5 hours. Acetic acid was evaporated
under reduced pressure and the residue was taken into
dichloromethane and washed with 1N NaOH solution. The aqueous phase
was back extracted with dichloromethane. The combined organic
phases were dried over anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated and the residue was purified by
column chromatography (silica gel, 0-8% methanol/dichloromethane
gradient) to give the title compound (15 mg, 0.036 mmol, 54.0%
yield) as a white solid. 1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.88 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.78 (d, J=2.9 Hz, 1H), 7.73
(dd, J=4.5, 1.1 Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.0, 1.8 Hz,
1H), 7.38 (d, J=8.0 Hz, 2H), 6.97 (dd, J=8.5, 4.5 Hz, 1H),
6.82-6.76 (m, 1H), 5.24 (d, J=14.3 Hz, 1H), 4.52 (dd, J=60.4, 26.1
Hz, 3H), 3.55 (s, 3H), 3.01 (s, 3H). MS ESI (+) 421.1
(M+H).sup.+.
Example 245
4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 245a
4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-met-
hyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1313] Example 245a was prepared according to the procedure used
for the preparation of Example 244a, substituting
2-bromo-5-chloropyridine for 3-bromopyridine to provide the title
compound
Example 245b
4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1314] Example 245b was prepared according to the procedure used
for the preparation of Example 244b, substituting example 245a for
example 244a to provide the title compound
Example 245c
4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1315] Example 245c was prepared according to the procedure used
for the preparation of Example 244c, substituting example 245b for
example 244b to provide the title compound. 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 16.38-16.29 (m, 1H), 11.86 (s, 1H), 7.95 (d,
J=25.9 Hz, 2H), 7.64 (s, 1H), 7.49-7.27 (m, 4H), 6.19 (d, J=8.3 Hz,
1H), 5.69 (d, J=15.8 Hz, 1H), 4.62 (d, J=13.5 Hz, 1H), 4.51 (d,
J=13.5 Hz, 1H), 4.29 (d, J=15.6 Hz, 1H), 3.58 (s, 3H), 3.01 (s,
3H). MS (ESI+) m/z 455.1.
Example 246
4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,-
4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1316] A mixture of Example 233d (0.058 g, 0.098 mmol) in dioxane
(2 mL) at ambient temperature under argon was treated with excess
4N HCl in dioxane (7 mL). The reaction mixture was stirred at
ambient temperature for 16 hours and then quenched with the slow
addition of saturated sodium bicarbonate solution until pH=8. The
mixture was partitioned between aqueous sodium bicarbonate solution
and ethyl acetate. The aqueous layer was extracted with additional
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
reverse phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100%
gradient) to afford the title compound as the trifluoroacetate salt
(0.024 g, 0.042 mmol, 43% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.79 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H),
7.59 (s, 1H), 7.39 (dd, J=40.3, 7.9 Hz, 3H), 7.18 (d, J=9.0 Hz,
1H), 6.72 (d, J=9.1 Hz, 1H), 6.62 (s, 1H), 4.72 (s, 2H), 4.57 (s,
2H), 3.53 (s, 3H), 3.50 (bs, 1H), 3.01 (s, 3H). MS (ESI+) m/z 460.1
(M+H).sup.+.
Example 247
4-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triaza-
dibenzo[cd,f]azulen-11(10H)-one
[1317] A mixture of Example 5f (0.0515 g, 0.150 mmol) and
benzaldehyde (0.0318 g, 0.300 mmol) in dichloromethane (6 mL) was
treated with acetic acid (0.086 mL, 1.500 mmol). The reaction
mixture was stirred at 60.degree. C. for 1 hour then cooled to
0.degree. C. (ice bath) and treated with sodium
triacetoxyborohydride (0.0669 g, 0.300 mmol). The reaction mixture
was removed from 0.degree. C. ice bath and stirred at ambient
temperature for 16 hours. The reaction mixture was quenched by the
slow addition of saturated sodium bicarbonate solution and then
extracted twice with dichloromethane. The combined organic layers
were washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by recrystallization from methanol and
dimethylsulfoxide to afford the title compound (0.0145 g, 0.033
mmol, 22% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.80
(s, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.56 (s, 1H), 7.27-7.16 (m, 7H),
6.99 (d, J=2.2 Hz, 1H), 4.43 (s, 2H), 4.25 (s, 2H), 4.05 (s, 2H),
3.65 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 434.1 (M+H).sup.+.
Example 248
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 248a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-5-ylamino)phenyl)-1H-p-
yrrolo[2,3-c]pyridin-7(6H)-one
[1318] A mixture of Example 5d (0.300 g, 0.618 mmol),
5-iodopyrimidine (0.382 g, 1.853 mmol), cesium carbonate (0.403 g,
1.236 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(XPhos) (0.147 g, 0.309 mmol), and palladium (II) acetate (0.035 g,
0.154 mmol) in toluene (12 mL) and tert-butanol (3 mL) under argon
was heated in a sealed tube in a microwave reactor at 160.degree.
C. for 1 hour. The reaction mixture was cooled to ambient
temperature and filtered through filter paper. The resulting
filtrate was concentrated to near dryness and mixed with ethanol
(10 mL), dioxane (20 mL), and excess 5N sodium hydroxide solution
(10 mL). The reaction mixture was stirred at ambient temperature
for 1 hour and then concentrated to 5 mL and partitioned between
saturated ammonium chloride aqueous solution and ethyl acetate. The
aqueous phase was extracted once more 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 column
chromatography on silica gel eluting with 5% methanol in
dichloromethane to afford the title compound (0.066 g, 0.161 mmol,
26% yield).
Example 248b
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1319] A mixture of Example 248a (0.040 g, 0.098 mmol) and
paraformaldehyde (0.015 g, 0.488 mmol) in acetic acid (10 mL) under
argon was stirred at 75.degree. C. for 2 hours. The reaction
mixture was concentrated to a semi-solid and purified by reverse
phase HPLC (C18, CH.sub.3CN/water (0.1% TFA), 0-100% gradient) and
dried under vacuum to afford the title compound (0.0065 g, 0.015
mmol, 15% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.59
(s, 1H), 8.31 (s, 1H), 7.95 (s, 3H), 7.59 (s, 1H), 7.51-7.46 (m,
1H), 7.40-7.35 (m, 2H), 4.87 (s, 2H), 4.54 (s, 2H), 3.56 (s, 3H),
2.96 (s, 3H). MS (ESI+) m/z 422.1 (M+H).sup.+.
Example 249
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-
-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1320] A mixture of Example 5f (208 mg, 0.606 mmol),
picolinaldehyde (0.116 mL, 1.211 mmol) and acetic acid (0.347 mL,
6.06 mmol) in dichloromethane (12 mL) was heated under reflux, for
2 hours. The reaction mixture was cooled to ice/water bath
temperature for 15 minutes and then sodium triaceteoxyborohydride
(297 mg, 1.333 mmol) was added to the reaction mixture under argon.
The mixture was stirred at 0.degree. C. for 15 minutes, allowed to
warm slowly to ambient temperature over 2 hours, and then stirred
at ambient temperature for 16 hours. The pH of the mixture was
adjusted to pH=6-7 by the addition of saturated aqueous bicarbonate
solution, and the mixture was then extracted with dichloromethane.
The organic layers were combined, dried over anhydrous magnesium
sulfate, filter, and concentrated. The residue was triturated with
methanol and dimethylsulfoxide, and the resulting solid was
collected and dried to provide the title compound (108 mg, 41%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.80 (bs, 1H),
8.46 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.64
(td, J=7.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.29-7.15 (m, 4H), 7.03 (d,
J=2.5 Hz, 1H), 4.45-4.39 (m, 4H), 4.13 (s, 2H), 3.65 (s, 3H), 2.92
(s, 3H). (ESI+) m/z 435.1 (M+H).sup.+.
Example 250
10-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1321] Example 250 was prepared according to the procedure used for
the preparation of Example 249, substituting
pyridazine-3-carbaldehyde for picolinaldehyde to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.82 (bs,
1H), 9.08 (dd, J=4.7, 1.8 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H),
7.62-7.51 (m, 3H), 7.30-7.19 (m, 2H), 7.03 (d, J=2.6 Hz, 1H), 4.56
(s, 2H), 4.43 (s, 2H), 4.15 (s, 2H), 3.65 (s, 3H), 2.92 (s, 3H).
(ESI+) m/z 436.4 (M+H).sup.+.
Example 251
(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxop-
yridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11-
(1 OH)-one
[1322] Preparatory chiral SFC separation of the product from
Example 238 (0.0204 g) on a WHELK-O S.S column. (21.times.250 mm, 5
micron column, eluting with 30% methanol in supercritical CO.sub.2
at 70 mL/min for 20 minutes) afforded the title compound as the
first eluted peak. The stereochemistry was randomly assigned to
this first eluted peak (8.6 mg, 84% recovery). 1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.90 (bs, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.74
(s, 1H), 7.64-7.72 (m, 1H), 7.43 (ddd, J=8.9, 6.7, 2.1 Hz, 1H),
7.21 (dd, J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m, 2H),
6.67 (s, 1H), 6.46 (dd, J=9.1, 1.3 Hz, 1H), 6.00 (td, J=6.6, 1.4
Hz, 1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.37-4.55 (m, 3H), 3.66 (s,
3H), 3.44-3.54 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.1
(M+H)+.
Example 252
(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxop-
yridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11-
(1 OH)-one
[1323] Preparatory chiral SFC separation of the product from
Example 238 (0.0204 g) on a WHELK-O S.S column. (21.times.250 mm, 5
micron column, eluting with 30% methanol in supercritical CO.sub.2
at 70 mL/min for 20 minutes) afforded the title compound as the
second eluted peak. The stereochemistry was randomly assigned to
this second eluted peak (7.9 mg, 77% recovery). 1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.90 (bs, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.74
(s, 1H), 7.68 (d, J=6.3 Hz, 1H), 7.43 (ddd, J=8.9, 6.7, 2.1 Hz,
1H), 7.21 (dd, J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89 (m,
2H), 6.67 (s, 1H), 6.46 (d, J=9.1 Hz, 1H), 6.00 (td, J=6.6, 1.3 Hz,
1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.36-4.55 (m, 3H), 3.66 (s, 3H),
3.44-3.51 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.1 (M+H)+.
Example 253
10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 253a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl-
)amino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1324] Example 207a (0.16 g, 0.33 mmol),
2-bromo-5-(trifluoromethyl)pyridine (0.112 g, 0.495 mmol),
diacetoxypalladium (0.019 g, 0.083 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.079 g, 0.165 mmol) and cesium carbonate (0.215 g, 0.66 mmol)
were combined in a 20-mL microwave vial and sparged with nitrogen
for 30 minutes. To this were added nitrogen-sparged anhydrous
toluene (2.4 mL) and tert-butanol (0.6 mL). The reaction mixture
was heated at 105.degree. C. overnight, then cooled to ambient
temperature and partitioned between ethyl acetate and water. The
organic layer was washed with brine, 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, 25-100% ethyl acetate in dichloromethane, then 5-15%
methanol in dichloromethane) to give 0.077 g (37%) of the title
compound and 0.0245 g (16%) of Example 253b.
Example 253b
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl-
)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1325] A mixture of Example 253a (0.077 g, 0.122 mmol) in
tetrahydrofuran (1.5 mL) was treated with tetrabutylammonium
fluoride (0.028 g, 0.107 mmol), heated at 50.degree. C. for 50
minutes and then at 60.degree. C. for one hour. It was then stirred
at ambient temperature overnight. Additional tetrabutylammonium
fluoride (0.028 g, 0.107 mmol) was added and heating was continued
at 60.degree. C. for 3 hours. The reaction mixture was concentrated
to dryness, triturated with ethyl acetate and then dried in a
vacuum oven at 70.degree. C. to give 0.054 g (93%) of the title
compound.
Example 253c
10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1 OH)-one
[1326] To a 5-mL microwave vial equipped with a magnetic stirbar
were added Example 253b (0.025 g, 0.052 mmol), paraformaldehyde
(0.006 g, 0.207 mmol), and acetic acid (1.2 mL). The vial was
capped and heated at 75.degree. C. for 45 minutes. Additional
paraformaldehyde (0.006 g, 0.207 mmol) was added and heating was
continued for 1 hour at 75.degree. C. The reaction mixture was then
concentrated. The residue was dissolved in acetonitrile (3 mL) and
water (0.75 mL), treated with sodium acetate (0.043 g, 0.518 mmol)
and heated at 50.degree. C. for 1 hour. The reaction mixture was
cooled to ambient temperature, partitioned between ethyl acetate
and water, washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography (silica gel, 0-8% methanol in dichloromethane)
to give 0.026 g (103%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.91 (s, 1H), 8.33 (s, 1H), 7.95 (s, 1H),
7.67 (s, 1H), 7.62 (d, J=7.63 Hz, 1H), 7.44 (m, 2H), 7.34 (s, 1H),
6.29 (s, 1H), 5.83 (s, 1H), 4.64 (m, 1H), 4.53 (m, 1H), 4.35 (d,
J=14.95 Hz, 1H), 3.58 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z 489.1
(M+H).sup.+.
Example 254
4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 254a
[1327] A mixture of Example 207a (0.146 g, 0.3 mmol),
4-bromo-2-fluoropyridine (0.069 g, 0.390 mmol),
2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.072 g,
0.150 mmol), palladium(II) acetate (0.017 g, 0.075 mmol), and
cesium carbonate (0.244 g, 0.750 mmol) in toluene (3 mL) and
tert-butanol (0.750 mL) was heated at 160.degree. C. for 1 hour.
Two more identical runs were conducted, and the combined reaction
mixtures were partitioned between water and ethyl acetate. The
aqueous layer was extracted with additional 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 100:10:1 ethyl
acetate/methanol/NH.sub.4OH to afford 0.14 g (36%) of the title
compound.
Example 254b
4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro--
1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1328] A mixture of Example 254a (0.13 g, 0.305 mmol) and
paraformaldehyde (0.027 g, 0.914 mmol) in acetic acid (6 mL) was
heated at 75.degree. C. for 4 hours. The solvent was evaporated,
and the residue was purified by reverse phase preparative HPLC
(C18, CH.sub.3CN/water (0.1% trifluoroacetic acid), 0-100%
gradient) to afford the title compound as trifluoroacetic acid salt
(0.085 g, 0.154 mmol, 50.5% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.94 (s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.65
(d, J=17.7 Hz, 2H), 7.55-7.34 (m, 4H), 5.27 (d, J=16.3 Hz, 1H),
4.64 (d, J=13.6 Hz, 1H), 4.60-4.46 (m, 2H), 3.57 (s, 3H), 3.01 (s,
3H). MS (ESI+) m/z 438.9 [M+H].sup.+.
Example 255
10-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)--
3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1329] Example 255 was prepared according to the procedure used for
the preparation of Example 249, substituting
1-methyl-1H-pyrazole-3-carbaldehyde for picolinaldehyde, and the
residue was recrystallized from dichloromethane, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.75
(bs, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.29 (d, J=8.2
Hz, 1H), 7.23 (dd, J=8.2, 2.0 Hz, 1H), 7.15-6.97 (m, 1H), 5.96 (d,
J=2.1 Hz, 1H), 4.43 (bs, 2H), 4.23-4.04 (m, 4H), 3.75 (s, 2H), 3.63
(s, 3H), 2.92 (s, 3H). (ESI+) m/z 438.1 (M+H).sup.+.
Example 256
4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 256a
4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-me-
thyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1330] Example 207a (0.243 g, 0.5 mmol), 2-bromo-6-methoxypyridine
(0.188 g, 1 mmol), diacetoxypalladium (0.028 g, 0.125 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were
combined in a 5-mL microwave vial. Anhydrous toluene (4 mL) and
tert-butanol (1 mL) were added. The vial was capped and the mixture
was heated at 160.degree. C. for 1 hour in a Biotage microwave
reactor. The reaction mixture was filtered through a fritted funnel
to remove the palladium solids. The filtrate 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, 0-100% ethyl acetate in
dichloromethane, then 5-10% methanol in ethyl acetate) to give 0.15
g (51%) of the title compound and 0.08 g (37%) of Example 256b.
Example 256b
4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1331] A mixture of Example 256a (0.122 g, 0.206 mmol) and
tetrabutylammonium fluoride (0.108 g, 0.412 mmol) in
tetrahydrofuran (3.5 mL) was heated at 60.degree. C. for 50 minutes
and then concentrated. The residue was purified by flash
chromatography (silica gel, 0-20% methanol in dichloromethane) and
trituration in dichloromethane to give 0.077 g (71%) of the title
compound. A portion of this material was then combined with a
portion of the deprotected material obtained in Example 256a (0.133
g total) and purified by reverse phase HPLC (C18,
acetonitrile/water (0.1% trifluoroacetic acid), 5-70%) to provide
0.071 g (43% recovery) of the title compound as the trifluoroacetic
acid salt.
Example 256c
4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-
-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1332] A mixture of Example 256b (0.043 g, 0.077 mmol) and
paraformaldehyde (0.005 g, 0.155 mmol) were combined in a 5-mL
microwave vial. The vial was capped and the mixture was sparged
with nitrogen for 30 minutes. To this was added nitrogen-sparged
acetic acid (3 mL). The resulting mixture was stirred at ambient
temperature for 4 hours. The reaction mixture was then quenched
with methanol and concentrated to dryness keeping the bath
temperature below 30.degree. C. The residue was purified by reverse
phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid),
5-75%) to provide 0.019 g (43%) of the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.85 (d, J=1.83 Hz, 1H), 7.93 (d, J=1.53 Hz, 1H), 7.64 (s,
1H), 7.44 (m, 1H), 7.39 (m, 1H), 7.31 (d, J=2.44 Hz, 1H), 7.17 (t,
J=7.93 Hz, 1H), 5.90 (d, J=7.63 Hz, 1H), 5.78 (d, J=15.56 Hz, 1H),
5.58 (d, J=7.93 Hz, 1H), 4.62 (m, 1H), 4.52 (m, 1H), 4.22 (d,
J=15.26 Hz, 1H), 3.74 (s, 3H), 3.58 (s, 3H), 2.99 (m, 3H). MS
(ESI+) m/z 451.1 (M+H).sup.+.
Example 257
4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 257a
4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)ph-
enyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1333] A mixture of Example 5d (77 mg, 0.159 mmol) and
2,2-dimethyl-3-morpholinopropanal (0.056 mL, 0.317 mmol) was
stirred in dichloromethane (5 mL). To this mixture was added acetic
acid (0.045 mL, 0.793 mmol). The resulting partial suspension was
heated under reflux for 1.5 hour. The reaction mixture was cooled
in an ice/water bath for 15 minutes and then sodium
triacetoxyborohydride (106 mg, 0.476 mmol) was added to the mixture
under argon. The mixture was stirred at 0.degree. C. for 15 minutes
and then allowed to warm slowly to ambient temperature over 1 hour.
The mixture was then stirred at ambient temperature for 16 hours.
Saturated aqueous sodium bicarbonate solution was added followed by
addition of saturated aqueous ammonium chloride and water. The
mixture was extracted with dichloromethane and the layers
separated. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated to provide the title
compound.
Example 257b
4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)ph-
enyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1334] Example 257a (130 mg, 0.203 mmol) was dissolved in dioxane
(8 mL) and ethanol (4 mL). To this mixture was added 5N aqueous
sodium hydroxide solution (5 mL) and the mixture was stirred at
ambient temperature for 4 hours. The mixture was concentrated to
approximately 1/3 of the volume and then partitioned between
saturated aqueous ammonium chloride and ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was triturated with a mixture of ethyl
ether and ethyl acetate, filtered, and dried, to provide the title
compound.
Example 257c
4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3-
,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1335] A mixture of Example 257b (38 mg, 0.077 mmol) and
paraformaldehyde (12.5 mg, 0.411 mmol) in tetrahydrofuran (10 mL)
was stirred at ambient temperature. To resulting suspension was
added 1M solution of titanium tetrachloride (0.82 mL). The reaction
mixture was stirred for 24 hours at ambient temperature and then
added to a mixture of saturated aqueous sodium bicarbonate and
ethyl acetate. The organic layer was separated and the aqueous
layer 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, 2% methanol/dichloromethane) to provide the title
compound (10.8 mg, 28% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.75 (bs, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.51 (s, 1H), 7.38
(d, J=8.2 Hz, 1H), 7.24 (dd, J=8.2, 2.0 Hz, 1H), 7.10 (d, J=2.5 Hz,
1H), 4.42 (s, 2H), 4.13 (s, 2H), 3.63 (s, 3H), 3.37 (m, 4H), 2.91
(s, 3H), 2.13 (bs, 4H), 1.88 (bs, 2H), 0.63 (s, 6H). (ESI+) m/z
499.2 (M+H).sup.+.
Example 258
4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 258a
4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-m-
ethyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1336] Example 207a (0.243 g, 0.5 mmol), 2-bromo-5-fluoropyrimidine
(0.177 g, 1 mmol), diacetoxypalladium (0.028 g, 0.125 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were
combined in a 5-mL microwave vial and sparged with nitrogen for 30
minutes. A nitrogen-sparged solution of anhydrous toluene (3.2 mL)
and tert-butanol (0.8 mL) was added. The reaction mixture was
heated at 110.degree. C. for 3 hours, cooled to ambient
temperature, and filtered through a fritted funnel to remove the
palladium solids. The filtrate 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 triturated with methanol,
filtered, and dried in a vacuum oven at 70.degree. C. to give 0.215
(74%) of the title compound.
Example 258b
4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-m-
ethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1337] A mixture of Example 258a (0.215 g, 0.37 mmol) in
tetrahydrofuran (15 mL) was treated with tetrabutylammonium
fluoride (0.145 g, 0.554 mmol) and stirred at 60.degree. C. for 1
hour and 40 minutes. The reaction mixture was cooled to ambient
temperature and concentrated. The concentrate was slurried in
dichloromethane and the solid was collected by filtration and dried
in a vacuum oven at 70.degree. C. to give 0.068 g (43%) of the
title compound.
Example 258c
4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydr-
o-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1338] A mixture of Example 258b (0.059 g, 0.137 mmol) and
paraformaldehyde (0.016 g, 0.548 mmol) were combined in a 5-mL
microwave vial. The vial was capped and sparged with nitrogen for
30 minutes. Nitrogen-sparged acetic acid (5 mL) was added and the
mixture was heated at 75.degree. C. for 3 hours and 40 minutes. The
reaction mixture was concentrated to dryness, slurried in water and
treated with sodium acetate until basic. The resulting mixture was
heated at 50.degree. C. for 2 hours and then cooled to ambient
temperature. The solid was collected by filtration, rinsed with 300
mL of water and dried in a vacuum oven at 70.degree. C. overnight.
The solid was then slurried in ethyl acetate, stirred for 1 hour
and filtered. To this solid (0.04 g, 0.091 mmol) in methanol (0.25
mL) was added hydrogen chloride solution (4 M in 1,4-dioxane) (0.3
mL, 1 mmol). The resulting mixture was stirred at ambient
temperature for 30 minutes. The solid was collected by filtration
and dried in a vacuum oven at 70.degree. C. to give 0.0354 (54%) of
the title compound as the HCl salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.87 (d, J=2.14 Hz, 1H), 8.31 (s, 2H), 7.83
(d, J=1.53 Hz, 1H), 7.60 (s, 1H), 7.37 (m, 2H), 7.30 (d, J=2.44 Hz,
1H), 5.70 (d, J=15.56 Hz, 1H), 4.60 (m, 1H), 4.49 (m, 1H), 4.34 (d,
J=15.56 Hz, 1H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 440.1
(M+H).sup.+.
Example 259
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 259a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1-to-
syl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1339] Example 207a (0.243 g, 0.5 mmol), 4-bromopyrimidine (0.159
g, 1 mmol), diacetoxypalladium (0.028 g, 0.125 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.12 g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were
combined in a 5-mL microwave vial and sparged with nitrogen for 30
minutes. A nitrogen-sparged solution of anhydrous toluene (3.2 mL)
and tert-butanol (0.8 mL) was added. The reaction mixture was
heated at 110.degree. C. for 16.5 hours, cooled to ambient
temperature and filtered through a fritted funnel to remove the
palladium solids. The filtrate 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, 20 to 100% of a 3:1 mixture of ethyl
acetate/ethanol in heptanes) to provide an impure mixture. The
material was subjected to a second flash chromatography (silica
gel, 45 to 50% of a 3:1 mixture of ethyl acetate/ethanol in
heptanes) to provide 0.042 g (15%) of the title compound.
Example 259b
6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1H-p-
yrrolo[2,3-c]pyridin-7(6H)-one
[1340] A mixture of Example 259a (0.042 g, 0.075 mmol) in
tetrahydrofuran (2 mL) was treated with tetrabutylammonium fluoride
(0.02 g, 0.075 mmol) and heated at 60.degree. C. for 45 minutes.
Additional tetrabutylammonium fluoride (0.02 g, 0.075 mmol) was
added and heating was continued for another 1.25 hours. The
reaction mixture was cooled to ambient temperature, concentrated,
and slurried in ethyl acetate. The solid was collected by
filtration and then purified by reverse phase HPLC (C18,
acetonitrile/water (0.1% trifluoroacetic acid), 5-70%) to provide
0.039 g (99%) of the title compound.
Example 259c
10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4-
,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1341] To a 5-mL microwave vial equipped with a magnetic stirbar
were added Example 259b (0.039 g, 0.075 mmol), paraformaldehyde
(0.011 g, 0.375 mmol) and acetic acid (1.3 mL). The vial was capped
and heated at 75.degree. C. for 40 minutes. The reaction mixture
was concentrated. The residue was dissolved in acetonitrile (3 mL)
and water (0.75 mL) and treated with sodium acetate until basic.
The resulting mixture was heated at 50.degree. C. for one hour and
then cooled to ambient temperature. 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 reverse
phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid),
10-60%) to provide 0.004 g (9%) of the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.87 (d, J=0.61 Hz, 1H), 8.24 (m, 2H), 7.82 (s, 1H), 7.60
(s, 1H), 7.35 (m, 3H), 6.60 (t, J=4.73 Hz, 1H), 5.79 (d, J=15.56
Hz, 1H), 4.60 (m, 1H), 4.49 (d, J=13.43 Hz, 1H), 4.30 (d, J=15.26
Hz, 1H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 422.1
(M+H).sup.+.
Example 260
4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 260a
4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl-
)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1342] A mixture of Example 5d (106 mg, 0.218 mmol) and
2-(3-(dimethylamino)propoxy)benzaldehyde (0.067 mL, 0.314 mmol) was
stirred in dichloroethane (5 mL). To this mixture was added acetic
acid (0.062 mL, 1.091 mmol). The resulting partial suspension was
heated under reflux for 1.5 hour. The reaction mixture was cooled
in an ice/water bath for 15 minutes and then sodium
triacetoxyborohydride (146 mg, 0.655 mmol) was added to the mixture
under argon. The mixture was stirred at 0.degree. C. for 15 minutes
and then allowed to warm slowly to ambient temperature over 1 hour.
The mixture was then stirred at ambient temperature for 16 hours.
Saturated aqueous sodium bicarbonate solution was added followed by
saturated aqueous sodium carbonate and water. The mixture was
extracted with dichloromethane and the layers separated. The
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue was purified by flash chromatography
(silica gel, 4-10% methanol in dichloromethane) to provide the
title compound.
Example 260b
4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl-
)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1343] Example 260a (101 mg, 0.149 mmol) was dissolved in dioxane
(5 mL). To this mixture was added 5N aqueous sodium hydroxide
solution (5 mL) and the mixture was stirred at 80.degree. C. for 4
hours. The mixture was partitioned between saturated aqueous
ammonium chloride and ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 10%
methanol in dichloromethane) to provide the title compound.
Example 260c
4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl-
)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1344] A mixture of Example 260b (43 mg, 0.082 mmol) and
paraformaldehyde (10 mg, 0.329 mmol) in tetrahydrofuran (10 mL) was
stirred at ambient temperature. To resulting suspension was added
1M solution of titanium tetrachloride (0.66 mL). The reaction
mixture was stirred for 24 hours at ambient temperature and then
added to a mixture of saturated aqueous sodium bicarbonate and
ethyl acetate. The organic layer was separated and the aqueous
layer 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,
CH.sub.3CN/water (0.1% trifluoroacetic acid), 0-100% gradient) to
afford the title compound (16.5 mg, 38%) as the trifluoroacetic
acid salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.83 (s,
1H), 9.41 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.25-7.15 (m, 3H),
7.11 (d, J=7.3 Hz, 1H), 7.06 (d, J=2.7 Hz, 1H), 6.95 (d, J=8.2 Hz,
1H), 6.83 (t, J=7.4 Hz, 1H), 4.44 (s, 2H), 4.25 (s, 2H), 4.12 (s,
2H), 4.00 (t, J=5.9 Hz, 2H), 3.57 (s, 3H), 3.16 (dt, J=9.7, 5.3 Hz,
2H), 2.94 (s, 3H), 2.77 (d, J=4.5 Hz, 6H), 2.05 (dq, J=11.6, 5.9
Hz, 2H). (ESI+) m/z 535.1 (M+H).sup.+.
Example 261
2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-tri-
azadibenzo[cd,f]azulen-4(3H)-yl)-2-phenylacetonitrile
[1345] A mixture of Example 5f (57.7 mg, 0.168 mmol), benzaldehyde
(19.6 mg, 0.185 mmol), and sodium cyanide (9.3 mg, 0.185 mmol) in
methanol (8 mL) was heated to 60.degree. C. over 30 minutes. Acetic
acid (0.481 mL, 8.40 mmol) was added, and the partial suspension
was heated at 60.degree. C. for 18 hours. To the cooled reaction
mixture was added water (10 mL) and the resulting precipitate
collected by filtration. The precipitate was purified by reverse
phase HPLC (C18, CH.sub.3CN/water (0.1% trifluoroacetic acid),
0-100% gradient) to afford the title compound (20 mg, 26%). .sup.1H
NMR (400 MHz, 90.degree. C., DMSO-d.sub.6) .delta. 11.53 (s, 1H),
7.76 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J=12.7 Hz, 7H), 6.93
(d, J=2.7 Hz, 1H), 5.64 (s, 1H), 4.43 (d, J=1.6 Hz, 2H), 4.19 (s,
2H), 3.64 (s, 3H), 2.88 (s, 3H). (ESI+) m/z 459.1 (M+H).sup.+.
Example 262
2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide
Example 262a
2-(2-(((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-y-
l)-4-((methylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide
[1346] A mixture of Example 5d (260 mg, 0.536 mmol) and
2-(2-formylphenoxy)acetamide (80 mg, 0.446 mmol) was stirred in
dichloroethane (7 mL). To this mixture was added acetic acid (0.128
mL, 2.232 mmol). The resulting partial suspension was heated at
80.degree. C. for 2.5 hours. The reaction mixture was cooled in an
ice/water bath for 15 minutes and then sodium triacetoxyborohydride
(299 mg, 1.34 mmol) was added to the mixture under argon. The
mixture was stirred at 0.degree. C. for 15 minutes and then allowed
to warm slowly to ambient temperature over 1 hour. The mixture was
then stirred at ambient temperature for 16 hours. Saturated aqueous
sodium bicarbonate solution was added followed by addition of
water. The mixture was extracted with dichloromethane and the
layers separated. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography (silica gel, 1-3% methanol in
dichloromethane) to provide the title compound.
Example 262b
2-(2-(((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((m-
ethylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide
[1347] Example 262a (170 mg, 0.262 mmol) was dissolved in dioxane
(10 mL). To this mixture was added 5N aqueous sodium hydroxide
solution (3 mL) and the mixture was stirred at 80.degree. C. for 6
hours. The mixture was partitioned between saturated aqueous
ammonium chloride and ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated to
provide the title compound.
Example 262c
2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-
-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide
[1348] A mixture of Example 262b (49 mg, 0.099 mmol) and
paraformaldehyde (12 mg, 0.396 mmol) in tetrahydrofuran (10 mL) was
stirred at ambient temperature. To the resulting suspension was
added a 1M solution of titanium tetrachloride (0.79 mL). The
reaction mixture was stirred for 16 hours at ambient temperature
and then added to a mixture of saturated aqueous sodium bicarbonate
and ethyl acetate. The organic layer was separated and the aqueous
layer 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,
CH.sub.3CN/water (0.1% trifluoroacetic acid), 0-70% gradient) to
afford the title compound (3.4 mg, 7%).sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.51 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H),
7.21 (s, 2H), 7.16 (t, J=7.9 Hz, 1H), 7.12-6.96 (m, 4H), 6.89 (d,
J=8.3 Hz, 1H), 6.81 (t, J=7.4 Hz, 1H), 4.41 (d, J=5.6 Hz, 4H), 4.28
(s, 2H), 4.17 (s, 2H), 3.65 (s, 3H), 2.89 (s, 3H). (ESI+) m/z 507.2
(M+H).sup.+.
Example 263
4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic
Acid
[1349] The preparation of Example 263 was described in Example
209a. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.21 (s, 1H),
12.44 (s, 1H), 7.83 (d, J=1.22 Hz, 1H), 7.71 (s, 1H), 7.28 (dd,
J=8.24, 1.53 Hz, 1H), 7.10 (m, 1H), 7.01 (d, J=7.93 Hz, 1H), 6.88
(td, J=8.54, 2.44 Hz, 1H), 6.82 (td, J=9.23, 5.95 Hz, 1H), 5.09 (s,
2H), 4.49 (s, 2H), 3.63 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 500.1
(M+H).sup.+.
Example 264
10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 264a
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)a-
mino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1350] A mixture of Example 5d (72.4 mg, 0.149 mmol) and
2-(pyridin-2-ylmethoxy)benzaldehyde (0.027 mL, 0.124 mmol) was
stirred in dichloroethane (5 mL). To this mixture was added acetic
acid (0.036 mL, 0.621 mmol). The resulting partial suspension was
heated at 80.degree. C. for 2.5 hour. The reaction mixture was
cooled in an ice/water bath for 15 minutes and then sodium
triacetoxyborohydride (83 mg, 0.373 mmol) was added to the mixture
under argon. The mixture was stirred at 0.degree. C. for 15 minutes
and then allowed to warm slowly to ambient temperature over 1 hour.
The mixture was then stirred at ambient temperature for 18 hours.
Saturated aqueous sodium bicarbonate solution was added followed by
the addition of water. The mixture was extracted with
dichloromethane and the layers separated. The organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was purified by flash chromatography (silica gel, 1-2%
methanol in dichloromethane) to provide the title compound.
Example 264b
6-methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)a-
mino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1351] Example 264a (90 mg, 0.132 mmol) was dissolved in dioxane (8
mL). To this mixture was added 5N aqueous sodium hydroxide solution
(2 mL) and the mixture was stirred at 85.degree. C. for 4 hours.
The mixture was partitioned between saturated aqueous ammonium
chloride and ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated to provide
the title compound.
Example 264c
10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-
-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11 (10H)-one
[1352] A mixture of Example 264b (44 mg, 0.083 mmol) and
paraformaldehyde (10 mg, 0.333 mmol) in tetrahydrofuran (10 mL) was
stirred at ambient temperature. To resulting suspension was added a
1M solution of titanium tetrachloride (0.67 mL). The reaction
mixture was stirred for 7 hours at ambient temperature and then
added to a mixture of saturated aqueous sodium bicarbonate and
ethyl acetate. The organic layer was separated and the aqueous
layer 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,
CH.sub.3CN/water (0.1% trifluoroacetic acid), 0-100% gradient) to
afford the title compound (19.7 mg, 44%).sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.97 (d, J=2.9 Hz, 1H), 8.63 (dd, J=5.0, 1.6
Hz, 1H), 7.88 (td, J=7.7, 1.7 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.59
(s, 1H), 7.50-7.37 (m, 2H), 7.28-7.12 (m, 5H), 7.01 (d, J=8.2 Hz,
1H), 6.87 (t, J=7.5 Hz, 1H), 5.20 (s, 2H), 4.46 (s, 2H), 4.34 (s,
2H), 4.31 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H). (ESI+) m/z 541.1
(M+H).sup.+.
Example 265
(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
Example 265a
(R)-2-bromo-4-(ethylsulfonyl)-N-(1-phenylethyl)aniline
[1353] A mixture of Example 2b (661 mg, 2.476 mmol),
(R)-1-phenylethanamine (526 mg, 4.340 mmol), and
N-ethyl-N-isopropylpropan-2-amine (1.12 mL, 6.420 mmol) in
dimethylsulfoxide (12 mL) was heated at 100.degree. C. for 16
hours. The mixture was cooled to ambient temperature and
partitioned between saturated aqueous ammonium chloride and ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2% ethanol and 6% ethyl acetate
in heptane) to provide the title compound.
Example 265b
(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1-tosyl--
1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1354] A mixture of Example 265a (320 mg, 0.869 mmol), Example if
(558 mg, 1.30 mmol), cesium fluoride (528 mg, 3.480 mmol) and
tetrakis(triphenylphosphine)palladium(O) (100 mg, 0.087 mmol) was
sparged with argon for 15 minutes followed by the addition of a
degassed dimethoxyethane (20 mL) and methanol (10 mL) mixture. The
reaction mixture was heated at 85.degree. C. for 2.5 hours. The
mixture was cooled to ambient temperature and partitioned between
saturated aqueous sodium chloride and ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and
concentrated to provide the title compound.
Example 265c
(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1H-pyrro-
lo[2,3-c]pyridin-7(6H)-one
[1355] Example 265b (170 mg, 0.262 mmol) was dissolved in dioxane
(20 mL). To this mixture was added 5N aqueous sodium hydroxide
solution (5 mL) and the mixture was stirred at 85.degree. C. for 4
hours. The mixture was partitioned between saturated aqueous
ammonium chloride and ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 1-2%
methanol in dichloromethane) to provide the title compound.
Example 265d
(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
[1356] A mixture of Example 265c (140 mg, 0.321 mmol) and
paraformaldehyde (39 mg, 1.286 mmol) in tetrahydrofuran (10 mL) was
stirred at ambient temperature. To resulting suspension was added
1M solution of titanium tetrachloride (2.57 mL). The reaction
mixture was stirred for 4 hours at ambient temperature and then
added to a mixture of saturated aqueous sodium bicarbonate and
ethyl acetate. The organic layer was separated and the aqueous
layer extracted with ethyl acetate. The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by recrystallization from
methanol and dimethysulfoxide to provide the title compound (109
mg, 76%).sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6) .delta.
11.50 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.64 (s, 1H), 7.60 (dd,
J=8.3, 2.2 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.29-7.12 (m, 5H), 6.91
(s, 1H), 4.38 (q, J=6.7 Hz, 1H), 4.23-4.01 (m, 2H), 3.67 (s, 3H),
3.28 (q, J=7.4 Hz, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.16 (t, J=7.3 Hz,
3H). (ESI+) m/z 448.0 (M+H).sup.+.
Example 266
10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,-
5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one
Example 266a
3-bromo-2-chloro-5-(pyrrolidin-1-ylsulfonyl)pyridine
[1357] 5-bromo-6-chloropyridine-3-sulfonyl chloride (4.7 g, 16.2
mmol) in dichloromethane (60 mL) at 0.degree. C. was treated
drop-wise with pyrrolidine (2.7 mL, 32.3 mmol) and stirred for 20
minutes at 0.degree. C. The ice bath was removed and stirring was
continued at ambient temperature for 45 minutes. The reaction
mixture was concentrated, slurried in water and filtered. The solid
was then slurried in diethyl ether and filtered to give 4.66 g
(88%) of the title compound.
Example 266b
[1358] To a mixture of Example 266a (1 g, 3.1 mmol) and
pyridin-2-amine (0.36 g, 3.8 mmol) in dimethyl sulfoxide (10 mL)
was added sodium hydride (0.25 g, 6.2 mmol). The mixture was
stirred at ambient temperature for 1.5 hours and then at 50.degree.
C. for 1 hour. The reaction mixture was cooled to ambient
temperature and water was added to induce precipitation. The solid
was collected by filtration, rinsed with additional water and dried
by pulling air through. The solid was then slurried in diethyl
ether, stirred for 1 hour, and filtered. The diethyl ether filtrate
was concentrated. Both the solid as well as the residue from the
concentration were purified individually by flash chromatography
(silica gel, 5 to 60% ethyl acetate in heptanes) and then combined
to give 0.785 g (67%) of the title compound.
Example 266c
6-methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-
-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1359] Example 266b (0.066 g, 0.173 mmol), Example if (0.064 g,
0.15 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.004 g, 4.5
.mu.mol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(0.004 g, 0.015 mmol) and sodium carbonate (0.068 g, 0.645 mmol)
were combined and sparged with nitrogen for 30 minutes. To this
were added nitrogen-sparged 1,4-dioxane (0.8 mL) and water (0.2
mL). The reaction mixture was stirred at 60.degree. C. for 4 hours
and then 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 to 100% ethyl acetate in heptanes) to
provide 0.049 g (54%) of the title compound.
Example 266d
6-methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1360] A mixture of Example 266c (0.047 g, 0.078 mmol) in
1,4-dioxane (0.75 mL) and ethanol (0.25 mL) was treated with sodium
hydroxide solution (4 M aqueous, 0.1 mL, 0.4 mmol) and heated at
60.degree. C. for 30 minutes. 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.
The residue was purified by reverse phase HPLC (C18,
acetonitrile/water (0.1% trifluoroacetic acid), 20-90%) to provide
0.04 g (92%) of the title compound as the trifluoroacetic acid
salt.
Example 266e
10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,-
5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one
[1361] To a 5-mL microwave vial equipped with a magnetic stirbar
were added Example 266d (0.031 g, 0.055 mmol), paraformaldehyde
(0.008 g, 0.275 mmol) and acetic acid (1 mL). The vial was capped
and heated at 70.degree. C. for 45 minutes. Additional
paraformaldehyde (0.008 g, 0.275 mmol) was added and heating was
continued at 80.degree. C. for 90 minutes. Additional
paraformaldehyde (0.016 g, 0.55 mmol) was again added and heating
was continued overnight at 80.degree. C. The reaction mixture was
concentrated and then taken up in acetonitrile (3 mL). Saturated
sodium bicarbonate solution was added to achieve pH=10. Water (0.5
mL) was added to provide a homogeneous solution. The mixture was
heated at 50.degree. C. overnight. The reaction mixture was cooled
to ambient temperature, diluted with water (5 mL) and neutralized
with hydrochloric acid solution (2 M aqueous). The layers were
separated. 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%
trifluoroacetic acid), 15-90%) to provide 0.007 g (21%) of the
title compound as the trifluoroacetic acid salt. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.97 (d, J=1.83 Hz, 1H), 8.75 (d,
J=2.14 Hz, 1H), 8.62 (d, J=2.14 Hz, 1H), 8.09 (dd, J=5.04, 1.07 Hz,
1H), 7.92 (s, 1H), 7.46 (m, 1H), 7.34 (d, J=2.75 Hz, 1H), 6.73 (dd,
J=6.71, 5.49 Hz, 1H), 6.57 (d, J=8.54 Hz, 1H), 5.15 (s, 2H), 3.64
(s, 3H), 3.31 (m, 4H), 1.74 (m, 4H). LCMS m/z 463.21.
Example 267
(S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-tr-
iazadibenzo[cd,f]azulen-11(10H)-one
[1362] Example 267 was prepared according to the procedure used for
the preparation of Example 265, substituting (S)-1-phenylethanamine
for (R)-1-phenylethanamine to provide the title compound. .sup.1H
NMR (400 MHz, 90.degree. C., DMSO-d.sub.6) .delta. 11.52 (s, 1H),
8.09 (d, J=2.2 Hz, 1H), 7.65 (s, 1H), 7.60 (dd, J=8.4, 2.2 Hz, 1H),
7.41 (d, J=8.4 Hz, 1H), 7.29-7.12 (m, 5H), 6.91 (d, J=2.6 Hz, 1H),
4.38 (q, J=6.6 Hz, 1H), 4.22-4.01 (m, 2H), 3.67 (s, 3H), 3.29 (q,
J=7.4 Hz, 2H), 3.19 (s, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.16 (t, J=7.3
Hz, 3H). (ESI+) m/z 448.0 (M+H).sup.+.
Example 268
(R)-methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propa-
noate
[1363] The product from Example 82 was purified by chiral
chromatography on a Chiralpak OJ-H column (21.times.250 mm, 5
micron) eluting with a 7:13 mixture of methanol/carbon dioxide.
Fractions of the first eluted enantiomer were collected and
concentrated. The compound isolated was randomly assigned as the
(R) enantiomer. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.91 (s, 1H),
7.85 (d, J=1.5 Hz, 1H), 7.70 (s, 1H), 7.24 (dd, J=8.2, 1.7 Hz, 1H),
7.13 (s, 1H), 7.11-7.06 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.97-6.85
(m, 2H), 5.04 (t, J=7.6 Hz, 1H), 4.57-4.42 (m, 2H), 3.64 (s, 3H),
3.55 (s, 3H), 2.93 (s, 3H), 2.46-2.36 (m, 2H), 1.96-1.85 (m, 1H),
1.59-1.48 (m, 1H). (ESI+) m/z 542 (M+H).sup.+.
Example 269
(S)-methyl
3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)--
11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propa-
noate
[1364] The product from Example 82 was purified by chiral
chromatography on a Chiralpak OJ-H column (21.times.250 mm, 5
micron) eluting with a 7:13 mixture of methanol/carbon dioxide.
Fractions of the second eluted enantiomer were collected and
concentrated. The compound isolated was randomly assigned as the
(S) enantiomer. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.89
(s, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.24 (dd, J=8.2, 1.7
Hz, 1H), 7.12 (s, 1H), 7.11-7.04 (m, 1H), 6.99 (d, J=8.2 Hz, 1H),
6.96-6.84 (m, 2H), 5.03 (t, J=7.6 Hz, 1H), 4.57-4.40 (m, 2H), 3.64
(s, 3H), 3.55 (s, 3H), 2.93 (s, 3H), 2.46-2.37 (m, 2H), 1.97-1.84
(m, 1H), 1.60-1.47 (m, 1H). (ESI+) m/z 542 (M+H).sup.+.
Example 270
4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsul-
fonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 270a
4-bromo-2-iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[1365] To a solution of n-butyl lithium (2.5 M, 36 mL, 90 mmol in
tetrahydrofuran) in anhydrous tetrahydrofuran (200 mL) was added
diisopropylamine (7.33 g, 72.4 mmol) dropwise at -70.degree. C. and
then the reaction mixture was stirred at -70.degree. C. to
-50.degree. C. for 45 minutes. To the solution of Example 1c (23.0
g, 60.3 mmol) in anhydrous tetrahydrofuran (400 mL) was added the
above lithium diisopropylamide solution dropwise at -70.degree. C.
and then stirred for 1.5 hours. Then the solution of iodine (35.2
g, 139 mmol) in anhydrous tetrahydrofuran (300 mL) was added
dropwise to the above mixture at -70.degree. C. The reaction
mixture was stirred at -70.degree. C. for another 3 hours and
poured into aqueous Na.sub.2S.sub.2O.sub.3 solution. The suspension
was filtered and the filter cake was washed with dichloromethane
and then dried to give the title compound (20 g, 39.4 mmol, 65.4%
yield) as white solid.
Example 270b
4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1366] To the reaction mixture of Example 270a (15 g, 29.6 mmol)
and sodium iodide (7.09 g, 47.3 mmol) in acetonitrile (300 mL) was
added chlorotrimethylsilane (5.88 mL, 46.0 mmol) dropwise at room
temperature. The reaction mixture was stirred at room temperature
for 1 hour. Water (0.266 mL, 14.79 mmol) was added dropwise to the
reaction mixture and the reaction mixture was stirred at 65.degree.
C. for 4 hours. After cooling to room temperature, the reaction
mixture was filtered to give crude product, which was then
re-dissolved in dichloromethane. The solid was filtered off and the
filtrate was concentrated under reduced pressure to give title
compound (11 g, 22.31 mmol, 75% yield) as white solid.
Example 270c
4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1367] To a solution of Example 270b in dimethylformamide (51.7 mL)
was added sodium hydride (0.538 g, 13.45 mmol) in portions at
0.degree. C., and the mixture was stirred for 30 minutes, followed
by the dropwise addition of iodomethane (0.839 mL, 13.45 mmol). The
resulting mixture was stirred at room temperature overnight. The
reaction mixture was quenched with saturated aqueous ammonium
chloride solution. The resulting suspension was filtered and the
filter cake was dissolved in dichloromethane, dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was washed with ethyl acetate and then dried to afford
the title compound (5 g, 9.86 mmol, 95% yield).
Example 270d
4-bromo-6-methyl-2-(1-methyl-H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyri-
din-7(6H)-one
[1368] A mixture of Example 270c (0.431 g, 0.85 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.177 g, 0.850 mmol), tris(dibenzylideneacetone)dipalladium(O)
(0.019 g, 0.021 mmol),
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane
(0.025 g, 0.085 mmol), and sodium carbonate (0.135 g, 1.275 mmol)
in dioxane (5 mL) and water (1.25 mL) was stirred at 50.degree. C.
for 3 hours. The mixture was concentrated to dryness and extracted
with ethyl acetate (20 mL). The filtrate was concentrated and the
residue purified by silica gel flash chromatography (petroleum
ether/ethyl acetate 1:1-0:1) to give the title compound (0.353 g,
0.697 mmol, 82% yield).
Example 270e
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1369] A mixture of Example 270d (0.5 g, 1.084 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.330
g, 1.301 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.079
g, 0.108 mmol), and potassium acetate (0.160 g, 1.626 mmol) in
1,4-dioxane (5 mL) was stirred at 100.degree. C. for 16 hours. The
mixture was filtered and concentrated. The residue was purified by
silica gel flash chromatography (petroleum ether/ethyl acetate
1:1-0:1) to give the title compound (0.3 g, 0.395 mmol, 36.5%
yield).
Example 270f
2-bromo-N-(2,4-difluorophenyl)-4-(methylsulfonyl)aniline
[1370] A mixture of 2-bromo-4-(methylsulfonyl) aniline (0.8 g, 3.20
mmol), 2,4-difluoro-1-iodobenzene (0.768 g, 3.20 mmol),
tris(dibenzylideneacetone)dipalladium(O) (0.146 g, 0.160 mmol),
X-phos (2.78 g, 4.80 mmol), and cesium carbonate (0.104 g, 0.320
mmol) in 1,4-dioxane (10 mL) was stirred at 100.degree. C. for 16
hours. The mixture was filtered and the filtrate was concentrated
to dryness. The residue was washed with petroleum ether/ethyl
acetate 1:1 to the title compound (0.9 g, 2.485 mmol, 78%
yield).
Example 270g
4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-m-
ethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1371] A mixture of Example 270e (150 mg, 0.295 mmol), Example 270f
(107 mg, 0.295 mmol), tris(dibenzylideneacetone)dipalladium(O)
(6.75 mg, 7.38 .mu.mol), potassium phosphate, dibasic (77 mg, 0.443
mmol), and
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62
mg, 0.030 mmol) in 1,4-dioxane (12 mL) and water (3.00 mL) was
stirred at 60.degree. C. for 3 hours. The mixture was concentrated
to dryness and extracted with ethyl acetate (20 mL). The filtrate
was concentrated and the residue was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate 1:1-0:1)
to provide the title compound (150 mg, 0.158 mmol, 53.6%
yield).
Example 270h
4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-m-
ethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1372] To a solution of Example 270g (50 mg, 0.075 mmol) in
1,4-dioxane (10 mL) was added sodium hydroxide (50 mg, 1.250 mmol)
and water (2 mL). The mixture was stirred at 80.degree. C. for 5
hours. The mixture was adjusted to pH 5 by 1N HCl and then
extracted with ethyl acetate. The organic phase was dried over
anhydrous saturated sodium sulfate, filtered, and concentrated to
give the crude product (50 mg, 0.041 mmol, 54.7% yield) as a yellow
solid, which was used in the next step without further
purification.
Example 270i
4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsul-
fonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1373] To a solution of Example 270h (100 mg, 0.196 mmol) in
tetrahydrofuran (5 mL) was added paraformaldehyde (5.89 mg, 0.196
mmol) and TiCl.sub.4 (0.022 mL, 0.196 mmol) at 0.degree. C., and
the mixture was stirred at ambient temperature for 3 hours. The
mixture was diluted with water (10 mL) and ethyl acetate (10 mL).
It was then extracted with ethyl acetate three times. The combined
organic layer was dried over anhydrous sodium sulfate and then
concentrated, and the residue was purified by reverse phase
preparative HPLC (C18, CH.sub.3CN/water (0.1% trifluoroacetic
acid), 0-100% gradient) to afford the title compound (25 mg, 0.047
mmol, 23.94% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.12 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.91 (d, J=14.6 Hz, 2H),
7.70 (d, J=8.4 Hz, 1H), 7.35-6.91 (m, 4H), 4.85 (s, 2H), 3.90 (s,
3H), 3.68 (s, 3H), 3.31 (s, 3H). MS (ESI+) m/z 522.0
[M+H].sup.+.
Example 271
4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfony-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 271a
2-bromo-N-(4-chlorophenyl)-4-(methylsulfonyl)aniline
[1374] A mixture of 2-bromo-4-(methylsulfonyl)aniline (0.8 g, 3.20
mmol), 1-chloro-4-iodobenzene (0.763 g, 3.20 mmol),
tris(dibenzylideneacetone)dipalladium (0.293 g, 0.320 mmol), cesium
carbonate (0.052 g, 0.160 mmol) and Xantphos (2.78 g, 4.80 mmol)
was stirred at 90.degree. C. for 16 hours under nitrogen. The
reaction mixture cooled to ambient temperature and was filtered and
the filtrated was concentrated. The residue was washed with
petroleum ether/ethyl acetate (3:1) to provide the title compound
(0.8 g, 1.996 mmol, 62.4% yield).
Example 271b
4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methy-
l-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1375] A mixture of Example 270e (150 mg, 0.295 mmol), Example 271a
(106 mg, 0.295 mmol), tris(dibenzylideneacetone)dipalladium (6.75
mg, 7.38 .mu.mol), potassium phosphate, dibasic (77 mg, 0.443
mmol), and
1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62
mg, 0.030 mmol) in dioxane (12 mL) and water (3 mL) was stirred at
50.degree. C. for 3 hours. The mixture was concentrated and
extracted with ethyl acetate (20 mL). The filtrate was concentrated
and the solid was washed with petroleum ether/ethyl acete (1:1) to
give the title compound (0.15 g, 0.161 mmol, 54.5% yield).
Example 271c
4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methy-
l-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1376] To a solution of Example 271b (150 mg, 0.227 mmol) in
1,4-dioxane (10 mL) was added sodium hydroxide (80 mg, 2.000 mmol)
and water (2 mL). The reaction mixture was stirred at 60.degree. C.
for 3 hours. The mixture cooled to ambient temperature and the pH
was adjusted to pH=5 by the addition of 1N HCl. The mixture was
then extracted with ethyl acetate, dried over anhydrous sodium
sulfate, filtered, and concentrated to give the title compound (80
mg, 0.079 mmol, 34.8% yield).
Example 271d
4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfony-
l)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1377] To a 5-mL microwave vial equipped with a magnetic stir bar
was added Example 271c (70 mg, 0.134 mmol), paraformaldehyde (12.08
mg, 0.402 mmol), and acetic acid (2 mL). The vial was capped and
heated at 75.degree. C. for 1 hour. The mixture was concentrated in
vacuo. The residue was suspended in methanol (10 mL) and acetic
acid (1 mL) and heated at 85.degree. C. for 20 minutes and then
allowed to cool to ambient temperature. The resulting solid was
collected by filtration and washed with methanol to give the title
compound as an off white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.12 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H),
7.97-7.82 (m, 2H), 7.58 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H),
6.18 (d, J=8.6 Hz, 2H), 5.12 (s, 1H), 4.61 (s, 1H), 3.94 (s, 3H),
3.60 (s, 3H), 3.34-3.09 (m, 3H). MS (ESI+) m/z 518.0
[M+H].sup.+.
Example 272
(R)--N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
Example 272a
4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
Acid
[1378] Example 208e (7.25 g, 24.2 mmol) in tetrahydrofuran/ethanol
(1:2, 210 mL) was heated at 75.degree. C. to dissolve the solid.
The mixture was then cooled to 35.degree. C. To this solution was
added 1M aqueous lithium hydroxide (97 mL). The mixture was heated
at 75.degree. C. for 2 hours and then cooled to ambient
temperature. The reaction mixture was then mixed with 1N HCl (100
mL) and water (300 mL) and allowed to stir at ambient temperature
overnight. The resulting precipitate was collected by filtration,
rinsed with water, and then dried to provide the title compound
(6.41 gm. 98%).
Example 272b
4-bromo-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-car-
boxamide
[1379] A mixture of Example 272a (5.4 g, 19.9 mmol) in dimethyl
sulfoxide (100 mL) was treated with
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (8.33 g, 21.91 mmol) and
N-ethyl-N-isopropylpropan-2-amine (10.5 mL, 60.1 mmol) and stirred
for 5 minutes. Ethylamine solution (2 M in tetrahydrofuran) (11 mL,
22.00 mmol) was added and stirring was continued at ambient
temperature for 7 hours. The reaction mixture was then diluted with
600 mL of water and stirred overnight at ambient temperature. The
resulting solid was collected by filtration and rinsed with 1 L of
water. The solid was dried to provide the title compound (5.54 g,
93%).
Example 272c
N-ethyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-
-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1380] A mixture of Example 272b (5.4 g, 18.11 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (13.80
g, 54.3 mmol), X-Phos (0.363 g, 0.761 mmol),
tris(dibenzylideneacetone)dipalladium (0.166 g, 0.181 mmol), and
oven dried potassium acetate (5.33 g, 54.3 mmol) was degassed with
a stream of nitrogen blowing into the flask and over the solids to
purge the flask for about 1 hour. To this mixture was then added
via cannula degassed, anhydrous dioxane (60 mL) and the mixture was
heated at 75.degree. C. overnight. The reaction mixture was cooled
to ambient temperature and then diluted with water and ethyl
acetate and stirred for 30 minutes. The mixture was diluted further
with ethyl acetate and methanol was added to help the solids
dissolve. The mixture was partitioned. The resulting organic layer
was washed with saturated aqueous sodium chloride, and the combined
aqueous washes were back extracted with 10% methanol/ethyl acetate.
The combined organic extracts were stirred with 10 g.
SiliaMetS.RTM. Thiol palladium scavenger (Silicycle) for one hour.
Anhydrous sodium sulfate was added directly to this mixture and
stirring continued for another 30 minutes. The entire mixture was
then filtered through a Buchner funnel, rinsed with ethyl acetate,
and the resulting filtrate concentrated under reduced pressure. The
resulting residue was mixed with 200 mL of 10% diethyl
ether/heptane and sonicated for 30 minutes. The resulting solid was
collected by vacuum filtration, washed with 100 mL of 10% % diethyl
ether/heptane followed by 200 mL of heptane, and dried to provide
the title compound (5.1 g, 82% yield).
Example 272d
(R)-2-bromo-4-(ethylsulfonyl)-N-(1-phenylpropyl)aniline
[1381] A mixture of Example 2b (522 mg, 1.954 mmol),
(R)-1-phenylpropan-1-amine (801 mg, 5.860 mmol), and
N-ethyl-N-isopropylpropan-2-amine (0.683 mL, 3.910 mmol) in
dimethylsulfoxide (10 mL) was heated at 120.degree. C. for 18
hours. The mixture was cooled to ambient temperature and
partitioned between saturated aqueous ammonium chloride and ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 2% ethanol and 6% ethyl acetate
in heptane) to provide the title compound.
Example 272e
(R)--N-ethyl-4-(5-(ethylsulfonyl)-2-((1-phenylpropyl)amino)phenyl)-6-methy-
l-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1382] A mixture of Example 272d (288 mg, 0.753 mmol), Example 272c
(200 mg, 0.579 mmol), potassium phosphate (369 mg, 1.738 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (20.3
mg, 0.070 mmol) and tris(dibenzylideneacetone)dipalladium(O) (21.2
mg, 0.023 mmol) was sparged with argon for 15 minutes followed by
addition of degassed tetrahydofuran (6 mL) and water (1.5 mL)
mixture. The reaction mixture was heated at 60.degree. C. for 3
hours. The mixture was cooled to ambient temperature and
partitioned between saturated aqueous sodium chloride and ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 8% ethanol and 25% ethyl acetate
in heptane) to provide the title compound.
Example 272f
(R)--N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,-
11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide
[1383] A mixture of Example 272e (100 mg, 0.192 mmol) and
paraformaldehyde (23 mg, 0.768 mmol) in tetrahydrofuran (6 mL) was
stirred at ambient temperature. To resulting suspension was added
1M solution of titanium tetrachloride (0.39 mL). The reaction
mixture was stirred for 1 hour at ambient temperature and then at
60.degree. C. for 2 hours. The mixture was cooled to ambient
temperature and partitioned between saturated aqueous sodium
chloride and ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by recrystallization from methanol to provide
the title compound (87 mg, 85%).sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6) .delta. 11.79 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.94
(t, J=5.4 Hz, 1H), 7.64-7.54 (m, 2H), 7.34 (d, J=8.4 Hz, 1H),
7.27-7.12 (m, 5H), 4.76 (d, J=16.5 Hz, 1H), 4.48 (d, J=16.5 Hz,
1H), 4.27 (t, J=7.1 Hz, 1H), 3.68 (s, 3H), 3.21-3.32 (m, 4H), 1.76
(p, J=7.2 Hz, 2H), 1.15 (dt, J=16.7, 7.3 Hz, 6H), 0.52 (t, J=7.2
Hz, 3H). (ESI+) m/z 532.9 (M+H).sup.+.
Example 273
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyrid-
in-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 273a
N-(2-bromo-4-((methylsulfonyl)methyl)phenyl)pyridin-2-amine
[1384] Example 273a was prepared according to the procedure used
for the preparation of Example 58h, substituting 2-iodopyridine for
1-chloro-4-iodobenzene, to give the title compound.
Example 273b
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyr-
idin-2-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1385] Example 273b was prepared according to the procedure used
for the preparation of Example 270g, substituting Example 273a for
Example 270f, to give the title compound.
Example 273c
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyr-
idin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1386] Example 273c was prepared according to the procedure used
for the preparation of Example 270h, substituting Example 273b for
Example 270g, to give the title compound.
Example 273d
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyrid-
in-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1387] Example 273d was prepared according to the procedure used
for the preparation of Example 270i, substituting Example 273c for
Example 270h, to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.99 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H),
7.92 (m, 2H), 7.63 (s, 1H), 7.46 (dd, J=8.0, 1.6 Hz, 1H), 7.37 (d,
J=8.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.47 (dd, J=6.7, 5.2 Hz, 1H),
6.01 (d, J=8.4 Hz, 1H), 5.94 (d, J=15.6 Hz, 1H), 4.63 (d, J=13.6
Hz, 1H), 4.52 (d, J=13.6 Hz, 1H), 4.33 (d, J=15.7 Hz, 1H), 3.94 (s,
3H), 3.59 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 501.0
[M+H].sup.+.
Example 274
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 274a
2-bromo-4-(methylsulfonyl)-N-phenylaniline
[1388] Example 274a was prepared according to the procedure used
for the preparation of Example 270f, substituting iodobenzene for
2,4-difluoro-1-iodobenzene, to give the title compound.
Example 274b
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino-
)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1389] Example 274b was prepared according to the procedure used
for the preparation of Example 270g, substituting Example 274a for
Example 270f, to give the title compound.
Example 274c
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino-
)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1390] Example 274c was prepared according to the procedure used
for the preparation of Example 270h, substituting Example 274b for
Example 270g, to give the title compound.
Example 274d
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dih-
ydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1391] Example 274d was prepared according to the procedure used
for the preparation of Example 270i, substituting Example 274c for
Example 270h, to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.06 (s, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.31
(s, 1H), 8.06 (s, 1H), 7.92 (dd, J=8.2, 2.2 Hz, 1H), 7.85 (s, 1H),
7.56 (d, J=8.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.51 (s, 1H), 6.23 (d,
J=8.0 Hz, 2H), 3.95 (s, 3H), 3.59 (s, 3H), 3.38 (s, 3H). MS (ESI+)
m/z 486.0 [M+H].sup.+.
Example 275
10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 275a
N-(2-bromo-4-(methylsulfonyl)phenyl)pyridin-2-amine
[1392] Example 274a was prepared according to the procedure used
for the preparation of Example 270f, substituting 2-iodopyridine
for 2,4-difluoro-1-iodobenzene, to give the title compound.
Example 275b
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-y-
lamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1393] Example 275b was prepared according to the procedure used
for the preparation of Example 270g, substituting Example 275a for
Example 270f, to give the title compound.
Example 275c
6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-y-
lamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1394] Example 275c was prepared according to the procedure used
for the preparation of Example 270h, substituting Example 275b for
Example 270g, to give the title compound.
Example 275d
10-methyl-2-(1-methyl-TH-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-
-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1395] Example 275d was prepared according to the procedure used
for the preparation of Example 270i, substituting Example 275c for
Example 270h, to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.06 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.26
(s, 1H), 8.04 (s, 1H), 7.97-7.85 (m, 3H), 7.61 (d, J=8.3 Hz, 1H),
7.35 (s, 1H), 6.56 (d, J=6.1 Hz, 1H), 6.13 (d, J=8.5 Hz, 1H), 5.88
(d, J=16.1 Hz, 1H), 4.37 (s, 1H), 3.95 (s, 3H), 3.61 (s, 3H), 3.37
(s, 3H). MS (ESI+) m/z 487.0 [M+H]+.
Example 276
4-(4-fluorophenyl)-10-methyl-2-(1-methyl-H-pyrazol-4-yl)-7-((methylsulfony-
l)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
Example 276a
2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline
[1396] Example 276a was prepared according to the procedure used
for the preparation of Example 58h, substituting
1-fluoro-4-iodobenzene for 1-chloro-4-iodobenzene, to give the
title compound.
Example 276b
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2--
(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1397] Example 276b was prepared according to the procedure used
for the preparation of Example 270g, substituting Example 276a for
Example 270f, to give the title compound.
Example 276c
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2--
(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1398] Example 276c was prepared according to the procedure used
for the preparation of Example 270h, substituting Example 276b for
Example 270g, to give the title compound.
Example 276d
4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfon-
yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one
[1399] Example 276d was prepared according to the procedure used
for the preparation of Example 270i, substituting Example 276c for
Example 270h, to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.02 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H),
7.90 (s, 1H), 7.60 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.35 (d, J=7.9
Hz, 1H), 6.75 (t, J=8.9 Hz, 2H), 6.13 (dd, J=9.2, 4.4 Hz, 2H), 4.57
(s, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z
518.0 [M+H].sup.+.
Biological Examples
Bromodomain Domain Binding Assay
[1400] 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
[1401] 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 (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]triazolo[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)
[1402]
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)
[1403]
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
[1404] 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
[1405] 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.
[1406] 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.
[1407] 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.
[1408] After a one-hour equilibration at room temperature, TR-FRET
ratios were determined using an Envision multilabel plate reader
(Ex 340, Em 495/520).
[1409] 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.
[1410] MX-1 Cell Line Proliferation Assay
[1411] 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 370 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 or 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003,
0.0001, and 0.00003 .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.
[1412] 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 Binding Ki: Binding Ki:
Cellular TR-FRET BRD4 BRD4 proliferation: Compound assay (BDI_K57-
(BDII_E352- EC.sub.50 of Example # protocol E168) (.mu.M) M457)
(.mu.M) (.mu.M) 1 E 0.0327 0.0105 0.0272 2 E 0.0246 0.00836 0.0192
3 E 0.046 0.00891 0.0487 4 E 2 3.09 ND 5 E 0.765 0.758 ND 6 E
0.00108 0.00171 0.00201 7 B 0.0511 0.0267 0.0145 8 E 0.000646
0.00377 0.00568 9 G 0.000453 0.00111 0.000721 10 E 0.00694 0.00599
0.0608 11 G 0.00161 0.00257 0.00164 12 G 0.00134 0.000472 0.0040 13
G 0.00484 0.00768 0.00726 14 E 0.0069 0.000882 0.0146 15 E 0.00522
0.000631 0.00875 16 E 0.0926 0.0189 0.337 17 E 0.165 0.0539 ND 18 E
0.145 0.0241 0.343 19 E 0.246 0.0438 0.37 20 E 0.158 0.0245 0.544
21 G 0.00443 0.003 0.00105 22 G 0.000875 0.00095 0.00171 23 E
0.0017 0.000783 0.0070 24 E 0.000963 0.000801 0.00107 25 E 0.00174
0.000847 0.0087 26 G 0.000701 0.000719 0.00103 27 E 0.00119 0.00101
0.00127 28 E 0.0011 0.00117 0.0137 29 E 0.00695 0.00274 0.00103 30
E 0.00498 0.00136 0.00139 31 G 0.00167 0.00118 0.000752 32 G
0.00101 0.00114 0.00138 33 G 0.0383 0.0228 0.495 34 G 0.00245
0.00389 0.0147 35 G 0.0355 0.0951 0.331 36 G 0.00505 0.00625 >1
37 G 0.00336 0.0024 >1 38 G >0.238 >0.408 ND 39 G
>0.238 >0.408 ND 40 G 0.0294 0.136 0.398 41 G 0.0495 0.0578
>1 42 G 0.00156 0.00203 0.00544 43 G 0.00729 0.0247 ND 44 G
0.00261 0.00247 0.0487 45 G 0.00392 0.00375 0.141 46 G 0.0137
0.00748 0.152 47 G 0.00137 0.00127 0.00833 48 G 0.00112 0.000855
0.00441 49 G 0.00199 0.00221 0.00863 50 G 0.00344 0.00551 0.0422 51
G 0.00443 0.0132 0.174 52 G 0.0174 0.00499 0.247 53 G 0.00478
0.0219 ND 54 G 0.00585 0.00145 ND 55 G 0.00896 0.0159 0.146 56 G
0.0144 0.0353 0.197 57 G 0.0647 0.0906 ND 58 G 0.00202 0.000617
0.00538 59 G 0.0031 0.000972 0.0038 60 G 0.00255 0.0331 0.115 61 G
0.0211 0.00374 >1 62 G 0.00723 0.00473 0.91 63 G 0.0822 0.0736
ND 64 G 0.00269 0.00285 0.0846 65 G >0.238 0.238 ND 66 G
>0.238 >0.408 ND 67 G >0.238 >0.408 ND 68 G 0.0127
0.00422 0.0401 69 G 0.00325 0.00324 0.0431 70 G 0.00741 0.00188
0.131 71 G 0.0304 0.0267 ND 72 G 0.0262 0.037 ND 73 G 0.0165 0.0194
ND 74 G >0.238 0.369 ND 75 G >0.238 >0.408 ND 76 G
>0.238 >0.408 ND 77 G >0.238 0.275 ND 78 G 0.216 0.126 ND
79 G >0.238 >0.408 ND 80 G >0.238 >0.408 ND 81 G 0.0517
0.0323 ND 82 G 0.0133 0.00112 0.979 83 G >0.238 >0.408 ND 84
G 0.00224 0.00386 0.0177 85 G 0.0108 0.0111 0.0489 86 G 0.0103
0.0139 ND 87 G 0.00254 0.0021 0.00469 88 G 0.00346 0.00176 ND 89 G
0.00577 0.00453 ND 90 G 0.00132 0.00201 0.0306 91 G 0.00327 0.00115
0.00181 92 G 0.00374 0.00558 ND 93 G 0.00284 0.00163 0.00259 94 G
0.00603 0.00349 0.00602 95 G 0.00218 0.00253 0.0141 96 G 0.00346
0.00161 ND 97 G 0.00321 0.00135 ND 98 G 0.00234 0.00315 0.00441 99
G 0.0155 0.00166 0.165 100 G 0.0298 0.00741 ND 101 G 0.00483
0.00277 ND 102 G 0.00941 0.0269 0.151 103 G 0.00812 0.00471 ND 104
G 0.0347 0.0262 ND 105 G 0.00549 0.00268 0.0162 106 G 0.00589
0.00191 0.0192 107 G 0.00642 0.00379 0.00704 108 G 0.0139 0.00211
0.165 109 G 0.0641 0.0156 ND 110 G 0.0417 0.0199 ND 111 G 0.0077
0.00331 0.084 112 G 0.0532 0.0152 ND 113 G 0.0856 0.0109 ND 114 G
0.112 0.0255 ND 115 G 0.0087 0.00271 0.00783 116 G 0.016 0.0112 ND
117 G 0.0723 0.00127 >1 118 G 0.0126 0.00138 0.174 119 G 0.0119
0.000602 0.134 120 G 0.00928 0.00159 >1 121 G 0.00665 0.000799
>1 122 G 0.0108 0.000922 >1 123 G 0.00995 0.000983 >1 124
G 0.00884 0.00278 0.944 125 G 0.00926 0.00236 0.342 126 G 0.0536
0.08 ND 127 G 0.00268 0.00135 0.0417 128 G 0.0291 0.002 0.0729 129
G 0.0162 0.0025 0.25 130 G 0.215 0.0146 ND 131 G 0.0107 0.00235
>1 132 G 0.0113 0.00314 >1 133 G 0.00929 0.0014 0.204 134 G
0.0144 0.00111 0.182 135 G 0.0114 0.00214 0.51 136 G 0.0132 0.00133
0.0492 137 G 0.0517 0.00387 0.24 138 G 0.0225 0.00194 0.256 139 G
0.0175 0.00233 0.627 140 G 0.00999 0.00224 0.936 141 G 0.0208
0.0109 0.319 142 G 0.00861 0.00060 0.0518 143 G 0.0549 0.00306
0.175 144 G >0.238 0.0188 0.318 145 G 0.0551 0.00138 0.0806 146
G 0.00142 0.017 0.124 147 G 0.00702 0.00097 0.0203 148 G 0.00677
0.00054 0.0319 149 G 0.00178 0.00082 0.00193 150 G 0.00405 0.0108
ND 151 G 0.00114 0.0023 0.00426 152 G 0.00718 0.011 ND 153 G
0.00372 0.00918 ND 154 G 0.0507 0.0531 ND 155 G 0.0427 0.0478 0.349
156 G 0.0468 0.0421 0.214 157 G 0.0396 0.0239 0.0774 158 G 0.0603
0.0773 ND 159 G 0.0386 0.0198 0.0578 160 G 0.125 0.118 ND 161 G
0.0321 0.0214 0.0416 162 G 0.0471 0.0604 ND 163 G 0.0574 0.0454 ND
164 G 0.0417 0.030 0.0725 165 G 0.0814 0.0796 ND 166 G 0.060 0.0733
ND 167 G 0.0692 0.0763 ND 168 G 0.0932 0.124 ND 169 G 0.0124
0.00467 0.0699 170 G 0.00707 0.0252 0.0576 171 G 0.0164 0.0292 ND
172 G 0.0578 0.0128 0.551 173 G 0.00672 0.00314 0.0199 174 G 0.0126
0.00153 0.239 175 G 0.015 0.0019 0.0999 176 G 0.00101 0.00355
0.0142 177 G 0.00202 0.00127 0.00372 178 G 0.00436 0.00438 0.123
179 G 0.0201 0.0807 ND 180 G 0.00151 0.0027 ND 181 G 0.00333 0.0171
ND 182 G 0.00131 0.0020 0.00108 183 G 0.00384 0.0155 ND 184 G
0.00434 0.00682 ND 185 G 0.00419 0.0102 0.0283 186 G 0.00421 0.0092
ND 187 G 0.00574 0.050 ND 188 G 0.00364 0.00462 ND 189 G 0.00582
0.0223 ND 190 G 0.0267 0.0309 ND 191 G 0.00100 0.00338 0.0107 192 G
0.00165 0.00108 0.00125 193 G 0.00185 0.0124 0.0317 194 G 0.00133
0.00038 0.00147 195 G 0.00266 0.00062 0.00377 196 G 0.00114 0.00172
0.00382 197 G 0.00152 0.00265 0.00266 198 G 0.00159 0.00063 0.00069
199 G 0.00081 0.00121 0.0108 200 G 0.00818 0.00205 0.0342 201 G
0.00085 0.0032 0.0278 202 G 0.00079 0.00035 0.0043 203 G 0.00099
0.00071 0.00543 204 G 0.0461 0.00122 >1 205 G 0.20 0.0291 >1
206 G 0.00096 0.00051 0.00141 207 G 0.00092 0.00209 0.00133 208 G
0.00341 0.00115 0.0107 209 G 0.0012 0.00086 0.00654 210 G 0.00172
0.00080 0.0133 211 G 0.00567 0.00747 0.118 212 G 0.00239 0.0050
0.155 213 G 0.00065 0.00042 0.0014 214 G 0.0408 0.00325 0.431 215 G
0.0657 0.00587 0.454 216 G 0.0573 0.0658 0.603 217 G 0.193 0.0426
>1 218 G 0.00064 0.00064 0.00136 219 G 0.0399 0.00476 0.301 220
G 0.0516 0.00261 0.285 221 G 0.0316 0.0123 0.033 222 G 0.17 0.0294
0.16 223 G >0.238 >0.408 ND 224 G 0.00164 0.0014 0.00584 225
G 0.00325 0.00239 0.0122 226 G 0.00384 0.00186 0.00782 227 G
0.00794 0.00118 0.134 228 G 0.0245 0.00222 0.0849 229 G 0.00411
0.00196 0.0412 230 G >0.238 0.0581 0.528 231 G 0.039 0.00542
0.149 232 G 0.108 0.00848 0.363 233 G 0.00615 0.00377 ND 234 G
0.0103 0.0094 >1 235 G 0.0161 0.00651 0.162 236 G 0.0859 0.030
>1 237 G 0.0218 0.0121 0.313 238 G 0.0621 0.0046 0.275 239 G
0.0319 0.00212 0.294 240 G 0.00314 0.00193 0.0859 241 G 0.00307
0.00176 0.0515
242 G 0.0126 0.00378 >1 243 G 0.00185 0.00347 0.153 244 G
0.00043 0.00102 0.00213 245 G 0.00054 0.00094 0.00109 246 G 0.00432
0.0036 0.0117 247 G 0.00222 0.00242 0.00494 248 G 0.00339 0.00329
0.0256 249 G 0.0061 0.0191 0.0177 250 G 0.0088 0.0225 0.845 251 G
>0.238 0.142 ND 252 G 0.0161 0.00224 0.108 253 G 0.00070 0.00118
0.0013 254 G 0.00112 0.00071 0.0039 255 G 0.00453 0.00733 0.0343
256 G 0.00059 0.00054 0.00035 257 G 0.00234 0.00919 0.0211 258 G
0.00092 0.00239 0.00443 259 G 0.0034 0.00305 0.019 260 G 0.00726
0.0034 0.219 261 G 0.00932 0.00778 >1.0 262 G 0.00937 0.0132 ND
263 G 0.00704 0.00807 >1.0 264 G 0.00697 0.00153 0.899 265 G
0.0256 0.00421 0.17 266 G 0.0178 0.00815 0.0427 267 G 0.0727 0.0947
ND 268 G 0.0828 0.0164 ND 269 G 0.00569 0.00092 ND 270 G 0.011
0.00335 0.0807 271 G 0.00391 0.00164 0.0852 272 G 0.0589 0.00635 ND
273 G 0.00112 0.00088 ND 274 G 0.00283 0.00156 ND 275 G 0.00209
0.00085 ND 276 G 0.00119 0.00118 ND ND = not determined.
LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay
[1413] 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 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 Example # % inhibition Mouse strain 6 64 SCID 7 53 SCID
8 53 SCID 9 79 SCID 12 90 SCID 15 68 SCID 23 54 SCID 24 78 SCID 26
88 SCID 27 79 SCID 29 76 SCID 30 81 SCID 31 83 SCID 42 86 CD1 58 39
CD1 59 68 CD1 60 44 CD1 149 86 CD1 151 57 CD1 173 87 CD1 182 77 CD1
191 60 CD1 192 73 CD1 194 53 CD1 195 85 CD1 196 79 CD1 198 86 CD1
199 90 CD1 202 47 CD1 206 76 CD1 207 65 CD1
Xenograft Tumor Growth Inhibition Assay
[1414] 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 (8-10/group) occurred
when the mean tumor volume reached approximately 250 mm.sup.3.
Compounds were formulated in 2.5% DMSO, 10% ethanol, 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-(100.times.(mean tumor volume of treatment group/mean
tumor volume of control group))
[1415] Results are shown in Table 3.
TABLE-US-00003 TABLE 3 OPM-2 human multiple myeloma cancer
xenograft model Compound of Dose route, % removed Example # mg/kg
regimen % TGI.sup.a from study.sup.b 9 1.85 PO, QD x21 87*** 56 9
3.75 PO, QD x21 nd.sup.c 100 12 1.5 IP, QD x21 82** 11 12 1.5 IP,
QD x21 91*** 22 12 3 IP, QD x21 89** 11 12 3 IP, QD x21 nd.sup.c
100 12 3 PO, 3 on 4 81*** 0 off x3 weeks 12 3 PO, QD x11 72*** 0 12
1.5 PO, QD x21 87*** 22 12 3 PO, QD x21 94*** 56 173 1.25 PO, QD
x21 49** 0 173 2.5 PO, QD x21 nd.sup.c 67 196 2.5 PO, QD x21 84***
0 196 5 PO, QD x21 92*** 44 199 1.25 PO, QD x21 91*** 38 199 2.5
PO, QD x21 nd.sup.c 50 199 5 PO, QD x21 nd.sup.c 50 207 0.25 PO, QD
x21 60*** 0 207 0.5 PO, QD x21 93*** 11 207 0.5 PO, QD x21 94*** 13
207 1.0 PO, QD x21 97*** 44 213 0.5 PO, QD x21 82*** 13 213 1 PO,
QD x21 96*** 25 213 1 PO, QD x21 95*** 13 213 2 PO, QD x21 nd.sup.c
63 .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, **p < 0.01, * p < 0.05. .sup.bPercentage of
treatment group that were removed from study due to morbidity or
weight loss in excess of 20%. .sup.cNot determined.
[1416] 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.
* * * * *